Identification of candidate biomarkers and signaling pathways associated with Alzheimer’s disease using bioinformatics analysis of next generation sequencing data

Alzheimer's disease (AD) is the most co mmon cause of dementia, and one of the most common health problems all over the world. However, the specific molecular mechanisms of AD have not been fully investigated. The current investigation aimed to elucidate potential key candida te genes and signaling pathways in AD. Next generation sequencing (NGS) dataset GSE203206 was downloaded from the Gene Expression Omnibus (GEO) database, which included data from 39 AD samples and 8 normal control samples. Differentially expr essed genes (DEGs) were identified using t-tests in the li mma R bioconductor package. These DEGs were subsequently investig ated by Gene ontology (GO) and pathway enrichment analysis, and a protein-protein intera ction (PPI) network and modules were constructed and analyzed. The miRNA-hub gene regulatory network and TF-hub gene regulatory network analysis were performed to identify key miRNAs and TFs. The receiver operating characteristic (ROC) curve analysis was performed to estimate the clinical diag nostic value of the hub genes. A total of 958 DEGs, including 479 up regulated genes and 479 down regulated genes, were screened between AD and normal cont rol samples. GO and pathway enrichment analysis

revealed that the up regulated genes were mainly enriched in response to stimulus, cytoplasm, small molecule bi nding and signal transduction, whereas down regulated genes were mainly enriched in multicellular organism development, cell junction, ion binding and cardiac conduction. The PPI network contained 4886 nodes and 10342 edges. HSP90AA1, FN1, KIT, YAP1, LSM2, SKP1, EIF5A2, TAF9, DDX39B and CDK7 were identified as the top hub genes. The regulatory network analysis rev ealed that microRNA (miRNA) hsa-mir-545- 3p and hsa-miR-548f-5p, and transcriptio n factor (TF) PLAG1 and MEF2A might be involved in the development of AD. Th ese findings provide new insights into the pathogenesis of AD. The hub genes, miRN As and TFs have the potential to be used as diagnostic and therapeutic markers.

Alzheimer's disease; GEO; bioinformatics; biomarker; protein-protein interaction (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint

Alzheimer's disease (AD) is a severe neurodegenerative disorder characterized by extracellular senile plaques composed of amyloid β (A β ) [ 1], intracellular tau aggregates [2], and neuronal loss and neurofibrillary degeneration [ 3]. The clinical incidence of AD is high, and its main features include slowly destroys memory and thinking skills [4]. AD occurring worldwide with an incidence of about 24 million persons, presenting at before the age of 60, and leading to both physical and psychological substantial burden for individuals and society [ 5]. At present, it is generally believed that the onset of AD might be caused by various risk factors such as age [ 6], genetic factors [ 7], head injuries [ 8], vascular diseases [ 9], infections [ 10], inflammation [ 11], environmental factors [ 12], diabetes mellitus [13], obesity [ 14], hypertension [ 15] and cardiovascular diseases [ 16]. The other neurological complications of AD include multiple sclerosis [ 17], Huntington's disease [ 18], schizophrenia [ 19], autism spectrum disorder [ 20], amyotrophic lateral sclerosis [ 21], stroke [ 22], epilepsy [ 23], dementia [24], Parkinson's diseases [ 25], bipolar disorder [ 26] and depression [ 27]. However, the specific regulatory mechanism of AD is still unclear, and further exploration is needed. Debate on the leading strategy for AD management continues despite great progress in treating AD in current decade s. Extensive investigation have shown recent therapeutic approaches in AD included cholinesterase inhibitors [28] and N- methyl-D-aspartate receptor noncompetitive antagonist [ 29] targeting several crucial signaling pathways. However, AD might also can be caused by many unknown causes, which cannot be well solved by current drug treatment and AD is still a complicated incurable neurodegenerative disease [ 30]. Thus, it is necessary for us to utilize bioinformatics and next generation sequencing (NGS) technology to explore the molecular pathogenesis or potential treatments of AD. Bioinformatics methods a nd NGS technology are widely used to find molecular changes in the occurrence and development of diseases and are effective ways to explore the pathogenesis of diseases [31-32]. The biomarkers and signaling pathways that are being used for the etiological diagnosis of AD are genetic markers. The genetic markers include APOE3 [ 33], OPRM1 and OPRL1 [ 34], NRF2 [ 35], INPP5D [ 36] and PICALM [37 ]. The signaling pathways include insulin signaling pathway [ 38], TREM2 signaling pathway [ 39], PI3K/Akt (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint signaling pathway [ 40], Notch signaling pathway [ 41] and CREB signaling pathway [ 42]. However, there are few reports on the use of bioinformatics and NGS data analysis to explore the molecular mechanisms of AD. Bioinformatics and NGS data analysis can be used to screen and identify genes related to diseases. The purpose of th is investigation is to identify molecular biomarkers in AD using bioinformatics and NGS methods, in order to provide potential targets. NGS dataset (GSE203206) [ 43] downloaded from the gene expression omnibus (GEO) (https://www.ncbi.nlm.nih.gov/geo ) [44] were used to identify Differential expressed genes (DEGs), gene ontology (GO) and REACTOME pathway enrichment analyses were performed, and a protein-protein interaction (PPI) network was constr ucted using the STRING database and Cytoscape software, and also modules were isolated and analyzed form PPI network. A miRNA-hub gene regulatory network and TF-hub gene regulatory network were also constructed to pred ict potential target miRNAs and TFs. The predictive capability of the hub genes anal yzed by receiver operating characteristic (ROC) curve and logistic regression analyses. The final results will help us obtain novel treatment targets for AD.

Next generation sequencing (NGS) data source The GEO database is a public function al genomics database, from which the (GSE203206) [ 43] NGS dataset (GPL20301, Illumina HiSeq 4000 (Homo sapiens)) was downloaded. GSE203206 contai ned 47 samples, of which we chose 39 AD samples and 8 normal co ntrol samples. Based on these data, the next step was carried out. Identification of DEGs The limma package [ 45] of the R bioconductor is used to screen DEGs. We adjusted p-value to correct the false discovery rate caused by the multiple tests and determined it by the Benjamini & Hochberg method [ 46]. DEGs were selected with threshold of log2FC > 0.7764 or log2FC < -0.664 and adj.P.Val 0.7764 were considered as up- regulated genes, and log2FC < -0.664 as down-regulated genes. And the volcano (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint plot and Heatmap of DEGs were drawn by “ggplot2” and “gplot” R bioconductor package. GO and pathway enrichment analyses of DEGs One online tool, g:Profiler ( http://biit.cs.ut.ee/gprofiler/) [ 47], was applied to carried out the functional annotation for DEGs. GO (http://www.geneontology.org) [48] generally perform enrichment analysis of genomes. And there are mainly biological processes (BP), cellular comp onents (CC) and molecular functions (MF) in the GO enrichment analysis. REACTOME pathway (https://reactome.org/) [49] is a comprehensive database of genom ic, chemical, and systemic functional information. Therefore, g:Profiler was us ed to make enrichment analysis of GO and REACTOME pathway. P-value <0.05 were considered to be significantly enriched. Construction of the PPI network and module analysis Protein-protein interaction (PPI) refers to the dynamic and complex molecular network of interactions that arise between different proteins. The String Database (http://string-db.org) [ 50] is a database for PPI analysis, providing experimental and predictive interaction information, and subject to visualization using Cytoscape (version 3.10.2) ( http://www.cytoscape.org/) [ 51] software. The Network Analyzer plugin of Cytoscape was used to score each node gene by 4 selected algorithms, including node degree [ 52], betweenness [53], stress [54] and closeness [55]. The results obtained by PPI network analysis were further module analyzed using Cytoscape Software. During the analysis, PEWCC algorithm [ 56] was used to identify the most significant module of the PPI network. Construction of the miRNA-hub gene regulatory network Bioinformatics techniques were used to co nstruct an interaction network between hub genes and miRNAs using the miRNet ( https://www.mirnet.ca/) [ 57] online tool. A miRNA- hub gene interaction network was drawn to facilitate the screening of target miRNAs. Based on the analysis of hub genes, target miRNAs associated with hub genes were selected, providing strong support for further investigation of the interactions between hub genes and miRNAs. The miRNA- hub gene interaction network was visualized using Cytoscape software [51]. (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Construction of the TF-hub gene regulatory network Bioinformatics techniques were used to co nstruct an interaction network between hub genes and TFs using the NetworkAnalyst ( https://www.networkanalyst.ca/) [58] online tool. A TF - hub gene interaction network was drawn to facilitate the screening of target TFs. Based on the anal ysis of hub genes, target TFs associated with hub genes were selected, providing strong support for further investigation of the interactions between hub genes and TFs. The TF- hub gene interaction network was visualized using Cytoscape software [51]. Receiver operating characteristic curve (ROC) analysis The ROC curve was subsequently established to evaluate the diagnostic accuracy of hub genes. ROC curves we re constructed using the "pROC" package in R bioconductor [59] and the area under the curve (AUC) was calculated to evaluate the diagnostic effectiveness of these hub genes in the verification datasets. AUC > 0.8 was considered the ideal diagnostic value.

Identification of DEGs The limma package of the R bioconductor tool that is specialized in analyzing DEGs in the AD group in relative to the normal control group. Besides, the two groups were compared using limma in the GEO NGS data set GSE203206 and the

were downloaded for further analysis. Up regulated genes of |log FC| > 0.7764, down regulated genes of |log FC| < -0.664 and adj.P.Val < 0.05 were identified as DEGs. Totally 958 DEGs, containing 479 up regulated genes and 479 down regulated genes were detected (Table 1). A volcano plot was drawn to validate the results (Fig. 1). A heatmap of the 958 DEGs is presented in Fig. 2. GO and pathway enrichment analyses of DEGs | With the purpose of investigating the biol ogical activities and pathways associated with DEGs among the AD cases, GO and REACTOME pathway enrichment analyses were performed on the 958 DEGs. Besides, the significantly enriched GO terms were cellular response to response to stimulus, biological regulation, multicellular organism development, developmental process (BP); cytoplasm, (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint membrane, cell junction, plasma membrane (CC); small molecule binding, identical protein binding, ion binding, anion binding (MF) (Table 2). As revealed by the REACTOME enrichment analysis, the 958 DEGs were mostly associated with signal transduction, muscle contraction, cardiac conduction and neuronal system (Table 3). Construction of the PPI network and module analysis To analyze the PPI network of the 958 DEGs, the database STRING was applied. Cytoscape network visualization was obtained on the basis of the STRING database (Fig. 3). Analysis of PPI networks of AD DEGs revealed 4886 nodes and 10342 edges, respectively. Using the node degree, betweenness, stress and closeness algorithms, 10 hub ge nes were obtained through the Network Analyzer plugin of the software Cytoscape. Subsequently, according to the rank score, seven first-level hub genes, including HSP90AA1, FN1, KIT, YAP1, LSM2, SKP1, EIF5A2, TAF9, DDX39B and CDK7 were identified (Table 4). The PEWCC in the database was used for further module analysis. Two significant modules were obtained according to the degree of interconnection among hub genes. A total of 37 nodes and 179 edges were included in Module 1 (Fig. 4A), and a total of 37 nodes and 179 edges were included in Module 2 (Fig. 4B). Module 1 was mainly enriched in signal transduction, response to stimulus, biological regulation, cytoplasm and small molecule binding . Module 2 was mainly enriched in cell junction, plasma membrane, neuronal syst em, infectious disease, multicellular organism development and transmission across chemical synapses. Construction of the miRNA-hub gene regulatory network MiRNA-hub gene regulatory network was generated using the miRNet web tool. The network contained 4666 (miRNA: 4344; Hub Gene: 322 ) nodes and 47545 edges (Fig. 5). HSP90AA1 was regulated by 538 miRNAs (ex; hsa-mir-545-3p); FN1 was regulated by 439 mi RNAs (ex; hsa-mir-296-3p); YAP1 was regulated by 412 miRNAs (ex; hsa-mir-183-5p); STIP1 was regulated by 309 miRNAs (ex; hsa- miR-23a-5p); TTN was regulated by 297 miRNAs (ex; hsa-miR-3909); DDX39B was regulated by 370 miRNAs (ex; hsa-miR-548f-5p); TCERG1 was regulated by 334 miRNAs (ex; hsa-miR-429); EIF5A2 was regulated by 273 miRNAs (ex; hsa- (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint mir-4521); SKP1 was regulated by 234 miRNAs (ex; hsa-miR-4735-5p); PLRG1 was regulated by 216 miRNAs (ex; hsa-miR-489-3p) (Table 5). Construction of the TF-hub gene regulatory network TF-hub gene regulatory network was generated using the NetworkAnalyst web tool. The network contained 411 (TF:96; Hub Gene: 315) nodes and 2812 edges (Fig.6). LSM2 was regulated by 57 TFs (e x; PLAG1); SMAD7 was regulated by 14 TFs (ex; NFIC); FN1 was regulated by 14 TFs (ex; CREB1); ZAP70 was regulated by 14 TFs (ex; USF2); HSP90AA1 was re gulated by 13 TFs (ex; SREBF1); DDX39B was regulated by 56 TFs (ex; MEF2A); EIF5A2 was regulated by 10 TFs (ex; MAX); CDK7 was regulated by 9 TFs (ex; CEBPB); GTF2H4 was regulated by 9 TFs (ex; POU2F2); SUV 39H1 was regulated by 9 TFs (ex; NFYA) (Table 5). Receiver operating characteristic curve (ROC) analysis Furthermore, we assessed the diagnostic effica cy of individual hub genes. In the AD, HSP90AA1 (AUC = 0.909), FN1 (AUC = 0.926), KIT (AUC = 0.922), YAP1 (AUC = 0.906), LSM2 (AUC = 0.912), SKP1 (AUC = 0.920), EIF5A2 (AUC = 0.923), TAF9 (AUC = 0.914), DDX39B (AUC =0.902) and CDK7 (AUC = 0.918) demonstrated favorable diagnostic efficiency for differentiating patients with AD from normal controls (Fig.7).

AD is a major cause of central nervous system dysfunction in the elderly population and leads to a great public health burden [ 60]. Thus, outstanding screening NGS techniques and accurate diagnosis remains the great test for lowering the incidence of AD. In th e current investigation, integrated bioinformatics and NGS data analysis was used to identify the potential key genes related to AD. By performing DEGs analysis, 479 up regulated and 479 down regulated genes were succe ssfully identified (|log FC| > 0.7764, |log FC| < -0.664 and adjust P-value /i2 </i2 .05), respectively. Research has shown that HSPA1A [ 61], GSTM1 [ 62], HLA-DRB1 [ 63] and MPO (myeloperoxidase) [ 64] plays an important role in the pathogenesis of AD. Altering expressing level of HSPA1A [65], GSTM1 [ 66], HLA-DRB1 [ 67] and MPO (myeloperoxidase) [ 68] can (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint facilitate vascular diseases. A studies have indicated that its altered expression of HSPA1A [ 69], TGFB2-OT1 [ 70], GSTM1 [ 71], G0S2 [ 72], HCG18 [ 73], HLA- DRB1 [74], TRIM26 [75] and MPO (myeloperoxidase) [76] are closely associated with the onset and progression of inflammation . HSPA1A [ 77], GSTM1 [ 78], G0S2 [79], HCG18 [ 80], HLA-DRB1 [ 81] and MPO (myeloperoxidase) [ 82] are significantly related to the diabetes mellitus. HSPA1A [ 83], GSTM1 [78], SOX7 [84], G0S2 [85], HCG18 [86], HLA-DRB1 [87] and MPO (myeloperoxidase) [88] might serve as molecular markers for cardiovascular diseases. HSPA1A [ 89], GSTM1 [90] and MPO (myeloperoxidase) [91] might take part in the occurrence of obesity. HSPA1A [ 92], GSTM1 [ 93] and HLA-DRB1 [ 94] might be involved in the occurrence and development of schizophrenia. HSPA1A [ 95], GSTM1 [ 96], HLA-DRB1 [63] and MPO (myeloperoxidase) [97] might play an important role in the pathophysiology of Parkinson's diseases. KCNA6 [ 98], GSTM1 [ 99], SOX7 [100], HLA-DRB1 [101] and MPO (myeloperoxidase) [102] can participate in the occurrence and development of epilepsy. GSTM1 [103], SOX7 [104], HLA-DRB1 [105] and MPO (myeloperoxidase) [ 76] might mediate the process of brain injury. Previous studies have shown that GSTM1 [ 106], HCG18 [ 107], HLA-DRB1 [108], TRIM26 [75] and MPO (myeloperoxidase) [109] might promote infections. GSTM1 [110], HLA-DRB1 [ 111] and MPO (myeloperoxidase) [ 112] expression is altered in the patients with hypertension. GSTM1 [ 113], HLA-DRB1 [114] and MPO (myelope roxidase) [ 115] have been proposed as novel biomarkers for multiple sclerosis progression. Regulation of GSTM1 [116], HLA-DRB1 [117] and MPO (myeloperoxidase) [ 118] levels might be a novel treatment option against autism spectrum disorder. GSTM1 [ 119], HLA-DRB1 [ 120] and MPO (myeloperoxidase) [121] participates in the occurrence and development of stroke. Excessive activation of GSTM1 [ 122], HLA-DRB1 [ 123] and MPO (myeloperoxidase) [124] promotes the development of bipolar disorder. Research has reported that altere d MPO (myeloperoxidase) [ 125] expression in the amyotrophic lateral sclerosis. Studies have shown that MP O (myeloperoxidase) [126] plays a certain role in depression. This analysis led to the identification of DEGs as key biomarkers that could be of mechanistic relevance for AD pathogenesis and progression. In this investigation, the GO and REACTOME pathway enrichment analyses of the key DEGs in AD were analyzed by using g:Profiler online tool. These (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint analyses could help to find some key factors involved in the regulation of AD. For example, signal transduction [127], muscle contraction [128], signaling by receptor tyrosine kinases [ 129], hemostasis [ 130], signaling by WNT [ 131], extracellular matrix organization [ 132], cardiac conduction [ 133], neuronal system [ 134], transmission across chemical synapses [ 135], ion channel transport [ 136], nervous system development [ 137] and infectious disease [ 138] are involved in the regulation of the AD and might serve as signaling pathways of AD. The expression of HSP90AA1 [ 139], FN1 [ 140], YAP1 [ 141], PECAM1 [ 142], EPHA2 [143], KLF4 [ 144], HSPA2 [ 145], FLT1 [ 146], ITGA5 [ 147], ANXA2 [ 148], CASP7 [149], CGAS (cyclic GM P-AMP synthase) [ 150], MMP2 [151 ], TGFB2 [ 152], GSTM1 [153], CCL2 [ 154], LTF (lactotransferrin) [ 155], HSD17B1 [ 156], HLA- DQB1 [157], S100A10 [158], EFNB1 [159], ACVRL1 [160], BMP6 [161], MLKL (mixed lineage kinase domain like pseudokinase) [ 162], ADORA2A [ 163], ABCB1 [164], MMP14 [ 165], JMJD6 [ 166], CSF1 [ 167], PGF (placental growth factor) [ 168], PYGM (glycogen phosphorylase, muscle associated) [ 169], SERPINA5 [170], MDGA1 [ 171], FBXL7 [172], VGF (VGF nerve growth factor inducible) [ 173], GAP43 [ 174], THY1 [ 175], STMN2 [ 176], CNTN5 [ 177], NEUROD6 [178], RGS4 [ 179], RXFP1 [ 180], SYT1 [ 181], SNAP25 [ 182], VTN (vitronectin) [ 183], FGF14 [ 184], MEF2C [ 185], NRN1 [ 186], GABRG2 [ 187], HCN1 [188], PCP4 [189], RPH3A [190], AHI1 [191], CCKBR (cholecystokinin B receptor) [192], CNTNAP2 [193], SRI (sorcin) [194], RORB (RAR related orphan receptor B) [ 195], PAK3 [ 196], SEMA3A [197 ], UCHL1 [ 198], ELAVL4 [ 199], EGR1 [200], CHRM1 [ 201], MAP2 [ 202], LRRK2 [ 203], MAP1A [204 ], RYR2 [205], PLK2 [ 206], C9ORF72 [ 207], VAMP1 [ 208], SST (somatostatin) [ 209], PVALB (parvalbumin) [ 210], TAC1 [ 211], SPARCL1 [ 212], DLGAP2 [213], CAP2 [ 214], SV2B [ 215], LAMP5 [ 216], RAB3A [ 217], VSNL1 [ 218], SCG5 [219], DDX39B [ 220], CDK7 [221], HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase) [222], ABCA5 [ 223], TRPC3 [ 224] and FABP3 [225] were altered in the AD. HSP90AA1 [ 226], FN1 [227], YAP1 [ 228], PECAM1 [229], TTN (titin) [230], SMAD7 [ 231], LEF1 [232 ], PGR (progesterone receptor) [ 233], EPHA2 [143], KLF4 [ 144], HSPB1 [ 234], FLT1 [ 235], NFKB2 [ 236], TAB2 [237 ], ITGA5 [238], GNG12 [ 239], FOXO4 [240], GLI2 [ 241], GATA2 [ 242], ANXA2 [243], CYP1A1 [ 244], WWTR1 [ 245], CASP7 [ 246], CGAS (cyclic GMP-AMP synthase) [ 247], MMP2 [ 248], EPAS1 [ 249], SMAD6 [ 250], TGFB2 [ 251], LATS2 [252], GSTM1 [ 253], VANGL2 [ 254], RUNX3 [ 255], CCL2 [ 256], LTF (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint (lactotransferrin) [ 257], HSD17B1 [ 258], HLA-DQB1 [ 259], EFNB1 [ 260], DUSP1 [261], DLL4 [262], BMP6 [ 263], SOX17 [ 264], NFATC1 [ 265]. MLKL (mixed lineage kinase domain like pseudokinase) [ 266], S100A4 [ 267], TP63 [268], MASP2 [ 269], CYP27B1 [ 270], ABCB1 [ 271], MMP14 [ 272], SLC7A5 [273], NAIP (NLR family apoptosis inhibitory protein) [ 274], WNK4 [ 275], JMJD6 [276], FOXJ1 [ 277], FOXC1 [ 278], FOXF1 [ 279], CSF1 [ 280], PTGER4 [281], ENG (endoglin) [ 282], NPR1 [283 ], TIE1 [ 284], EDNRB (endothelin receptor type B) [ 285], ORAI1 [ 286], PPP1R13L [287], FBXL7 [ 288], HSPA12B [289], VGF (VGF nerve growth factor inducible) [ 290], GAP43 [ 291], MAS1 [292], THY1 [293], THY1 [294], NELL1 [295], RGS4 [296], CDKL5 [297], FGF9 [298], SNAP25 [ 299], ATP2B1 [ 300], TAGLN3 [ 301], VTN (vitronectin) [ 302], MEF2C [303], GABRG2 [304], HCN1 [305], PARP2 [306], TRIM45 [307], PAK1 [308], HAPLN1 [ 309], ATAT1 [ 310], CSMD1 [ 311], DCLK1 [ 312], HHIP (hedgehog interacting protein) [313], SLIT2 [314], AGBL4 [315], SEMA3A [316], UCHL1 [317], EGR1 [318], PAX5 [319], CITED2 [320], PTPRO (protein tyrosine phosphatase receptor type O) [321], LRRK2 [322], NRXN1 [323], TRIM67 [324], MYSM1 [325], CLASP2 [326], PLK2 [327], C9ORF72 [328], SST (somatostatin) [329], SPARCL1 [ 330], THEMIS (thymocyte selection associated) [ 331], ATP1A3 [ 332], KCNH1 [ 333], CRHR2 [ 334], TRIM9 [ 335], BTBD8 [ 336], LAMP5 [ 337], NUAK1 [ 338], FLT3 [ 339], SUV39H1 [ 340], PDE10A [ 341], PRMT8 [ 342], NCALD (neurocalcin delta) [ 343], CDK7 [ 344], HMGCR (3- hydroxy-3-methylglutaryl-CoA reductase) [ 345], PDP1 [ 346], NQO2 [ 347], CISD1 [ 348], LANCL2 [ 349], TRPC3 [ 350] and FABP3 [ 351] are found to be associated with inflammation. Genes include HSP90AA1 [352], FN1 [353], YAP1 [354], PECAM1 [ 355], TTN (titin) [ 230], SMAD7 [ 356], LEF1 [357], EPHA2 [358], KLF4 [359], COL1A2 [360], HSPB1 [361], FLT1 [362], TAB2 [363], FLT4 [364], GATA2 [ 365], ANXA2 [ 366], CYP1A1 [ 367], CGAS (cyclic GMP-AMP synthase) [ 368], MMP2 [ 369], EPAS1 [ 370], SMAD6 [ 371], SERPINH1 [ 372], LATS2 [252], GSTM1 [ 373], RUNX3 [ 374], CDKN1C [ 375], CCL2 [376], LTF (lactotransferrin) [ 377], DSP (desmoplakin) [ 378], KCNQ1 [379], HLA-DQB1 [259], DUSP1 [ 261], DLL4 [380 ], BMP6 [ 381], SOX17 [ 382], MLKL (mixed lineage kinase domain like pseudokinase) [ 383], TP63 [ 384], MASP2 [ 385], MSX1 [386]; ADORA2A [ 387], CYP27B1 [388 ], ABCB1 [ 389], MMP14 [ 390], ASPN (asporin) [ 391], JMJD6 [ 392], FLOT1 [ 393], FOXJ1 [ 394], FOXC1 [395], FOXF1 [ 396], CACNA1H [ 397], CSF1 [ 398], ENG (endoglin) [ 399], CELSR1 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint [400], TCAP (titin-cap) [ 401], NPR1 [ 402], TIE1 [ 403], RGL2 [404 ], PGF (placental growth factor) [ 405], EPHX1 [ 406], ORAI1 [ 407], NES (nestin) [ 408], DES (desmin) [ 409], RDH10 [410], PPP1R13L [ 411], HSPA12B [ 412], PCSK1 [413], GAP43 [ 414], MAS1 [415], THY1 [ 416], SCN8A [ 417], RGS4 [418 ], RXFP1 [419], CDKL5 [ 420], SVEP1 [ 421], NAP1L2 [422 ], BEX1 [423 ], FGF9 [424], ATP2B1 [ 425], FLRT3 [ 426], FGF12 [ 427], MEF2C [428 ], PARP2 [ 429], PAK1 [ 430], HAPLN1 [ 431], SCN5A [ 432], DCLK1 [ 433], RBFOX2 [ 434], SLIT2 [ 435], PAK3 [ 436], SEMA3A [ 316], UCHL1 [ 437], ADAM23 [ 438], EGR1 [439], PAX5 [440 ], CITED2 [ 441], MYBPHL (myosin binding protein H like) [ 442], LRRK2 [ 443], PLCB1 [ 444], RYR2 [ 445], PLK2 [ 446], SPARCL1 [447], ATP1A3 [ 448], KCNH1 [ 449], NSF (N-ethylmaleimide sensitive factor, vesicle fusing ATPase) [450], CAP2 [451], HTR2C [452], VDAC3 [453], VARS2 [454], FLT3 [ 455], CARNS1 [456], SUV39H1 [ 457], PDE10A [45 8], PKD2L1 [459], DIRAS3 [ 460], RSAD2 [ 461], ANKK1 [ 462], HMGCR (3-hydroxy-3- methylglutaryl-CoA reductase) [463], CISD1 [348], ABCA5 [464], TRPC3 [465], FABP3 [ 466] and PDE1A [ 467] are associated with the risk of cardiovascular diseases. Studies have shown that HSP90AA1 [468], YAP1 [469], DNAJB1 [470], PGR (progesterone receptor) [ 471], EPHA2 [ 472], KLF4 [473], HSPB1 [ 474], FLT1 [ 475], TAB2 [476 ], GLI2 [477] , GATA2 [ 478], ANXA2 [ 479], CASP7 [480], CGAS (cyclic GMP-AMP synthase) [ 481], MMP2 [ 482], SMAD6 [ 483], FZD2 [ 484], GSTM1 [ 485], CCL2 [ 486], LTF (lactotransferrin) [ 487], DUSP1 [488], BMP6 [ 489], SOX17 [ 490], NFATC1 [ 491], MLKL (mixed lineage kinase domain like pseudokinase) [492], S100A4 [493], MASP2 [494], ADORA2A [495], ABCB1 [496], FOXJ1 [497], FOXC1 [498], CSF1 [499], CELSR1 [500], EDNRB (endothelin receptor type B) [ 501], NES (nestin) [502], MDGA1 [503], HSPA12B [504], VGF (VGF nerve growth factor inducible) [ 290], GAP43 [ 505], THY1 [506], SCG2 [ 507], NEGR1 [ 508], SYT1 [ 509], SNAP25 [ 510], ATP2B1 [511], MEF2C [ 512], PARP2 [ 513], TRIM45 [ 307], PAK1 [ 514], NMNAT2 [ 515], SLIT2 [ 516], SEMA3A [ 517], UCHL1 [ 518], ELAVL4 [ 519], EGR1 [ 520], CHRM1 [ 521], MAP2 [522 ], LRRK2 [ 523], CLSTN3 [ 524], TRIM67 [ 525], C9ORF72 [526], VAMP1 [527], SST (somatostatin) [528], PVALB (parvalbumin) [529], SPARCL1 [ 530], NSF (N-ethylmaleimide sensitive factor, vesicle fusing ATPase) [ 531], SV2B [ 532], HTR2C [ 533], RPH3A [ 534], SUV39H1 [ 535], PDE10A [536], PRMT8 [342], ENO2 [537], GOT1 [538], ANKK1 [539], TRPC3 [540] and FABP3 [ 541] participate in regulating brain injury. HSP90AA1 [ 468], (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint PECAM1 [ 542], TTN (titin) [ 543], STIP1 [ 544], KLF4 [ 545], COL1A2 [ 546], TAB2 [547], GATA2 [548], ANXA2 [549], CYP1A1 [550], CASP7 [551], CGAS (cyclic GMP-AMP synthase) [ 552], MMP2 [ 553], GSTM1 [ 554], CCL2 [ 555], LTF (lactotransferrin) [ 556], KCNQ1 [ 557], HLA-DQB1 [ 558], DUSP1 [ 559], DLL4 [560], ABCB1 [ 561], MMP14 [ 562], FOXJ1 [ 563], ENG (endoglin) [ 564], CELSR1 [565], EDNRB (endothelin receptor type B) [566], EPHX1 [567], ORAI1 [568], NES (nestin) [ 569], HSPA12B [ 570], VGF (VGF nerve growth factor inducible) [ 571], GAP43 [ 572], THY1 [ 573], FGF9 [ 574], SNAP25 [510 ], VTN (vitronectin) [ 575], GABRG2 [ 576], PAK1 [ 577], NMNAT2 [ 578], SEMA3A [579], UCHL1 [ 580], SPAG6 [ 581], EGR1 [520 ], MAP2 [ 582], CITED2 [ 583], LRRK2 [ 584], SNCB (synuclein beta) [ 585], TRIM9 [ 335], GAD2 [ 586], SUV39H1 [587], PDE10A [588] and ENO2 [ 537] expression level is significantly altered in the stroke. HSP90AA1 [ 589], YAP1 [590 ], PECAM1 [591 ], SMAD7 [592], PGR (progesterone receptor) [ 593], EPHA2 [ 594], KLF4 [ 595], COL1A2 [596], FLT1 [597], NFKB2 [598], GATA2 [599], ANXA2 [600], CYP1A1 [601], CGAS (cyclic GMP-AMP synthase) [602], MMP2 [603], EPAS1 [604], VANGL2 [605], CCL2 [ 606], LTF (lactotransferrin) [ 607], KCNQ1 [ 608], HLA-DQB1 [609], SMAD9 [610], EFNB1 [611], DUSP1 [612], ACVRL1 [613], DLL4 [614], SOX17 [ 615], NFATC1 [ 616], S100A4 [ 617], CYP27B1 [388], ABCB1 [ 618], ASPN (asporin) [ 619], WNK4 [ 620], FOXC1 [ 621], FOXF1 [ 622], CACNA1H [623], ENG (endoglin) [ 624], TCAP (titin-cap) [ 625], NPR1 [ 626], SLC12A3 [627], ORAI1 [ 628], NES (nestin) [ 408], PCSK1 [ 629], VGF (VGF nerve growth factor inducible) [ 630], MAS1 [631 ], SNAP25 [ 632], ATP2B1 [ 633], FGF12 [634], MEF2C [ 635], CSMD1 [636], CCKBR (cholecystokinin B receptor) [ 637], GABRB3 [ 638], TTC21B [ 639], SEMA3A [ 640], UCHL1 [ 641], EGR1 [ 642], ALDH1A3 [ 643], CHN1 [ 644], RYR2 [ 645], PHF14 [ 646], SST (somatostatin) [647], SPARCL1 [ 648], NSF (N-ethylmaleimide sensitive factor, vesicle fusing ATPase) [ 649], CRHR2 [650], ATP1B1 [ 651], ATP1A1 [ 652], DLGAP1 [ 653], VARS2 [ 454], PDE10A [ 654] and TRPC3 [ 655] have been revealed to be regulated in hypertension. HSP90AA1 [ 656], YAP1 [657 ], COL1A2 [ 658], GATA2 [659], ANXA2 [ 660], CGAS (cyclic GMP-AMP synthase) [ 661], MMP2 [662], CCL2 [ 663], LTF (lactotransferrin) [ 664], S100A10 [ 665], DUSP1 [ 666], ADORA2A [667], ABCB1 [ 668], FLOT1 [669], CSF1 [670], NES (nestin) [ 671], MDGA1 [ 672], VGF (VGF nerve growth factor inducible) [ 673], GAP43 [ 674], THY1 [ 675], RGS4 [676 ], RXFP1 [ 180], CDKL5 [ 677], NEGR1 [ 678], SYT1 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint [679], SNAP25 [ 680], NRN1 [ 681], HCN1 [682 ], PAK1 [ 683], AHI1 [ 684], CNTNAP2 [ 685], SCN1A [ 686], SLIT2 [ 687], PAK3 [ 688], SEMA3A [ 689], UCHL1 [690], EGR1 [691 ], MAP2 [ 692], HTR5A [ 693], LRRK2 [ 694], NRXN1 [695], TRIM67 [696], MYSM1 [697], C9ORF72 [698], SST (somatostatin) [699], PVALB (parvalbumin) [700], TAC1 [701], SV2C [702], ATP1A3 [703], NSF (N- ethylmaleimide sensitive factor, vesicle fusing ATPase) [ 704], CRHR2 [ 705], HTR2C [ 452], RAB3B [ 706], ATP6V1B2 [ 707], HTR3B [ 708], DMXL2 [ 709], CACNA1E [ 710], TRANK1 [711], SUV39H1 [ 712], ANKK1 [ 713], NCALD (neurocalcin delta) [ 343] and TRPC3 [ 714] have been reported to be altered expression in depre ssion. Studies have found that the FN1 [ 227], YAP1 [ 715], PECAM1 [716], ZAP70 [717], SMAD7 [718], STIP1 [719], EPHA2 [720], KLF4 [721], NFKB2 [ 722], GNG12 [ 723], GATA2 [ 724], ANXA2 [ 725], CYP1A1 [726], CASP7 [ 727], CGAS (cyclic GMP-AMP synthase) [ 728], MMP2 [ 729], SMAD6 [ 730], LATS2 [ 731], GSTM1 [ 732], RUNX3 [ 733], CCL2 [ 734], LTF (lactotransferrin) [ 735], HLA-DQB1 [ 736], DUSP1 [ 737], DLL4 [ 738], BMP6 [739], NFATC1 [ 740], S100A4 [ 741], ABCC2 [742 ], APOBEC3F [ 743], ADORA2A [744], CYP27B1 [ 745], ABCB1 [ 746], NAIP (NLR family apoptosis inhibitory protein) [747], WNK4 [748], TRIM5 [749], YBX3 [750], FOXJ1 [ 751], CSF1 [752], GAS1 [ 753], NPR1 [ 754], ID3 [ 755], PGF (placental growth factor) [756], ORAI1 [ 757], GAP43 [ 758], THY1 [ 759], OPN4 [ 760], NELL1 [ 761], FGF9 [762], SNAP25 [ 763], ATP2B1 [ 764], FLRT3 [ 765], MEF2C [766 ], PAK1 [767], SLIT2 [ 768], UCHL1 [ 769], EGR1 [ 318], PAX5 [ 770], LRRK2 [ 771], C9ORF72 [ 772], ATP1A3 [ 773], ATP1A1 [ 774], FLT3 [ 775], SUV39H1 [ 776], SPTLC2 [ 777], DDX39B [ 778], ENO2 [ 779], RSAD2 [ 780], CDK7 [ 781], HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase) [ 782] and LANCL2 [ 783] plays a vital role in the development of infection. The expression levels of KIT (KIT proto-oncogene, receptor tyrosine kinase) [ 784], PECAM1 [ 785], GSTM1 [786], ADORA2A [ 787], CACNA1H [ 788], LAMB1 [ 789], NEGR1 [ 790], SNAP25 [791], EXT1 [ 792], FGF12 [ 793], MEF2C [794 ], CSMD3 [ 795], AHI1 [796], SCN2A [797], CNTNAP2 [798], GABRB3 [799], SCN1A [800], SEMA3A [801], UCHL1 [ 802], ALDH1A3 [ 803], PAX5 [ 804], MAP2 [ 805], ANK3 [ 806], LRRK2 [ 807], NRXN1 [ 808], ATP2B2 [ 809], RYR2 [ 810], SST (somatostatin) [811], PVALB (parvalbumin) [ 812], TAC1 [ 813], SPARCL1 [ 814], DLGAP2 [815], ATP1A3 [ 816], SNCB (synuclein beta) [ 817], NSF (N-ethylmaleimide sensitive factor, vesicle fusing ATPase) [ 818], GAD1 [ 819], CRHR2 [820 ], (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint HTR2C [821], SYN3 [822], NAPB (NSF attachment protein beta) [ 823], DMXL2 [709], ATP1A1 [ 824], RPH3A [ 825], UBLCP1 [826]. ENO2 [827 ], SLC25A12 [828], ZNF711 [ 829], HMGCR (3-hydroxy-3-met hylglutaryl-CoA reductase) [830] and FABP3 [ 831] have been proved to be elevated in autism spectrum disorder. Some researchers have reported that altered genes include KIT (KIT proto-oncogene, receptor tyrosine kinase) [ 832], TTN (titin) [ 833], HSPB1 [ 834], CYP1A1 [835], MMP2 [836], FZD2 [837], CCL2 [838], S100A4 [839], CYP27B1 [840], ABCB1 [841], CACNA1H [842], CSF1 [843], ENG (endoglin) [844], VGF (VGF nerve growth factor inducible) [ 845], GAP43 [846], STMN2 [847], MEF2C [848], SEMA3A [ 849], UCHL1 [ 850], ELAVL4 [ 851], LRRK2 [ 852], C9ORF72 [207], KIFAP3 [ 853], SPTLC2 [ 854] and GOT1 [ 855] expression in the amyotrophic lateral sclerosi s. Transcription of YAP1 [ 856], PGR (progesterone receptor) [857], KLF4 [ 858], COL1A2 [ 859], HSPA2 [ 860], HSPB1 [ 861], FLT1 [862], TAB2 [ 863], PPP2R1B [ 864], FLT4 [ 865], GATA2 [ 866], ANXA2 [ 867], CYP1A1 [868], CGAS (cyclic GMP-AMP synthase) [869], MMP2 [870], SMAD6 [371], GSTM1 [ 871], CDKN1C [ 872], CCL2 [873 ], LTF (lactotransferrin) [ 874], KCNQ1 [ 875], DUSP1 [ 876], S100A4 [ 877], CYP27B1 [ 878], ABCB1 [ 879], MMP14 [880], WNK4 [ 881], EDNRB (endothelin receptor type B) [ 882], PGF (placental growth factor) [ 883], CDKN2C [ 884], PCSK1 [885], VGF (VGF nerve growth factor inducible) [ 886], GAP43 [ 887], THY1 [ 888], RGS4 [889 ], FGF9 [890], NEGR1 [ 891], SNAP25 [ 892], EXT1 [ 893], AHI1 [ 894], SCN5A [ 895], DCLK1 [ 433], CNTNAP2 [ 896], HHIP (hedgehog interacting protein) [ 897], SLIT2 [898], PAK3 [ 899], EGR1 [ 900], CITED2 [901 ], PTPRO (protein tyrosine phosphatase receptor type O) [902], LRRK2 [903], CLSTN3 [904], TRIM67 [324], SST (somatostatin) [ 905], GAD2 [ 906], FLT3 [ 907], SUV39H1 [ 908], PDE10A [909], ANKK1 [ 910], NCALD (neurocalcin delta) [ 911], HMGCR (3-hydroxy-3- methylglutaryl-CoA reductase) [ 830], CISD1 [ 912] and FABP3 [913] were significantly altered in patients with obesity. A previous study reported that the YAP1 [914], PECAM1 [ 915], SMAD7 [ 916], KLF4 [ 917], FLT1 [ 918], ANXA2 [919], MMP2 [ 920], EPAS1 [ 921], TGFB2 [ 922], GSTM1 [923], CCL2 [ 924], LTF (lactotransferrin) [ 925], HLA-DQB1 [ 926], EFNB1 [927], SOX17 [ 928], CYP27B1 [929], FOXC1 [ 930], ENG (endoglin) [ 931], EDNRB (endothelin receptor type B) [ 932], GAP43 [ 933], ADCYAP1 [ 934], FGF9 [ 935], NEGR1 [936], AHI1 [ 937], DCLK1 [ 938], SEMA3A [ 939], UCHL1 [ 940], MAP2 [ 941], LRRK2 [942], NRXN1 [323], C9ORF72 [943], SST (somatostatin) [944], PVALB (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint (parvalbumin) [945], TAC1 [946], SPARCL1 [947], THEMIS (thymocyte selection associated) [ 948], GRIA3 [ 949], SYN3 [ 950] and GAD2 [ 951] genes were associated with multiple sclerosis. PECAM1 [ 952], ZAP70 [953], KLF4 [ 954], HSPB1 [955 ], FLT1 [956], TAB2 [ 957], FOXO4 [ 958], GLI2 [ 959], ANXA2 [867], CYP1A1 [ 960], CGAS (cyclic GMP-AMP synthase) [ 869], MMP2 [ 961], SERPINH1 [ 962], TGFB2 [ 963], LATS2 [ 964], GSTM1 [ 965], RUNX3 [ 966], CDKN1C [967], CCL2 [968]. LTF (lactotransferrin) [ 969], KCNQ1 [608], DLL4 [970], BMP6 [ 971], MLKL (mixed lineage kinase domain like pseudokinase) [972], S100A4 [973], MASP2 [974], ADORA2A [975], CYP27B1 [976]. ABCB1 [977], MMP14 [ 165], WNK4 [978], FLOT1 [ 979], CSF1 [980 ], ENG (endoglin) [981], EDNRB (endothelin receptor type B) [882], SLC12A3 [982], EPHX1 [983], ORAI1 [984], PCSK1 [ 413], GAP43 [ 985], MAS1 [986 ], THY1 [987], STMN2 [988], RGS4 [989], ADCYAP1 [990], FGF9 [991], NEGR1 [992], SNAP25 [993], VTN (vitronectin) [994], MEF2C [995], PAK1 [996], AHI1 [997], DCLK1 [998], HHIP (hedgehog interacting protein) [ 999], RBFOX2 [ 1000], SLIT2 [ 1001], SEMA3A [1002], UCHL1 [1003], EGR1 [1004], CITED2 [1005], PCSK2 [1006], LRRK2 [ 1007], RYR2 [ 1008], SST (somatostatin) [ 329], ICA1 [ 1009], CRHR2 [705], HTR3B [ 1010], GAD2 [ 1011], ATP1A1 [ 1012], CACNA1E [1013], SUV39H1 [ 1014], PDE10A [ 909], MSH5 [ 1015], ANKK1 [ 1016], HMGCR (3- hydroxy-3-methylglutaryl-CoA reductase) [ 1017], CISD1 [ 1018], LANCL2 [1019], TRPC3 [1020 ], FABP3 [1021 ], PDE1A [ 467] and PDE1A [1022] have been proposed as biomarkers for diabetes mellitus progression. Regulation of ZAP70 [ 1023], STIP1 [ 1024], KLF4 [ 1025], HSPB1 [ 1026], ITGA5 [ 1027], GATA2 [ 1028], CYP1A1 [ 1029], CGAS (cyclic GMP-AMP synthase) [ 1030], MMP2 [ 1031], TGFB2 [ 922], GSTM1 [ 1032], RUNX3 [ 1033], CCL2 [ 1034], LTF (lactotransferrin) [ 1035], HLA-DQB1 [ 1036], MSX1 [ 1037], ADORA2A [495], ABCB1 [ 1038], CSF1 [ 1039], RCC1 [ 1040], VGF (VGF nerve growth factor inducible) [ 1041], GAP43 [ 1042], THY1 [ 1043], SLC17A6 [ 1044], SYT1 [1045], SNAP25 [182], SYT4 [1046], MEF2C [1047], NMNAT2 [1048], CSMD1 [1049], CCKBR (cholecystokinin B receptor) [ 1050], SEMA3A [ 1051], UCHL1 [1052], ELAVL4 [1053], EGR1 [ 1054], CHRM1 [ 1055], MAP2 [ 1056], PTPRO (protein tyrosine phosphatase receptor type O) [ 1057], LRRK2 [ 203], STX1B [1058], SH3GL2 [ 1059], MTR (5-methyltetrahydrofolate-homocysteine methyltransferase) [ 1060], PLK2 [ 1061], C9ORF72 [ 1062], SST (somatostatin) [1063], PVALB (parvalbumin) [ 1064], SV2C [ 1065], SNCB (synuclein beta) (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint [1066], CAP2 [ 214], TRIM9 [1067 ], HTR2C [ 1068], SYN3 [ 1069], PDE10A [1070], ANKK1 [ 1071], GNL1 [ 1072], NQO2 [ 1073], CISD1 [ 1074], ABCA5 [1075] and FABP3 [ 1076] levels might be a novel treatment option against Parkinson's disease. Previous studies have shown that SMAD7 [ 1077], KLF4 [1078], FOXO4 [ 1079], ANXA2 [ 1080], CYP1A1 [1081 ], CGAS (cyclic GMP- AMP synthase) [ 1082], MMP2 [ 1083], GSTM1 [ 1084], CCL2 [ 1085], KCNQ1 [1086], HLA-DQB1 [ 1087], DUSP1 [ 1088], ABCC2 [ 1089], ADORA2A [ 1090], ABCB1 [1091], CACNA1H [ 1092], CELSR1 [ 1093], EPHX1 [ 1094], ORAI1 [1095], NES (nestin) [ 1096], GAP43 [ 1097], SCN8A [ 417], CDKL5 [ 1098], SERPINI1 [1099], FGF9 [1100], SYT1 [1101], SNAP25 [1102], GABRA1 [1103], FGF12 [1104], MEF2C [ 1105], GABRG2 [304], HCN1 [1106], CSMD3 [ 1107], PPP3CA [ 1108], SCN2A [ 1109], SCN5A [ 1110], CNTNAP2 [ 1111], GABRB3 [1112], SCN1A [ 1113], SLIT2 [ 1114], RORB (RAR related orphan receptor B) [1115], SEMA3A [ 1116], UCHL1 [ 1117], SLC4A10 [ 1118], ADAM23 [ 1119], EGR1 [1120], GABRB2 [ 1121], CHRM1 [ 1122], TUBB3 [ 1123], MAP2 [1124 ], ANK3 [ 1125], STX1B [1126 ], PLCB1 [ 1127], NRXN1 [ 1128], RYR2 [ 1129], VPS13A [1130], MTR (5-methyltetrahydrofolate-homocysteine methyltransferase) [1131], TUBB2A [1132], C9ORF72 [ 1133], SST (somatostatin) [ 1134], PVALB (parvalbumin) [1135], DLGAP2 [ 1136], KCNH1 [1137], NSF (N-ethylmaleimide sensitive factor, vesicle fusing ATPase) [ 1138], ATP1A3 [1139], GRIA3 [ 1140], GAD1 [ 1141], SV2B [ 1142], HTR2C [ 1143], NAPB (NSF attachment protein beta) [ 823], ATP6V1B2 [ 1144], CACNA1E [ 1145], VARS2 [ 1146], RPH3A [825], RPP21 [ 1147], IARS1 [ 1148], ANKK1 [1149 ] and TRPC3 [ 1150] might promote epilepsy. Recent studies have also suggested that RRAS (RAS related) [1151], CGAS (cyclic GMP-AMP synthase) [ 1152], DUSP1 [1153 ], ADORA2A [1154], NFATC4 [1155], VGF (VGF nerve growth factor inducible) [ 1156], FGF9 [1157], SNAP25 [1158], UCHL1 [1159], CHRM1 [1160], MAP2 [1161], NRXN1 [1162], VPS13A [ 1163], C9ORF72 [ 1164] , SST (somatostatin) [ 1165] and PDE10A [ 1166] might promote Huntington's disease. LEF1 [ 1167], GSTM1 [1168], CCL2 [1169], HLA-DQB1 [1170], ABCB1 [1171], MDGA1 [1172], VGF (VGF nerve growth factor inducible) [ 1173], THY1 [ 675], SCN8A [ 1174], RGS4 [1175], CDKL5 [1176], ADCYAP1 [1177], SNAP25 [1178], NRN1 [1179], AHI1 [1180], CSMD1 [1181], RORB (RAR related orphan receptor B) [1182], GABRB2 [1183], MAP2 [692 ], CITED2 [ 1184], ANK3 [ 1125], HTR5A [1185 ], C9ORF72 [1186], SST (somatostatin) [ 1187], ATP1A3 [ 1186], NSF (N-ethylmaleimide (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint sensitive factor, vesicle fusing ATPase) [ 1187], GRIA3 [ 1188], CAP2 [ 1191], CADPS (calcium dependent secretion activator) [ 1192], GAD1 [ 1193], HTR2C [1194], HTR3B [ 1195], TRANK1 [ 711], PDE10A [ 1196], ANKK1 [ 1197] and TRPC3 [ 1198] might play an important role in the onset, development, and treatment of bipolar disorder. Some studies have shown that HSPB1 [ 1199], GLI2 [1200], CGAS (cyclic GMP-AMP synthase) [ 1201], MMP2 [1202], FZD1 [1203], GSTM1 [1204], CCL2 [1205], HLA-DQB1 [1206], BMP6 [1207], MASP2 [1208], ADORA2A [1209], ABCB1 [1210], CELSR1 [1211], ZIC2 [1212], DES (desmin) [1213], MDGA1 [ 1172], VGF (VGF nerve growth factor inducible) [ 1214], GAP43 [ 1215], THY1 [ 675], RGS4 [ 1216], ADCYAP1 [ 1217], SCG2 [507 ], FGF9 [ 1218], SYT1 [1219 ], SNAP25 [ 680], FGF14 [ 1220], MEF2C [ 1221], NRN1 [ 1179], GABRG2 [ 1222], HCN1 [ 1223], PCDH8 [ 1224], PAK1 [ 1225], RAB3A [ 1226], AHI1 [ 1180], CSMD1 [ 1227], SCN2A [ 1228], SCN5A [ 1229], DCLK1 [ 1230], CCKBR (cholecystokinin B receptor) [ 1231], CNTNAP2 [ 685], GABRB3 [1232], SCN1A [ 800], PAK3 [ 1233], SEMA3A [ 689], UCHL1 [ 1234], EGR1 [ 1235], GABRB2 [ 1183], CHRM1 [ 1236], MAP2 [ 1237], ANK3 [ 1238], HTR5A [1239], LRRK2 [1240], PLCB1 [1241], NRXN1 [1242], MAP1A [1243], RYR2 [ 1244], C9ORF72 [ 1245], VAMP1 [ 1246], SST (somatostatin) [ 1247], PVALB (parvalbumin) [1248], DLGAP2 [1249], ATP1A3 [1250], KCNH1 [1251], SNCB (synuclein beta) [ 1252], NSF (N-ethylmaleimide sensitive factor, vesicle fusing ATPase) [ 1187], GRIA3 [ 1253], CAP2 [ 214], GAD1 [ 1254], HTR2C [1255], SYN3 [ 1256], HTR3B [ 1257], CHRM4 [ 1258], DMXL2 [ 709], GAD2 [1259], DLGAP1 [ 1260], VSNL1 [ 1261], PDE10A [ 1262], ANKK1 [ 1263], FSTL5 [ 1264], NQO2 [ 1265] and FABP3 [ 831] plays a certain role in schizophrenia. GATA2 [ 1266], MMP2 [ 1267], S100A4 [ 1268], EDNRB (endothelin receptor type B) [1269], PGF (placental growth factor) [1270], ORAI1 [1271], MAS1 [1272 ], VTN (vitronectin) [ 1273], SEMA3A [ 1274], UCHL1 [1275], EGR1 [1276 ], SUV39H1 [ 1277] and PDE10A [ 1278] were significantly altered in patients with vascular disease. ANXA2 [ 1279], MMP2 [ 1280], CCL2 [1281], ABCB1 [ 1282], PGF (placental growth factor) [ 1283], VGF (VGF nerve growth factor inducible) [ 1284], GAP43 [ 1285], SNAP25 [ 1286], CNTNAP2 [1287], UCHL1 [ 1288], CHRM1 [ 1055], MAP2 [ 1289], LRRK2 [ 1290], C9ORF72 [1133], SST (somatostatin) [ 1291], DLGAP2 [213], SNCB (synuclein beta) [1066], TRIM9 [1067], PDE10A [ 1292] and FABP3 [ 1293] can participate in the occurrence and development of dementia. The results of this investigation (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint suggest that enriched genes might play a key role in the pathogenesis of AD and its associated complications. The complexity and diversity of AD have hindered our accurate understanding of the disease. In this investigation, we used a comprehensive bioinformatics approach to find hub gene s form PPI network and modules that influence the progression of AD and its associated complications. HSP90AA1 [139], FN1 [ 140], YAP1 [ 141], DDX39B [ 220], CDK7 [221], HSPA2 [ 145], HSPA1A [61], SYT1 [181], VAMP1 [208] and SNAP25 [182] might be involved in the development of AD. Regulation of HSP90AA1 [ 226], FN1 [227 ], YAP1 [228], SKP1 [1294], CDK7 [ 344], HSPB1 [ 234], HSPA1A [ 69], HSPA12B [ 289] and SNAP25 [299] levels might be a novel treatment option against inflammation. Previous studies have demo nstrated that HSP90AA1 [ 352], FN1 [ 353], YAP1 [354], HSPB1 [361], HSPA1A [83], HSPA12B [412] and NSF (N-ethylmaleimide sensitive factor, vesicle fusing ATPase) [ 450] are linked with the development mechanisms of cardiovascular diseases. HSP90AA1 [ 468], YAP1 [469 ], HSPB1 [474], DNAJB1 [ 470], HSPA12B [504 ], SYT1 [509 ], NSF (N-ethylmaleimide sensitive factor, vesicle fusing ATPase) [ 531], VAMP1 [ 527] and SNAP25 [ 510] participate in pathogenic processes of brain injury. Previous research suggested some biomarkers, such as HSP90AA1 [ 468], STIP1 [ 544], HSPA12B [ 570] and SNAP25 [ 510] could be valuable in the diagnosis and prognosis of stroke. HSP90AA1 [ 589], YAP1 [ 590], NSF (N-ethylmaleimide sensitive factor, vesicle fusing ATPase) [ 649] and SNAP25 [ 632] expression has significant diagnosis value in hypertension patients and acts as potential targets for hypertension.- targeted therapy. Research has shown that HSP90AA1 [ 656], YAP1 [ 657], SYT1 [679], NSF (N-ethylmaleimide sensitive factor, vesicle fusing ATPase) [ 704] and SNAP25 [680] plays an important role in the pathogenesis of de pression. Altered expression of FN1 [ 227], YAP1 [ 715], SKP1 [1295 ], DDX39B [ 778], CDK7 [781], STIP1 [ 719] and SNAP25 [ 763] are significantly associated with the infections. KIT (KIT proto-oncogene, receptor tyrosine kinase) [784], NAPB (NSF attachment protein beta) [ 823], NSF (N-ethylmaleimide sensitive factor, vesicle fusing ATPase) [818] and SNAP25 [791] are strongly involved in the pathogenesis of autism spectrum disorder. A recent study revealed that KIT (KIT proto- oncogene, receptor tyrosine kinase) [832 ] and HSPB1 [ 834] expression was elevated in amyotrophic lateral sclerosis. YAP1 [ 856], HSPB1 [ 861], HSPA2 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint [860], HSPA1A [89] and SNAP25 [892] expression has been found to be altered in patients with obesity. Altered levels of YAP1 [ 914] have been associated with impaired cognitive performance in patients with multiple sclerosis. Previous studies have shown that SKP1 [ 1296], HSPB1 [ 1026], STIP1 [1024 ], HSPA1A [95], SYT1 [1045], STX1B [1058] and SNAP25 [ 182] are closely associated with Parkinson's disease. Excessive activation of HSPB1 [ 955], HSPA1A [ 77] and SNAP25 [993] have been observed in diabetes mellitus. Altered levels of HSPB1 [1199], HSPA1A [ 92] , S Y T 1 [1219], NSF (N-ethylmaleimide sensitive factor, vesicle fusing ATPase) [1187], VAMP1 [1246] and SNAP25 [680] proteins exhibit schizophrenia. HSPA1A [ 65] plays an important role in the vascular disease. Changes in NAPB (NSF attachment protein beta) [ 823], SYT1 [ 1101], NSF (N- ethylmaleimide sensitive factor, vesicle fusing ATPase) [1138], STX1B [1126] and SNAP25 [1102] expression have been observed in epilepsy. The altered expression of NSF (N-ethylmaleimide sensitive factor, vesicle fusing ATPase) [ 1187] and SNAP25 [1178] are related to prognosis in bipolar disorder. SNAP25 [ 1158] is an emerging therapeutic target due to its regulated expression in Huntington's disease. SNAP25 [ 1286] provided a clear picture of th e prognosis of patients with dementia. LSM2, EIF5A2 and TAF9 might serve as a novel targets for early diagnosis and specific therapy of AD and its associated complications, and the related molecular mechanisms need to be further clarified. By intervening in AD hub genes, it might be a novel direction for individualized genomic therapy of AD and its associated complications. To find the most important regulatory molecules among the hub genes, we analyzed the correlation between the hub genes and constructed a miRNA-hub gene regulatory network and TF-hub ge ne regulatory network between the hub genes and the miRNA and the TF. The miRN As and TFs regulate the expression of many genes in cells, so abnormal expr ession of miRNAs and TFs might have an impact on the development of diseases. By examining the interaction between hub genes, miRNAs and TFs, we discovered that seve ral miRNAs and TFs are implicated in AD. Previous studies focused on the role of HSP90AA1 [ 139], FN1 [140], YAP1 [ 141], DDX39B [220], CDK7 [ 221], hsa-mir-545-3p [ 1297], hsa- mir-183-5p [ 1298], CREB1 [ 1299], USF2 [ 1300], MEF2A [ 1301] and CEBPB (CCAAT enhancer binding protein beta) [ 1302] in AD development and growth. HSP90AA1 [ 226], FN1 [ 227], YAP1 [ 228], TTN (titin) [ 230], SMAD7 [ 231], (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint SKP1 [ 1294], CDK7 [344 ], SUV39H1 [ 340], hsa-miR-23a-5p [1303 ], PLAG1 [1304] , N F I C ( n u c l e a r f a c t o r I C ) [1305], CREB1 [ 1306], MEF2A [1307 ] and CEBPB (CCAAT enhancer binding protein beta) [ 1308] are associated with prognosis in patients with inflammation. Increasing evidence has convincingly demonstrated that altered expression of HSP90AA1 [ 352], FN1 [ 353], YAP1 [354], TTN (titin) [ 230], SMAD7 [356], SUV39H1 [457], hsa-mir-296-3p [1309], NFIC (nuclear factor I C) [1310], CREB1 [1311], SREBF1 [1312], MEF2A [1313] and NFYA (nuclear transcriptio n factor Y subunit alpha) [ 1314] are a prognosis factors in cardiovascular diseases. HSP90AA1 [ 468], YAP1 [ 469], SUV39H1 [535], USF2 [1315] and CEBPB (CCAAT enhancer binding protein beta) [ 1316] have been reported involved in the brain injury. HSP90AA1 [468], STIP1 [544], TTN (titin) [543], SUV39H1 [587] and CEBPB (CCAAT enhancer binding protein beta) [ 1317] were identified as a candidate causal biomarkers of a stroke. HSP90AA1 [589], YAP1 [ 590], SMAD7 [ 592] and NFYA (nuclear transcription factor Y subunit alpha) [ 1314] were positively associated with hypertension. HSP90AA1 [656], YAP1 [657], SUV39H1 [712], hsa-mir-183-5p [1318], CREB1 [1319] and MAX (MYC associated factor X) [ 1320] expression might be regarded as an indicator of susceptibility to depression. Altered e xpression of FN1 [ 227], YAP1 [ 715], STIP1 [ 719], SMAD7 [ 718], ZAP70 [ 717], DDX39B [778 ], SKP1 [1295], CDK7 [ 781], SUV39H1 [ 776] and hsa-miR-23a-5p [1321] are associated with prognosis in patients with infections. YAP1 [856], SUV39H1 [908], hsa-mir- 296-3p [ 1322], hsa-miR-23a-5p [ 1323], PLAG1 [ 1324], SREBF1 [1325 ] and CEBPB (CCAAT enhancer binding protein beta) [1326] are a potential markers for the detection and prognosis of obesity at an early age. A previous study reported that YAP1 [ 914], SMAD7 [ 916] and hsa-mir-183-5p [1327] are altered expressed in multiple sclerosis. The levels of STIP1 [1024], ZAP70 [ 1023], SKP1 [ 1296], hsa-miR-23a-5p [1328], CREB1 [1329] and SREBF1 [1330] might be a predictive biomarkers for the Parkinson's disease. Research has revealed that TTN (titin) [833], hsa-mir-183-5p [ 1331], hsa-miR-23a-5p [ 1332] and SREBF1 [ 1330] are expressed in amyotrophic lateral sclerosis. SMAD7 [ 1077], hsa-miR-23a-5p [1333], hsa-mir-4521 [ 1334] and MEF2A [ 1335] might aid in the development of personalized therapies for patients with epilepsy. ZAP70 [953], SUV39H1 [1014], hsa-mir-296-3p [ 1322], hsa-miR-23a-5p [ 1336], CREB1 [ 1337] and SREBF1 [1338] are essential for diabetes mellitus development. Recent studies have shown that TCERG1 [ 1339] and CREB1 [ 1340] might play an important role in (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint regulating the Huntington's disease. SUV39H1 [1277] expression was shown to be regulated in vascular disease and associated with prognosis. Hsa-mir-183-5p [1298] and SREBF1 [1341] were associated with dementia. CREB1 [1342] was an important target biomarker of bipolar disorder. CREB1 [ 1343] and SREBF1 [1344] have been reported to be expressed in schizophrenia. Hence, novel biomarkers include LSM2, EIF5A2, PLRG1, GTF2H4, hsa-miR-3909, hsa-miR- 548f-5p, hsa-miR-429, hsa-miR-4735-5p, hsa-miR-489-3p and POU2F2 might play a role in the development of AD through transcriptional regulation-related mechanisms. This investigation sugg ests that these hub ge nes, miRNAs and TFs are closely related to the development of AD and its associated complications. In conclusion, the present investigation identified novel genes and signaling pathways which might be associated in AD progression through the integrated analysis of NGS dataset. These results might contribute to a better understanding of the molecular mechanisms which underl ie AD and provide a series of key biomarkers. However, further experiments are required to validate the findings of the current investigations. Additionally, the majority of included investigations focused on how a hub gene, miRNAs, TFs a nd signaling pathway contribute to the advancement of AD, with limited study concerning the interaction of mu lti-genes and multi-pathways. Therefore, further experiments with additional patient cohorts are also required to confirm the results of this investigation. In vivo and in vitro investigation of gene and pathway interaction is essential to delineate the specific roles of the identified novel genes, which might help to confirm gene functions and reveal the mechanisms underlying AD.

I thanks very much to Caldwell AB, Anantharaman BG, Ramachandran S, Galasko DR, Desplats PA, Wagner SL, Subramaniam S, Department of Bioengineering, University of California, La Jolla, San Diego, CA, the authors who deposited their NGS dataset GSE203206, into the public GEO database. Conflict of interest The authors declare that they have no conflict of interest. Ethical approval (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint This article does not contain any studies with human participants or animals performed by any of the authors. Informed consent No informed consent because this stud y does not contain human or animals participants. Availability of data and materials The datasets supporting the conclusions of this article are available in the GEO (Gene Expression Omnibus) ( https://www.ncbi.nlm.nih.gov/geo/) repository. [(GSE203206) https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc= GSE203206] Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Author Contributions B. V. - Writing original draft, and review and editing C. V. - Software and investigation Authors Basavaraj Vastrad ORCID ID: 0000-0003-2202-7637 Chanabasayya Vastrad ORCID ID: 0000-0003-3615-4450

1. Murphy MP, LeVine H 3rd. Alzheime r's disease and the amyloid-beta peptide. J Alzheimers Di s. 2010;19(1):311-323. doi: 10.3233/JAD-2010- 1221 2. Gorantla NV, Chinnathambi S. Autophagic Pathways to Clear the Tau Aggregates in Alzheimer's Disease. Cell Mol Neurobiol. 2021;41(6):1175- 1181. doi:10.1007/s10571-020-00897-0 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 3. Fukutani Y, Cairns NJ, Shiozawa M, Sasaki K, Sudo S, Isaki K, Lantos PL. Neuronal loss and neurofibrillary degene ration in the hippocampal cortex in late-onset sporadic Alzheimer's disease. Psychiatry Clin Neurosci. 2000;54(5):523-529. doi:10.1046/j.1440-1819.2000.00747.x 4. Zv ěř ová M. Clinical aspects of Alzheimer's disease. Clin Biochem. 2019;72:3-6. doi:10.1016/j.clinbiochem.2019.04.015 5. Reitz C. Genetic diagnosis and prognosis of Alzheimer's disease: challenges and opportunities. Expert Re v Mol Diagn. 2015;15(3):339-348. doi:10.1586/14737159.2015.1002469 6. Stern Y. Cognitive reserve in ageing and Alzheimer's disease. Lancet Neurol. 2012;11(11):1006-1012. doi:10.1016/S1474-4422(12)70191-6 7. Serrano-Pozo A, Das S, Hyman BT. APOE and Alzheimer's disease: advances in genetics, pathophysiology, and therapeutic approaches. Lancet Neurol. 2021;20(1):68-80. doi:10.1016/S1474-4422(20)30412-9 8. Tolppanen AM, Taipale H, Hartikainen S. Head or brain injuries and Alzheimer's disease: A nested case-control register study. Alzheimers Dement. 2017;13(12):1371-1379. doi:10.1016/j.jalz.2017.04.010 9. Guo T, Landau SM, Jagust WJ; Alzheimer’s Disease Neuroimaging Initiative. Age, vascular disease, and Alzheimer's disease pathologies in amyloid negative elderly adults. Al zheimers Res Ther. 2021;13(1):174. doi:10.1186/s13195-021-00913-5 10. Vigasova D, Nemergut M, Liskova B, Damborsky J. Multi-pathogen infections and Alzheimer's disease. Microb Cell Fact. 2021;20(1):25. doi:10.1186/s12934-021-01520-7 11. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, et al. Inflammation and Alzheimer's disease. Neurobiol Aging. 2000;21(3):383-421. doi:10.1016/s0197-4580(00)00124-x 12. Wainaina MN, Chen Z, Zhong C. Environmental factors in the development and progression of late-onset Alzheimer's disease. Neurosci Bull. 2014;30(2):253-270. doi:10.1007/s12264-013-1425-9 13. Burillo J, Marqués P, Jiménez B, Gon zález-Blanco C, Benito M, Guillén C. Insulin Resistance and Diabetes Mellitus in Alzheimer's Disease. Cells. 2021;10(5):1236. doi:10.3390/cells10051236 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 14. Picone P, Di Carlo M, Nuzzo D. Obesity and Alzheimer's disease: Molecular bases. Eur J Neurosci. 2020;52(8):3944-3950. doi:10.1111/ejn.14758 15. Malone JE, Elkasaby MI, Lerner AJ. Effects of Hypertension on Alzheimer's Disease and Related Disorders. Curr Hypertens Rep. 2022;24(12):615-625. doi:10.1007/s11906-022-01221-5 16. Leszek J, Mikhaylenko EV, Belousov DM, Koutsouraki E, Szczechowiak K, Kobusiak-Prokopowicz M, Mysiak A, Diniz BS, So masundaram SG, Kirkland CE, et al. The Links between Cardiovascular Diseases and Alzheimer's Disease. Curr Neur opharmacol. 2021;19(2):152-169. doi:10.2174/1570159X18666200729093724 17. Yuan D, Huang B, Gu M, Qin BE, Su Z, Dai K, Peng FH, Jiang Y. Exploring Shared Genetic Signatures of Alzheimer's Disease and Multiple Sclerosis: A Bioinformatic Analysis Study. Eur Neurol. 2023;86(6):363-376. doi:10.1159/000533397 18. Graves LV, Holden HM, Delano-Wood L, Bondi MW, Woods SP, Corey- Bloom J, Salmon DP, Delis DC, Gilbert PE. Total recognition discriminability in Huntington's and Alzheimer's disease. J Clin Exp Neuropsychol. 2017;39(2):120-130. doi:10.1080/13803395.2016.1204993 19. Zhuang Z, Yang R, Wang W, Qi L, Huang T. Associations between gut microbiota and Alzheimer's disease, major depressive disorder, and schizophrenia. J Neuroinflammation. 2020;17(1):288. doi: 10.1186/s12974- 020-01961-8 20. Alexiou A, Soursou G, Yarla NS, Md Ashraf G. Proteins Commonly Linked to Autism Spectrum Disorder and Alzheimer's Disease. Curr Protein Pept Sci. 2018;19(9):876-880. doi:10.2174/1389203718666170911145321 21. Verde F, Aiello EN, Adobbati L, Poletti B, Solca F, Tiloca C, Sangalli D, Maranzano A, Muscio C, Ratti A, Zago S, et al. Coexistence of Amyotrophic Lateral Sclerosis and Alzh eimer's Disease: Case Report and Review of the Literature. J Al zheimers Dis. 2023;95(4):1383-1399. doi:10.3233/JAD-230562 22. Zhou J, Yu JT, Wang HF, Meng XF, Tan CC, Wang J, Wang C, Tan L. Association between stroke and Alzheimer's disease: systematic review and meta-analysis. J Alzheimers Dis. 2015;43(2):479-489. doi: 10.3233/JAD- 140666 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 23. Fang Y, Si X, Wang J, Wang Z, Chen Y, Liu Y, Yan Y, Tian J, Zhang B, Pu J. Alzheimer Disease and Epilepsy: A Mendelian Randomization Study. Neurology. 2023;101(4):e399-e409. doi:10.1212/WNL.0000000000207423 24. Porsteinsson AP, Rangaraju S, Spires-Jones TL, O'Banion MK. Alzheimer's disease and related dementias: From risk factors to disease pathogenesis. Eur J Neurosci. 2022;56(9):5337-5341. doi:10.1111/ejn.15857 25. Mayo S, Benito-León J, Peña-Bautista C, Baquero M, Cháfer-Pericás C. Recent Evidence in Epigenomics and Proteomics Biomarkers for Early and Minimally Invasive Diagnosis of Alzheimer's and Parkinson's Diseases. Curr Neuropharmacol. 2021;19(8):1273-1303. doi:10.2174/1570159X19666201223154009 26. Besga A, Gonzalez I, Echeburua E, Savio A, Ayerdi B, Chyzhyk D, Madrigal JL, Leza JC, Graña M, Gonzalez-Pinto AM. Discrimination between Alzheimer's Disease and La te Onset Bipolar Disorder Using Multivariate Analysis. Front Aging Neurosci. 2015;7:231. doi:10.3389/fnagi.2015.00231 27. Huang YY, Gan YH, Yang L, Cheng W, Yu JT. Depression in Alzheimer's Disease: Epidemiology, Mechanisms, and Treatment. Biol Psychiatry. 2024;95(11):992-1005. doi:10.1016/j.biopsych.2023.10.008 28. Sharma K. Cholinesterase inhibitors as Alzheimer's therapeutics (Review). Mol Med Rep. 2019;20(2):1479-1487. doi:10.3892/mmr.2019.10374 29. Müller WE, Mutschler E, Riederer P. Noncompetitive NMDA receptor antagonists with fast open-channel blocking kinetics and strong voltage- dependency as potential therapeutic agents for Alzheimer's dementia. Pharmacopsychiatry. 1995;28(4):113-124. doi:10.1055/s-2007-979603 30. Peng Y, Jin H, Xue YH, Chen Q, Yao SY, Du MQ, Liu S. Current and future therapeutic strategies for Alzheimer's disease: an overview of drug development bottlenecks. Front Aging Neurosci. 2023;15:1206572. doi:10.3389/fnagi.2023.1206572 31. Pujar M, Vastrad B, Kavatagimath S, Vastrad C, Kotturshetti S. Identification of candidate biomarkers and pathways associated with type 1 diabetes mellitus using bioinformatic s analysis. Sci Rep. 2022;12(1):9157. doi:10.1038/s41598-022-13291-1 32. Ganekal P, Vastrad B, Vastrad C, Kotrashetti S. Identification of biomarkers, pathways, and potential therapeutic targets for heart failure (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint using next-generation sequencing data and bioinformatics analysis. Ther Adv Cardiovasc Dis. 2023;17:17539447231168471. doi:10.1177/17539447231168471 33. Quiroz YT, Aguillon D, Aguirre-Acevedo DC, Vasquez D, Zuluaga Y, Baena AY, Madrigal L, Hincapié L, Sanchez JS, Langella S, et al. APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer's Disease. N Engl J Med. 2024;390(23):2156-2164. doi:10.1056/NEJMoa2308583 34. Xu C, Liu G, Ji H, Chen W, Dai D, Chen Z, Zhou D, Xu L, Hu H, Cui W, et al. Elevated methylation of OPRM1 and OPRL1 genes in Alzheimer's disease. Mol Med Rep. 2018;18(5):4297-4302. doi:10.3892/mmr.2018.9424 35. Davies DA, Adlimoghaddam A, Albens i BC. Role of Nrf2 in Synaptic Plasticity and Memory in Alzhei mer's Disease. Cells. 2021;10(8):1884. doi:10.3390/cells10081884 36. Zajac DJ, Simpson J, Zhang E, Parikh I, Estus S. Expression of INPP5D Isoforms in Human Brain: Impact of Alzheimer's Disease Neuropathology and Genetics. Genes (Basel). 2023;14(3):763. doi:10.3390/genes14030763 37. Parikh I, Fardo DW, Estus S. Genetics of PICALM expression and Alzheimer's disease. PLoS One. 2014;9(3):e91242. doi:10.1371/journal.pone.0091242 38. Akhtar A, Sah SP. Insulin signaling pathway and related molecules: Role in neurodegeneration and Alzheimer's disease. Neurochem Int. 2020;135:104707. doi:10.1016/j.neuint.2020.104707 39. Deczkowska A, Weiner A, Amit I. The Physiology, Pathology, and Potential Therapeutic Applications of the TREM2 Signaling Pathway. Cell. 2020;181(6):1207-1217. doi:10.1016/j.cell.2020.05.003 40. Wang J, Zhang J, Yu ZL, Chung SK, Xu B. The roles of dietary polyphenols at crosstalk between type 2 diabetes and Alzheimer's disease in ameliorating oxidative stress and mitochondrial dysfunction via PI3K/Akt signaling pathways. Ageing Res Rev. 2024;99:102416. doi:10.1016/j.arr.2024.102416 41. Kapoor A, Nation DA. Role of Notch signaling in neurovascular aging and Alzheimer's disease. Semin Cell Dev Biol. 2021;116:90-97. doi:10.1016/j.semcdb.2020.12.011 42. Saura CA, Valero J. The role of CREB signaling in Alzheimer's disease and other cognitive disorders. Rev Neurosci. 2011;22(2):153-169. doi:10.1515/RNS.2011.018 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 43. Caldwell AB, Anantharaman BG, Ramachandran S, Nguyen P, Liu Q, Trinh I, Galasko DR, Desplats PA, Wagner SL, Subramaniam S. Transcriptomic profiling of sporadic Alzheimer's disease patients. Mol Brain. 2022;15(1):83. doi:10.1186/s13041-022-00963-2 44. Clough E, Barrett T. The Gene Expression Omnibus Database. Methods Mol Biol. 2016;1418:93-110. doi:10.1007/978-1-4939-3578-9_5 45. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43(7):e47. doi:10.1093/nar/gkv007 46. Green GH, Diggle PJ. On the operationa l characteristics of the Benjamini and Hochberg False Discove ry Rate procedure. Stat Appl Genet Mol Biol. 2007;6:Article27. doi:10.2202/1544-6115.1302 47. Reimand J, Kull M, Peterso n H, Hans en J, Vilo J. g:Profiler--a web-based toolset for functional profiling of gene lists from large-scale experiments. Nucleic Acids Res. 2007;35(We b Server issue):W193-W200. doi:10.1093/nar/gkm226 48. Thomas PD. The Gene Ontology and th e Meaning of Biological Function.

Mol Biol. 2017;1446:15 /i2 24. doi:10.1007/978-1-4939-3743-1_2 49. Fabregat A, Jupe S, Matthews L, Sidi ropoulos K, Gillespie M, Garapati P, Haw R, Jassal B, Korninger F, May B et al The Reactome Pathway Knowledgebase. Nucleic Acids Res. 2018;46(D1):D649–D655. doi:10.1093/nar/gkx1132 50. Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, Simonovic M, Doncheva NT, Morris JH , Bork P, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47(D1):D607-D613. doi:10.1093/nar/gky113 51. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 2003;13(11):2498-2504. doi:10.1101/gr.1239303 52. Luo X, Guo L, Dai XJ, Wang Q, Zhu W, Miao X, Gong H. Abnormal intrinsic functional hubs in alcohol dependence: evidence from a voxelwise degree centrality analysis. Neuropsychiatr Dis Treat. 2017;13:2011-2020. doi:10.2147/NDT.S142742 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 53. Li Y, Li W, Tan Y, Liu F, Cao Y, Lee KY. Hierarchical Decomposition for Betweenness Centrality Measure of Complex Networks. Sci Rep. 2017;7:46491.. doi:10.1038/srep46491 54. G i l b e r t M , L i Z , W u X N , R o h r L , G o m b o s S , H a r t e r K , S c h u l z e W X . Comparison of path-based centrality m easures in protein- protein interaction networks revealed proteins with pheno typic relevance during adaptation to changing nitrogen environments. J Proteomics. 2021;235:104114. doi:10.1016/j.jprot.2021.104114 55. Li G, Li M, Wang J, Li Y, Pan Y. United Neighborhood Closeness Centrality and Orthology for Predicting Essential Proteins. IEEE/ACM Trans Comput Biol Bioinform. 2020;17(4):1451-1458. doi:10.1109/TCBB.2018.2889978 56. Zaki N, Efimov D, Berengueres J. Protein complex detection using interaction reliability assessment and weighted clustering coefficient. BMC Bioinformatics. 2013;14:163. doi:10.1186/1471-2105-14 57. Fan Y, Xia J (2018) miRNet-Functional An alysis and Visual Exploration of miRNA-Target Interactions in a Network Context. Methods Mol Biol 1819:215-233. doi:10.1007/978-1-4939-8618-7_10 58. Zhou G, Soufan O, Ewald J, Ha ncock REW, Basu N, Xia J (2019) NetworkAnalyst 3.0: a visual analy tics platform for comprehensive gene expression profiling and meta-analysis. Nucleic Acids Res 47:W234-W241. doi:10.1093/nar/gkz240 59. Robin X, Turck N, Hainard A, Tiberti N, Lisacek F, Sanchez JC, Müller M. pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinformatics 2011;12:77. doi:10.1186/1471-2105-12-77 60. Rostagno AA. Pathogenesis of Alzheimer's Disease. Int J Mol Sci. 2022;24(1):107. doi:10.3390/ijms24010107 61. Wang Y, Yang Y, Liang C, Zhang H. Exploring the Roles of Key Mediators IKBKE and HSPA1A in Alzheimer's Disease and Hepatocellular Carcinoma through Bioinformatics Analysis. Int J Mol Sci. 2024;25(13):6934. doi:10.3390/ijms25136934 62. Jafarian Z, Saliminejad K, Kamali K, Ohadi M, Kowsari A, Nasehi L, Khorram Khorshid HR. Association of glutathione S-transferases M1, P1 and T1 variations and risk of late-ons et Alzheimer's disease. Neurol Res. 2018;40(1):41-44. doi:10.1080/01616412.2017.1390902 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 63. Le Guen Y, Luo G, Ambati A, Damotte V, Jansen I, Yu E, Nicolas A, de Rojas I, Peixoto Leal T, Miyashita A, et al. Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes. Proc Natl Acad Sci U S A. 2023;120(36):e2302720120. doi:10.1073/pnas.2302720120 64. Smyth LCD, Murray HC, Hill M, van Leeuwen E, Highet B, Magon NJ, Osanlouy M, Mathiesen SN, Mockett B, Singh-Bains MK, et al. Neutrophil- vascular interactions drive myeloperox idase accumulation in the brain in Alzheimer's disease. Acta Neur opathol Commun. 2022;10(1):38. doi:10.1186/s40478-022-01347-2 65. Dulin E, García-Barreno P, Guisasola MC. Extracellular heat shock protein 70 (HSPA1A) and classical vascular ri sk factors in a general population. Cell Stress Chaperones. 2010;15(6):929-937. doi:10.1007/s12192-010-0201- 2 66. Nørskov MS, Frikke-Schmidt R, Loft S, Sillesen H, Grande P, Nordestgaard BG, Tybjaerg-Hansen A. Copy number variation in glutathione S- transferases M1 and T1 and ischemic vascular disease: four studies and meta-analyses. Circ Cardiova sc Genet. 2011;4(4):418-428. doi:10.1161/CIRCGENETICS.111.959809 67. Lundström E, Gustafsson JT, Jönsen A, Leonard D, Zickert A, Elvin K, Sturfelt G, Nordmark G, Beng tsson AA, Sundin U, et al. HLA- DRB1*04/*13 alleles are associated with vascular disease and antiphospholipid antibodies in system ic lupus erythematosus. Ann Rheum Dis. 2013;72(6):1018-1025. doi:10.1136/annrheumdis-2012-201760 68. Lau D, Baldus S. Myeloperoxidase and its contributory role in inflammatory vascular disease. Pharmacol Ther. 2006;111(1):16-26. doi:10.1016/j.pharmthera.2005.06.023 69. Kotowska J, Jówko E, Cie ś liń ski I, Gromisz W, Sadowski J. IL-6 and HSPA1A Gene Polymorphisms May Influence the Levels of the Inflammatory and Oxidative Stress Parameters and Their Response to a Chronic Swimming Training. Int J Environ Res Public Health. 2022;19(13):8127. doi:10.3390/ijerph19138127 70. Huang S, Lu W, Ge D, Meng N, Li Y, Su L, Zhang S, Zhang Y, Zhao B, Miao J. A new microRNA signal path way regulated by long noncoding RNA TGFB2-OT1 in autophagy and infl ammation of vascular endothelial (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint cells. Autophagy. 2015;11(12):2172-2183. doi:10.1080/15548627.2015.1106663 71. Zeng X, Tian G, Zhu J, Yang F, Zhang R, Li H, An Z, Li J, Song J, Jiang J, et al. Air pollution associated acute respiratory inflammation and modification by GSTM1 and GSTT1 gene polymorphisms: a panel study of healthy undergraduates. Environ Health. 2023;22(1):14. doi:10.1186/s12940-022-00954-9 72. M a t s u n a g a N , I k e d a E , K a k i m o t o K , Watanabe M, Shindo N, Tsuruta A, Ikeyama H, Hamamura K, Higashi K, Yamashita T, et al. Inhibition of G0/G1 Switch 2 Ameliorates Renal Inflammation in Chronic Kidney Disease. EBioMedicine. 2016;13:262-273. doi:10.1016/j.ebiom.2016.10.008 73. Luo Y, He Y, Wang Y, Xu Y, Yang L. LncRNA HCG18 promotes inflammation and apoptosis in intervertebral disc degeneration via the miR- 495-3p/FSTL1 axis. Mol Cell Biochem. 2024;479(1):171-181. doi:10.1007/s11010-023-04716-0 74. Klimenta B, Nefic H, Prodanovic N, Jadric R, Hukic F. Association of biomarkers of inflammation and HLA-DRB1 gene locus with risk of developing rheumatoid arthritis in females. Rheumatol Int. 2019;39(12):2147-2157. doi:10.1007/s00296-019-04429-y 75. Zhao G, Li Y, Chen T, Liu F, Zheng Y, Liu B, Zhao W, Qi X, Sun W, Gao C. TRIM26 alleviates fatal immunopathology by regulating inflammatory neutrophil infiltration during Candida infection. PLoS Pathog. 2024;20(1):e1011902. doi:10.1371/journal.ppat.1011902 76. Chen S, Chen H, Du Q, Shen J. Targeting Myeloperoxidase (MPO) Mediated Oxidative Stress and Inflammation for Reducing Brain Ischemia Injury: Potential Application of Natural Compounds. Front Physiol. 2020;11:433. doi:10.3389/fphys.2020.00433 77. Rosas PC, Nagaraja GM, Kaur P, Panossian A, Wickman G, Garcia LR, Al- Khamis FA, Asea AA. Hsp72 (HSPA1A) Prevents Human Islet Amyloid Polypeptide Aggregation and Toxicity: A New Approach for Type 2 Diabetes Treatment. PLoS One. 2016;11(3):e0149409. doi:10.1371/journal.pone.0149409 78. Sobha SP, Kesavarao KE. Progonostic effect of GSTM1/GSTT1 polymorphism in determining cardiovascular diseases risk among type 2 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint diabetes patients in South Indi an population. Mol Biol Rep. 2023;50(8):6415-6423. doi:10.1007/s11033-023-08514-1 79. El-Assaad W, El-Kouhen K, Mohammad AH, Yang J, Morita M, Gamache I, Mamer O, Avizonis D, Hermance N, Kersten S, et al. Deletion of the gene encoding G0/G 1 switch protein 2 (G 0s2) alleviates high-fat-diet-induced weight gain and insulin resistance, a nd promotes browning of white adipose tissue in mice. Diabetologia. 2015;58(1):149-157. doi: 10.1007/s00125-014- 3429-z 80. Xia Y, Zhang Y, Wang H. Upregulated lncRNA HCG18 in Patients with Non-Alcoholic Fatty Liver Disease and Its Regulatory Effect on Insulin Resistance. Diabetes Metab Syndr Obes. 2021;14:4747-4756. doi:10.2147/DMSO.S333431 81. Sayad A, Akbari MT, Pajouhi M, Mostafavi F, Kazemnejad A, Zamani M. Investigation The Role of Gender on The HLA-DRB1 and -DQB1 Association with Type 1 Diabetes Mellitus in Iranian Patients. Cell J. 2013;15(2):108-115. 82. Gómez García A, Rivera Rodríguez M, Gómez Alonso C, Rodríguez Ochoa DY, Alvarez Aguilar C. Myeloperoxid ase is associated with insulin resistance and inflammation in overweight subjects with first-degree relatives with type 2 diabetes mellitu s. Diabetes Metab J. 2015;39(1):59-65. doi:10.4093/dmj.2015.39.1.59 83. Jenei ZM, Széplaki G, Merkely B, Karádi I, Zima E, Prohászka Z. Persistently elevated extracellular HSP70 (HSPA1A) level as an independent prognostic marker in post -cardiac-arrest patients. Cell Stress Chaperones. 2013;18(4):447-454. doi:10.1007/s12192-012-0399-2 84. Huang RT, Guo YH, Yang CX, Gu JN, Qiu XB, Shi HY, Xu YJ, Xue S, Yang YQ. SOX7 loss-of-function variation as a cause of familial congenital heart disease. Am J Transl Res. 2022;14(3):1672-1684. 85. Xiong T, Lv XS, Wu GJ, Guo YX, Liu C, Hou FX, Wang JK, Fu YF, Liu FQ. Single-Cell Sequencing Analysis and Multiple Machine Learning

Identified G0S2 and HPSE as Novel Biomarkers for Abdominal Aortic Aneurysm. Front Immunol. 2022;13:907309. doi:10.3389/fimmu.2022.907309 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 86. Luo Y, Jiang Y, Zhong T, Li Z, He J, Li X, Cui K. LncRNA HCG18 affects diabetic cardiomyopathy and its association with miR-9-5p/IGF2R axis. Heliyon. 2024;10(3):e24604. doi:10.1016/j.heliyon.2024.e24604 87. Sreekanth MS, Esdan Basha SK, Arun Kumar G, Govindaraju S, Pradeep Nayar N, Pitchappan RM. Association of IL-1 β +3953 C and HLA- DRB1*15 with Coronary Artery and Rh eumatic Heart Diseases in South India. Hum Immunol. 2016;77(12):1275-1279. doi:10.1016/j.humimm.2016.08.003 88. Ramachandra CJA, Ja KPMM, Chua J, Cong S, Shim W, Hausenloy DJ. Myeloperoxidase As a Multifaceted Target for Cardiovascular Protection. Antioxid Redox Signal. 2020;32(15):1135-1149. doi:10.1089/ars.2019.7971 89. Pilch W, Wyrostek J, Major P, Zuziak R, Piotrowska A, Czerwiń ska-Ledwig O, Grzybkowska A, Zasada M, Ziemann E, Ż ychowska M. The effect of whole-body cryostimulation on body composition and leukocyte expression of HSPA1A, HSPB1, and CRP in obese men. Cryobiology. 2020;94:100- 106. doi:10.1016/j.cryobiol.2020.04.002 90. Cui Z, Liu Y, Wan W, Xu Y, Hu Y, Ding M, Dou X, Wang R, Li H, Meng Y, et al. Ethacrynic acid targets GSTM1 to ameliorate obesity by promoting browning of white adipocytes. Protein Cell. 2021;12(6):493-501. doi:10.1007/s13238-020-00717-7 91. Qaddoumi MG, Alanbaei M, Hammad M M , A l K h a i r i I , C h e r i a n P , Channanath A, Thanaraj TA, Al-Mul la F, Abu-Farha M, Abubaker J. Investigating the Role of Myeloperoxidase and Angiopoietin-like Protein 6 in Obesity and Diabetes. Sci Rep. 2020;10(1):6170. doi: 10.1038/s41598- 020-63149-7 92. Kowalczyk M, Kucia K, Owczarek A, Suchanek-Raif R, Merk W, Paul- Samojedny M, Kowalski J. Associat ion Studies of HSPA1A and HSPA1L Gene Polymorphisms With Schizophr enia. Arch Med Res. 2018;49(5):342- 349. doi:10.1016/j.arcmed.2018.10.002 93. Liu H, Xu Y, Peng J. Glutathione S-Transferase M1/T1 Polymorphisms and Schizophrenia Risk: A New Method for Quality Assessment and a Systematic Review. Neuropsych iatr Dis Treat. 2023;19:97-107. doi:10.2147/NDT.S376942 94. Seshasubramanian V, Raghavan V, SathishKannan AD, Naganathan C, Ramachandran A, Arasu P, Rajendren P, John S, Mowry B, Rangaswamy T, (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint et al. Association of HLA-A, -B, -C, -DRB1 and -DQB1 alleles at amino acid level in individuals with schizophrenia: A study from South India. Int J Immunogenet. 2020;47(6):501-511. doi:10.1111/iji.12507 95. Asad Samani L, Ghaedi K, Majd A, Peymani M, Etemadifar M. Coordinated modification in expression levels of HSPA1A/B, DGKH, and NOTCH2 in Parkinson's patients' blood and substant ia nigra as a diagnostic sign: the transcriptomes' relationship. Ne urol Sci. 2023;44(8):2753-2761. doi:10.1007/s10072-023-06738-4 96. Pinhel MA, Sado CL, Longo Gdos S, Gregório ML, Amorim GS, Florim GM, Mazeti CM, Martins DP, Oliveira Fde N, Nakazone MA, et al. ullity of GSTT1/GSTM1 related to pesticides is associated with Parkinson's disease. Arq Neuropsiquiatr. 2013;71(8):527-532. doi:10.1590/0004-282X20130076 97. Boonpraman N, Yoon S, Kim CY, Moon JS, Yi SS. NOX4 as a critical effector mediating neuroinflammatory cytokines, myeloperoxidase and osteopontin, specifically in astrocytes in the hippocampus in Parkinson's disease. Redox Biol. 2023;62:102698. doi:10.1016/j.redox.2023.102698 98. Salpietro V, Galassi Deforie V, Efthymiou S, O'Connor E, Marcé-Grau A, Maroofian R, Striano P, Zara F, Morrow MM; SYNAPS Study Group; et al. De novo KCNA6 variants with attenuated KV 1.6 channel deactivation in patients with epilepsy. Ep ilepsia. 2023;64(2):443-455. doi:10.1111/epi.17455 99. Prabha TS, Kumaraswami K, Kutala VK. Association of GSTT1 and GSTM1 polymorphisms in South Indian Epilepsy Patients. Indian J Exp Biol. 2016;54(11):783-787. 100. Z h u Z , W an g S , C ao Q , L i G . C ir cU B Q L N 1 Pr o mo tes Pr o lif e r atio n but Inhibits Apoptosis and Oxidative Stress of Hippocampal Neurons in Epilepsy via the miR-155-Mediated S OX7 Upregulation. J Mol Neurosci. 2021;71(9):1933-1943. doi:10.1007/s12031-021-01838-2 101. Bui TP, Nguyen LTT, Le PL, Le NTT, Nguyen TD, Van Nguyen L, Van Nguyen AT, Trinh TH. Next-generation sequencing-based HLA typing reveals the association of HL A-B*46:01:01 and HLA-DRB1*09:01:02 alleles with carbamazepine-induced hypersensitivity reactions in Vietnamese patients with epilepsy. Hum Immunol. 2023;84(3):186-195. doi:10.1016/j.humimm.2023.01.005 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 102. Shao C, Yuan J, Liu Y, Qin Y, Wang X, Gu J, Chen G, Zhang B, Liu HK, Zhao J, et al. Epileptic brain fl uorescent imaging reveals apigenin can relieve the myeloperoxidase-mediated oxidative stress and inhibit ferroptosis. Proc Natl Acad Sci U S A. 2020;117(19):10155-10164. doi:10.1073/pnas.1917946117 103. Chernyak YI, Itskovich VB, D'yakovich OA, Kolesnikov SI. Role of cytochrome P450-dependent monooxygen ases and polymor phic variants of GSTT1 and GSTM1 genes in the formatio n of brain lesions in individuals chronically exposed to mercury. Bu ll Exp Biol Med. 2013;156(1):15-18. doi:10.1007/s10517-013-2266-2 104. Huang S, Wang HL. Salvianolic acid A improves nerve regeneration and repairs nerve defects in rats with brain injury by downregulating miR- 212-3p-mediated SOX7. Kaohsiung J Med Sci. 2023;39(12):1222-1232. doi:10.1002/kjm2.12779 105. Tur C, Ramagopalan S, Altmann DR, Bodini B, Cercignani M, Khaleeli Z, Miller DH, Thompson AJ, Ciccarelli O. HLA-DRB1*15 influences the development of brain tissue damage in early PPMS. Neurology. 2014;83(19):1712-1718. doi:10.1212/WNL.0000000000000959 106. Bortolli APR, Vieira VK, Treco IC, Pascotto CR, Wendt GW, Lucio LC. GSTT1 and GSTM1 polymorphisms with human papillomavirus infection in women from southern Brazil: a case-control study. Mol Biol Rep. 2022;49(7):6467-6474. doi:10.1007/s11033-022-07475-1 107. Greco S, Made' A, Mutoli M, Zhang L, Piella SN, Vausort M, Lumley AI, Beltrami AP, Srivastava PK, Mila ni V, et al. HCG18, LEF1AS1 and lncCEACAM21 as biomarkers of disease severity in the peripheral blood mononuclear cells of COVID-19 patients. J Transl Med. 2023;21(1):758. doi:10.1186/s12967-023-04497-6 108. Del Río-Ospina L, Camargo M, Soto-De León SC, Sánchez R, Moreno-Pérez DA, Patarroyo ME, Patarroyo MA. dentifying the HLA DRB1-DQB1 molecules and predicting epitopes associated with high-risk HPV infection clearance and redetection. Sci Rep. 2020;10(1):7306. doi:10.1038/s41598-020-64268-x 109. Hasmann A, Wehrschuetz-Sigl E, Marold A, Wiesbauer H, Schoeftner R, Gewessler U, Kandelbauer A, Schiffer D, Schneider KP, Binder B, et al. Analysis of myeloperoxidase activit y in wound fluids as a marker of (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint infection. Ann Clin Biochem. 2013;50(Pt 3):245-254. doi:10.1258/acb.2011.010249 110. Levy R, Le TH. Role of GSTM1 in Hypertension, CKD, and Related Diseases across the Life Span. Kidney360. 2022;3(12):2153-2163. doi:10.34067/KID.0004552022 111. Li QM, Li B, Sun YF, Zhang H, Yang XL, Cai LW, Chen H, Ding YH, Jiang J. Association of HLA-D RB1 single nucleotide polymorphisms with left ventricular remodelling in elderly patients with essential hypertension. J Int Me d Res. 2012;40(6):2152-2159. doi:10.1177/030006051204000613 112. Klinke A, Berghausen E, Friedrichs K , M o l z S , L a u D , R e m a n e L , Berlin M, Kaltwasser C, Adam M, Mehrkens D, et al. Myeloperoxidase aggravates pulmonary arterial hypertension by activation of vascular Rho- kinase. JCI Insight. 2018;3(11):e97530. doi:10.1172/jci.insight.97530 113. Aliomrani M, Sahraian MA, Shirkhanloo H, Sharifzadeh M, Khoshayand MR, Ghahremani MH. Correlation between heavy metal exposure and GSTM1 polymorphism in Iranian multiple sclerosis patients. Neurol Sci. 2017;38(7):1271-1278. doi:10.1007/s10072-017-2934-5 114. Alcina A, Abad-Grau Mdel M, Fe detz M, Izquierdo G, Lucas M, Fernández O, Ndagire D, Catalá-Rabasa A, Ruiz A, Gayán J, et al. Multiple sclerosis risk vari ant HLA-DRB1*1501 associates w ith high expression of DRB1 gene in different human popul ations. PLoS One. 2012;7(1):e29819. doi:10.1371/journal.pone.0029819 115. Pulli B, Bure L, Wojtkiewicz GR, Iwamoto Y, Ali M, Li D, Schob S, Hsieh KL, Jacobs AH, Chen JW. Multiple sclerosis: myeloperoxidase immunoradiology improves detection of acute and chronic disease in experimental model. Radiology. 2015;275(2):480-489. doi:10.1148/radiol.14141495 116. Rahbar MH, Samms-Vaughan M, Saroukhani S, Bressler J, Hessabi M, Grove ML, Shakspeare-Pellington S, Loveland KA, Beecher C, McLaughlin W. Associations of Metabolic Genes (GSTT1, GSTP1, GSTM1) and Blood Mercury Concentra tions Differ in Jamaican Children with and without Autism Spectrum Disorder. Int J Environ Res Public Health. 2021;18(4):1377. doi:10.3390/ijerph18041377 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 117. Guerini FR, Bolognesi E, Mensi MM, Zanette M, Agliardi C, Zanzottera M, Chiappedi M, Annunziata S, García-García F, Cavallini A, et al. HLA-A, -B, -C and -DRB1 Association with Autism Spectrum Disorder Risk: A Sex-Related Analysis in Italian ASD Children and Their Siblings. Int J Mol Sci. 2024;25(18):9879. doi:10.3390/ijms25189879 118. Ceylan MF, Tural Hesapcioglu S, Yavas CP, Senat A, Erel O. Serum Ischemia-Modified Albumin Levels, Myeloperoxidase Activity and Peripheral Blood Mononuclear cells in Autism Spectrum Disorder (ASD). J Autism Dev Disord. 2021;51(7):2511-2517. doi: 10.1007/s10803-020- 04740-9 119. Wang R, Wang Y, Wang J, Yang K. Association of glutathione S- transferase T1 and M1 gene polymorphisms with ischemic stroke risk in the Chinese Han population. Neural Regen Res. 2012;7(18):1420-1427. doi:10.3969/j.issn.1673-5374.2012.18.009 120. Murali V, Rathika C, Ramgopal S, Padma Malini R, Arun Kumar MJ, Neethi Arasu V, Jeyaram Illiayaraja K, Balakrishnan K. Susceptible and protective associations of HLA DRB1*/ DQB1* alleles and haplotypes with ischaemic stroke. Int J Immunogenet. 2016;43(3):159-165. doi:10.1111/iji.12266 121. Wang Y, Jia Y, Xu Q, Wang R, Sun L, Guo D, Shi M, Yang P, Wang Y, Liu F, et al. Association between myeloperoxidase and the risks of ischemic stroke, heart failure, and atrial fibrillation: A Mendelian randomization study. Nutr Metab Ca rdiovasc Dis. 202 3;33(1):210-218. doi:10.1016/j.numecd.2022.09.027 122. Mohammadynejad P, Saadat I, Ghanizadeh A, Saadat M. Bipolar disorder and polymorphisms of glutathione S-transferases M1 (GSTM1) and T1 (GSTT1). Psychiatry Res. 2011;186(1):144-146. doi:10.1016/j.psychres.2010.06.017 123. Le Clerc S, Lombardi L, Baune BT, Amare AT, Schubert KO, Hou L, Clark SR, Papiol S, Cearns M, Heilbronner U, et al. HLA-DRB1 and HLA- DQB1 genetic diversity modulates response to lithium in bipolar affective disorders. Sci Rep. 2021;11(1):17823. doi:10.1038/s41598-021-97140-7 124. Selek S, Altindag A, Saracoglu G, Aksoy N. Oxidative markers of Myeloperoxidase and Catalase and thei r diagnostic performance in bipolar disorder. J Affect Disord. 2015;181:92-95. doi:10.1016/j.jad.2015.03.058 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 125. Peng J, Pan J, Mo J, Peng Y. MPO/HOCl Facilitates Apoptosis and Ferroptosis in the SOD1G93A Motor Neuron of Amyotrophic Lateral Sclerosis. Oxid Med Ce ll Longev. 2022;2022:8217663. doi:10.1155/2022/8217663 126. Daher J. A Potential Link between Myeloperoxidase Modified LDL, Atherosclerosis and Depression. Int J Mo l Sci. 2024;25(16):8805. doi:10.3390/ijms25168805 127. Petersen RB, Nunomura A, Lee HG, Casadesus G, Perry G, Smith MA, Zhu X. Signal transduction cascades associated with oxidative stress in Alzheimer's disease. J Alzheimers Dis. 2007;11(2):143-152. doi:10.3233/jad-2007-11202 128. Mukhamedyarov MA, Grishin SN, Yusupova ER, Zefirov AL, Palotás A. Alzheimer's beta-amyloid-induced depolarization of skeletal muscle fibers: implications for motor dysfunctions in dementia. Cell Physiol Biochem. 2009;23(1-3):109-114. doi:10.1159/000204099 129. Majumder P, Roy K, Bagh S, Mukhopadhyay D. Receptor tyrosine kinases (RTKs) consociate in regulatory clusters in Alzheimer's disease and type 2 diabetes. Mol Cell Biochem. 2019;459(1-2):171-182. doi:10.1007/s11010-019-03560-5 130. Ziliotto N, Bernardi F, Piazza F. Hemostasis components in cerebral amyloid angiopathy and Alzheimer's disease. Neurol Sci. 2021;42(8):3177- 3188. doi:10.1007/s10072-021-05327-7 131. Jia L, Piña-Crespo J, Li Y. Restoring Wnt/ β -catenin signaling is a promising therapeutic strategy for Alzheimer's disease. Mol Brain. 2019;12(1):104. doi:10.1186/s13041-019-0525-5 132. Anwar MM, Özkan E, Gürsoy-Özdemir Y. The role of extracellular matrix alterations in mediating astrocyte damage and pericyte dysfunction in Alzheimer's disease: A comprehensive review. Eur J Neurosci. 2022;56(9):5453-5475. doi:10.1111/ejn.15372 133. Bordier P, Garrigue S, Lanusse S, Ma rgaine J, Robert F, Gencel L, Lafitte A. Cardiovascular effects and risk of syncope related to donepezil in patients with Alzheimer's dis ease. CNS Drugs. 2006;20(5):411-417. doi:10.2165/00023210-200620050-00005 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 134. Van Beek AH, Claassen JA. The cerebrovascular role of the cholinergic neural system in Alzheimer's disease. Behav Brain Res. 2011;221(2):537-542. doi:10.1016/j.bbr.2009.12.047 135. Guo L, Tian J, Du H. Mitochondrial Dysfunction and Synaptic Transmission Failure in Alzheimer's Disease. J Alzheimers Dis. 2017;57(4):1071-1086. doi:10.3233/JAD-160702 136. Liu R, Collier JM, Abdul-Rahman NH, Capuk O, Zhang Z, Begum G. Dysregulation of Ion Channels and Transporters and Blood-Brain Barrier Dysfunction in Alzheimer's Disease and Vascular Dementia. Aging Dis. 2024;15(4):1748-1770.. doi:10.14336/AD.2023.1201 137. Cui H, Freeman C, Jacobson GA, Small DH. Proteoglycans in the central nervous system: role in development, neural repair, and Alzheimer's disease. IUBMB Life. 2013;65(2):108-120. doi:10.1002/iub.1118 138. Douros A, Santella C, Dell'Aniello S, Azoulay L, Renoux C, Suissa S, Brassard P. Infectious Disease Burden and the Risk of Alzheimer's Disease: A Population-Based Study. J Alzh eimers Dis. 2021;81(1):329-338. doi:10.3233/JAD-201534 139. Astillero-Lopez V, Villar-Conde S, Gonzalez-Rodriguez M, Flores- Cuadrado A, Ubeda-Banon I, Saiz-Sanchez D, Martinez-Marcos A. Proteomic analysis identifies HSP90AA1, PTK2B, and ANXA2 in the human entorhinal cortex in Alzheimer's disease: Potential role in synaptic homeostasis and A β pathology through microglial and astroglial cells. Brain Pathol. 2024;34(4):e13235. doi:10.1111/bpa.13235 140. Bhattarai P, Gunasekaran TI, Belloy ME, Reyes-Dumeyer D, Jülich D, Tayran H, Yilmaz E, Flaherty D, Turgutalp B, Sukumar G, Alba C, et al. Rare genetic variation in fibronectin 1 (FN1) protects against APOE ε 4 in Alzheimer's disease. Acta Neuropathol. 2024;147(1):70. doi:10.1007/s00401-024-02721-1 141. Xu M, Zhang DF, Luo R, Wu Y, Zhou H, Kong LL, Bi R, Yao YG. A systematic integrated analysis of brain expression profiles reveals YAP1 and other prioritized hub genes as important upstream regulators in Alzheimer's disease. Alzheimers De ment. 2018;14(2):215-229. doi:10.1016/j.jalz.2017.08.012 142. Sanfilippo C, Castrogiovanni P, Imbesi R, Di Rosa M. CHI3L2 Expression Levels Are Correlated w ith AIF1, PECAM1, and CALB1 in the (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Brains of Alzheimer's Disease Pati ents. J Mol Neurosci. 2020;70(10):1598- 1610. doi:10.1007/s12031-020-01667-9 143. Ma X, Zhang Y, Gou D, Ma J, Du J, Wang C, Li S, Cui H. Metabolic Reprogramming of Microglia Enhances Proinflammatory Cytokine Release through EphA2/p38 MAPK Pathway in Al zheimer's Disease. J Alzheimers Dis. 2022;88(2):771-785. doi:10.3233/JAD-220227 144. Zhao K, Liu J, Sun T, Zeng L, Cai Z, Li Z, Liu R. The miR- 25802/KLF4/NF-κ B signaling axis regulates microglia-mediated neuroinflammation in Alzheimer's disease. Brain Behav Immun. 2024;118:31-48. doi:10.1016/j.bbi.2024.02.016 145. Dong Y, Li T, Ma Z, Zhou C, Wang X, Li J. HSPA1A, HSPA2, and HSPA8 Are Potential Molecular Biomarkers for Prognosis among HSP70 Family in Alzheimer's Diseas e. Dis Markers. 2022;2022:9480398. doi:10.1155/2022/9480398 146. He R, Cheng J, Qiu Y, Hu Y, Liu J, Wang TH, Cao X. IGF1R and FLT1 in female endothelial cells and CHD2 in male microglia play important roles in Alzheimer's disease based on gender difference analysis. Exp Gerontol. 2024;194:112512. doi:10.1016/j.exger.2024.112512 147. Mahzarnia A, Lutz MW, Badea A. A Continuous Extension of Gene Set Enrichment Analysis Using the Likelihood Ratio Test Statistics Identifies Vascular Endothelial Growth Factor as a Candidate Pathway for Alzheimer's Disease via ITGA5. J Alzheimers Dis. 2024;97(2):635-648. doi:10.3233/JAD-230934 148. Ye L, Zhao J, Xiao Z, Gu W, Liu X, Ajuyo NMC, Min Y, Pei Y, Wang D. Integrative Human Genetic and Cellular Analysis of the Pathophysiological Roles of AnxA2 in Alzheimer's Disease. Antioxidants (Basel). 2024;13(10):1274. doi:10.3390/antiox13101274 149. Zhang X, Zhu C, Beecham G, Vardarajan BN, Ma Y, Lancour D, Farrell JJ, Chung J; Alzheimer's Diseas e Sequencing Project; Mayeux R, et al. A rare missense variant of CASP7 is associated with familial late-onset Alzheimer's disease. Alzheimers Dement. 2019;15(3):441-452. doi:10.1016/j.jalz.2018.10.005 150. Govindarajulu M, Ramesh S, Beasley M, Lynn G, Wallace C, Labeau S, Pathak S, Nadar R, Moore T, Dhanasekaran M. Role of cGAS-Sting (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Signaling in Alzheimer's Disease. Int J Mol Sci. 2023;24(9):8151. doi:10.3390/ijms24098151 151. Ocenasova A, Shawkatova I, Javor J, Parnicka Z, Minarik G, Kralova M, Kiralyova I, Mikolaskova I, Durmanova V. MMP2 rs243866 and rs2285053 Polymorphisms and Alzheime r's Disease Risk in Slovak Caucasian Population. Life (Basel). 2023;13(4):882. doi:10.3390/life13040882 152. Peress NS, Perillo E. Differential ex pression of TGF-beta 1, 2 and 3 isotypes in Alzheimer's disease: a comparative immunohistochemical study with cerebral infarction, aged human and mouse control brains. J Neuropathol Exp Neurol. 1995;54(6):802-811. doi: 10.1097/00005072- 199511000-00007 153. Jafarian Z, Saliminejad K, Kamali K, Ohadi M, Kowsari A, Nasehi L, Khorram Khorshid HR. Association of glutathione S-transferases M1, P1 and T1 variations and risk of late-ons et Alzheimer's disease. Neurol Res. 2018;40(1):41-44. doi:10.1080/01616412.2017.1390902 154. Arfaei R, Mikaeili N, Daj F, Boroumand A, Kheyri A, Yaraghi P, Shirzad Z, Keshavarz M, Hassanshahi G, Jafarzadeh A, et al. Decoding the role of the CCL2/CCR2 axis in Alzheimer's disease and innovating therapeutic approaches: Keeping All options open. Int Immunopharmacol. 2024;135:112328. doi:10.1016/j.intimp.2024.112328 155. Wang L, Zhou BQ, Li YH, Jiang QQ, Cong WH, Chen KJ, Wen XM, Wu ZZ. Lactoferrin modification of berberine nanoliposomes enhances the neuroprotective effects in a mouse model of Alzheimer's disease. Neural Regen Res. 2023;18(1):226-232. doi:10.4103/1673-5374.344841 156. Lee JH, Gurney S, Pang D, Temkin A, Park N, Janicki SC, Zigman WB, Silverman W, Tycko B, Schupf N. Polymorphisms in HSD17B1: Early Onset and Increased Risk of Alzheimer's Disease in Women with Down Syndrome. Curr Gerontol Geriatr Res. 2012;2012:361218. doi:10.1155/2012/361218 157. Shigemizu D, Fukunaga K, Yamakawa A, Suganuma M, Fujita K, Kimura T, Watanabe K, Mushiroda T, Sakurai T, Niida S, et al. The HLA- DRB1*09:01-DQB1*03:03 haplotype is asso ciated with the risk for late- onset Alzheimer's disease in APOE [Formula: see text]4-negative Japanese adults. NPJ Aging. 2024;10(1):3. doi:10.1038/s41514-023-00131-3 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 158. King A, Szekely B, Calapkulu E, Al i H, Rios F, Jones S, Troakes C. The Increased Densities, But Different Distributions, of Both C3 and S100A10 Immunopositive Astrocyte-Like Cells in Alzheimer's Disease Brains Suggest Possible Roles for Both A1 and A2 Astrocytes in the Disease Pathogenesis. Brain Sci. 2020;10(8):503. doi:10.3390/brainsci10080503 159. Al Rahim M, Yoon Y, Dimovasili C, Shao Z, Huang Q, Zhang E, Kezunovic N, Chen L, Schaffner A, Huntley GW, et al. Presenilin1 familial Alzheimer disease mutants inactivate EFNB1- and BDNF-dependent neuroprotection against excitotoxicity by affecting neuroprotective complexes of N-methyl-d-aspartate receptor. Brain Commun. 2020;2(2):fcaa100. doi:10.1093/braincomms/fcaa100 160. Adams SL, Benayoun L, Tilton K, Mellott TJ, Seshadri S, Blusztajn JK, Delalle I.Immunohistochemical Analysis of Activin Receptor-Like Kinase 1 (ACVRL1/AL K1) Expression in the Rat and Human Hippocampus: Decline in CA3 During Progression of Alzheimer's Disease. J Alzheimers Dis. 2018;63(4):1433-1443. doi:10.3233/JAD-171065 161. Sun L, Guo C, Song Y, Sheng J, Xiao S; Alzheimer’s Disease Neuroimaging Initiative. Blood BMP6 Associated with Cognitive Performance and Alzheimer's Disease Diagnosis: A Long itudinal Study of Elders. J Alzheimers Dis. 2022;88(2):641-651. doi:10.3233/JAD-220279 162. Eftekharzadeh M, Simorgh S, Doshmanziari M, Hassanzadeh L, Shariatpanahi M. Human adipose-derived stem cells reduce receptor- interacting protein 1, receptor-interacting protein 3, and mixed lineage kinase domain-like pseudokinase as necroptotic markers in rat model of Alzheimer's disease. Indian J Pharmacol. 2020;52(5):392-401. doi:10.4103/ijp.IJP_545_19 163. Siokas V, Mouliou DS, Liampas I, Aloizou AM, Folia V, Zoupa E, Papadimitriou A, Lavdas E, Bogdanos DP, Dardiotis E. Analysis of ADORA2A rs5760423 and CYP1A2 rs762551 Genetic Variants in Patients with Alzheimer's Disease. Int J Mol Sci. 2022;23(22):14400. doi:10.3390/ijms232214400 164. Sita G, Hrelia P, Tarozzi A, Mo rroni F. P-glycoprotein (ABCB1) and Oxidative Stress: Focus on Alzheimer's Disease. Oxid Med Cell Longev. 2017;2017:7905486. doi:10.1155/2017/7905486 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 165. Cheng J, Liu HP, Lee CC, Chen MY, Lin WY, Tsai FJ. Matrix metalloproteinase 14 modulates diabetes and Alzheimer's disease cross-talk: a meta-analysis. Neurol Sci. 2018;39(2):267-274. doi:10.1007/s10072-017- 3166-4 166. Merchant JP, Zhu K, Henrion MY R, Zaidi SSA, Lau B, Moein S, Alamprese ML, Pearse RV 2nd, Bennett DA, Ertekin-Taner N, et al. Predictive network analysis identifies JMJD6 and other potential key drivers in Alzheimer's disease. Commun Biol. 2023;6(1):503. doi: 10.1038/s42003- 023-04791-5 167. Pons V, Lévesque P, Plante MM, Rivest S. Conditional genetic deletion of CSF1 receptor in microglia ameliorates the physiopathology of Alzheimer's disease. Alzheimers Res Ther. 2021;13(1):8. doi:10.1186/s13195-020-00747-7 168. Yang HS, Yau WW, Carlyle BC, Trombetta BA, Zhang C, Shirzadi Z, Schultz AP, Pruzin JJ, Fitzpatrick CD, Kirn DR, et al. Plasma VEGFA and PGF impact longitudinal tau and cognition in preclinical Alzheimer's disease. Brain. 2024;147(6):2158-2168. doi:10.1093/brain/awae034 169. Wang T, Zhou YQ, Wang Y, Zhang L, Zhu X, Wang XY, Wang JH, Han LK, Meng J, Zhang X, et al. Long-term potentiation-based screening identifies neuronal PYGM as a synaptic plasticity regulator participating in Alzheimer's disease. Zool Res. 2023;44(5):867-881. doi:10.24272/j.issn.2095-8137.2023.123 170. Matchett BJ, Lincoln SJ, Baker M, Tamvaka N, Labuzan SA, Hicks Sirmans TN, Moloney CM, Helminger J, Hinkle KM, Cabrera-Rodriguez J, et al. The SERPINA5 coding variant E228Q does not contribute to clinicopathologic characteristics in Alzheimer's disease: A cross-sectional study. Medicine (Baltimore). 2023;102(24):e34017. doi:10.1097/MD.0000000000034017 171. Rudan Njavro J, Klotz J, Dislich B, Wanngren J, Shmueli MD, Herber J, Kuhn PH, Kumar R, Koeglsperger T, Conrad M, et al. Mouse brain proteomics establishes MDGA1 and CACHD1 as in vivo substrates of the Alzheimer protease BACE1. FASEB J. 2020;34(2):2465-2482. doi:10.1096/fj.201902347R 172. Tosto G, Fu H, Vardarajan BN, Lee JH, Cheng R, Reyes-Dumeyer D, Lantigua R, Medrano M, Jimenez-Velazquez IZ, Elkind MS, et al. F- (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint box/LRR-repeat protein 7 is genetically associated with Alzheimer's disease. Ann Clin Transl Neurol. 2015;2(8):810-820. doi:10.1002/acn3.223 173. Beckmann ND, Lin WJ, Wang M, Cohain AT, Charney AW, Wang P, Ma W, Wang YC, Jiang C, Audrain M, et al. Multiscale causal networks identify VGF as a key regulator of Alzheimer's disease. Nat Commun. 2020;11(1):3942. doi:10.1038/s41467-020-17405-z 174. Franzmeier N, Dehsarvi A, Steward A, Biel D, Dewenter A, Roemer SN, Wagner F, Groß M, Brendel M, Moscoso A, et al. Elevated CSF GAP- 43 is associated with accelerated tau accumulation and spread in Alzheimer's disease. Nat Commun. 2024;15(1):202. doi:10.1038/s41467-023-44374-w 175. Doert A, Pilatus U, Zanella F, Müller WE, Eckert GP. ¹H- and ¹³C- NMR spectroscopy of Thy-1-APPSL mice brain extracts indicates metabolic changes in Alzheimer's disease. J Neural Transm (Vienna). 2015;122(4):541-550. doi:10.1007/s00702-015-1387-3 176. Agra Almeida Quadros AR, Li Z, Wang X, Ndayambaje IS, Aryal S, Ramesh N, Nolan M, Jayakumar R, Han Y, Stillman H, et al. Cryptic splicing of stathmin-2 and UNC13A mR NAs is a pathological hallmark of TDP-43-associated Alzheimer's diseas e. Acta Neuropathol. 2024;147(1):9. doi:10.1007/s00401-023-02655-0 177. Dauar MT, Picard C, Labonté A, Breitner J, Rosa-Neto P, Villeneuve S, Poirier J; PREVENT-AD Research Group. Contactin 5 and Apolipoproteins Interplay in Alzheimer's Disease. J Alzheimers Dis. 2024;98(4):1361-1375. doi:10.3233/JAD-231003 178. Satoh J, Yamamoto Y, Asahina N, Kitano S, Kino Y. RNA-Seq data mining: downregulation of NeuroD6 serves as a possible biomarker for alzheimer's disease brains . Dis Markers. 2014;2014:123165. doi:10.1155/2014/123165 179. Emilsson L, Saetre P, Jazin E. Low mRNA levels of RGS4 splice variants in Alzheimer's disease: association between a rare haplotype and decreased mRNA expression. Synapse. 2006;59(3):173-176. doi:10.1002/syn.20226 180. Lee JH, Koh SQ, Guadagna S, Francis PT, Esiri MM, Chen CP, Wong PT, Dawe GS, Lai MK. Altered relaxin family receptors RXFP1 and RXFP3 in the neocortex of depressed Alzheimer's disease patients. (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Psychopharmacology (Berl). 2016;233(4):591-598. doi: 10.1007/s00213- 015-4131-7 181. Shi Z, Zhang K, Zhou H, Jiang L, Xie B, Wang R, Xia W, Yin Y, Gao Z, Cui D, et al. Increased miR-34c medi ates synaptic deficits by targeting synaptotagmin 1 through ROS-JNK-p53 pathway in Alzheimer's Disease. Aging Cell. 2020;19(3):e13125. doi:10.1111/acel.13125 182. Wang Q, Tao S, Xing L, Liu J, Xu C, Xu X, Ding H, Shen Q, Yu X, Zheng Y. SNAP25 is a potential target for early stage Alzheimer's disease and Parkinson's disease. Eu r J Med Res. 2023;28(1):570. doi:10.1186/s40001-023-01360-8 183. Ruzha Y, Ni J, Quan Z, Li H, Qing H. Role of Vitronectin and Its Receptors in Neuronal Function and Neurodegenerative Diseases. Int J Mol Sci. 2022;23(20):12387. doi:10.3390/ijms232012387 184. W a n g L , J i n g R , W a n g X , W a n g B , G u o K , Z h a o J , G a o S , X u N , Xuan X. A method for the expression of fibroblast growth factor 14 and assessment of its neuroprotective effect in an Alzheimer's disease model. Ann Transl Med. 2021;9(12):994. doi:10.21037/atm-21-2492 185. Ren J, Zhang S, Wang X, Deng Y, Zhao Y, Xiao Y, Liu J, Chu L, Qi X. MEF2C ameliorates learning, memory, and molecular pathological changes in Alzheimer’s disease in vivo and in vitro. Acta Biochim Biophys Sin (Shanghai). 2022;54(1):77-90. doi:10.3724/abbs.2021012 186. Hurst C, Pugh DA, Abreha MH, Duong DM, Dammer EB, Bennett DA, Herskowitz JH, Seyfried NT. Integrated Proteomics to Understand the Role of Neuritin (NRN1) as a Mediator of Cognitive Resilience to Alzheimer's Disease. Mol Cell Proteomics. 2023;22(5):100542. doi:10.1016/j.mcpro.2023.100542 187. Wang J, Zhou C, Huang Z, et al. Repetitive Transcranial Magnetic Stimulation-Mediated Neuroprotec tion in the 5xFAD Mouse Model of Alzheimer's Disease Through GA BRG2 and SNAP25 Modulation. Mol Neurobiol. 2024. doi:10.1007/s12035-024-04354-7 188. Datta D, Perone I, Morozov YM, Ar ellano J, Duque A, Rakic P, van Dyck CH, Arnsten AFT. Localizatio n of PDE4D, HCN1 channels, and mGluR3 in rhesus macaque entorhinal cortex may confer vulnerability in Alzheimer's disease. Cereb Cortex. 2023;33(24):11501-11516. doi:10.1093/cercor/bhad382 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 189. Hu D, Dong X, Wang Q, Liu M, Luo S, Meng Z, Feng Z, Zhou W, Song W. PCP4 Promotes Alzheimer' s Disease Pathogenesis by Affecting Amyloid-β Protein Precursor Processing. J Alzheimers Dis. 2023;94(2):737- 750. doi:10.3233/JAD-230192 190. Nguyen DPQ, Pham S, Jallow AW, Ho NT, Le B, Quang HT, Lin YF, Lin YF. Multiple Transcriptomic Analyses Explore Potential Synaptic Biomarker Rabphilin-3A for Alzh eimer's Disease. Sci Rep. 2024;14(1):18717. doi:10.1038/s41598-024-66693-8 191. Sheu JJ, Yang LY, Sanotra MR, Wang ST, Lu HT, Kam RSY, Hsu IU, Kao SH, Lee CK, Shieh JC, et al. Reduction of AHI1 in the serum of Taiwanese with probable Alzheimer's disease. Clin Biochem. 2020;76:24- 30. doi:10.1016/j.clinbiochem.2019.11.011 192. Zhang N, Sui Y, Jendrichovsky P, Feng H, Shi H, Zhang X, Xu S, Sun W, Zhang H, Chen X, et al. Cholecystokinin B receptor agonists alleviates anterograde amnesia in cholecystokinin-deficient and aged Alzheimer's disease mice. Alzheimers Res Ther. 2024;16(1):109. doi:10.1186/s13195-024-01472-1 193. van Abel D, Michel O, Veerhuis R, Jacobs M, van Dijk M, Oudejans CB. Direct downregulation of CNTNAP2 by STOX1A is associated with Alzheimer's disease. J Alzheimers Dis. 2012;31(4):793-800. doi:10.3233/JAD-2012-120472 194. Berrocal M, Saez L, Mata AM. Sorcin Activates the Brain PMCA and Blocks the Inhibitory Effects of Molecular Markers of Alzheimer's Disease on the Pump Activity. Int J Mol Sci. 2021;22(11):6055. doi:10.3390/ijms22116055 195. Lehrer S, Rheinstein PH. RORB, an Alzheimer's disease susceptibility gene, is associated with viral encephalitis, an Alzheimer's disease risk factor. Clin Neurol Neurosurg. 2023;233:107984. doi:10.1016/j.clineuro.2023.107984 196. McPhie DL, Coopersmith R, Hines-Peralta A, Chen Y, Ivins KJ, Manly SP, Kozlowski MR, Neve KA, Neve RL. DNA synthesis and neuronal apoptosis caused by familial Alzheimer disease mutants of the amyloid precursor protein are mediated by the p21 activated kinase PAK3. J Neurosci. 2003;23(17):6914-6927. doi: 10.1523/JNEUROSCI.23-17- 06914.2003 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 197. Good PF, Alapat D, Hsu A, Chu C, Perl D, Wen X, Burstein DE, Kohtz DS. A role for semaphorin 3A signaling in the degeneration of hippocampal neurons during Alzhei mer's disease. J Neurochem. 2004;91(3):716-736. doi:10.1111/j.1471-4159.2004.02766.x 198. Tramutola A, Di Domenico F, Barone E, Perluigi M, Butterfield DA. It Is All about (U)biquitin: Role of Altered Ubiquitin-Proteasome System and UCHL1 in Alzheimer Disease. Oxid Med Cell Longev. 2016;2016:2756068. doi:10.1155/2016/2756068 199. van der Linden RJ, Gerritsen JS, Liao M, Widomska J, Pearse RV 2nd, White FM, Franke B, Young-Pearse TL, Poelmans G. RNA-binding protein ELAVL4/HuD ameliorates Alzheimer's disease-related molecular changes in human iPSC-derived neurons. Prog Neurobiol. 2022;217:102316. doi:10.1016/j.pneurobio.2022.102316 200. Hu YT, Chen XL, Huang SH, Zhu QB , Yu SY, Shen Y, Sluiter A, Verhaagen J, Zhao J, Swaab D, et al. Early growth response-1 regulates acetylcholinesterase and its relation with the course of Alzheimer's disease. Brain Pathol. 2019;29(4):502-512. doi:10.1111/bpa.12688 201. Sanfilippo C, Giuliano L, Castrogi ovanni P, Imbesi R, Ulivieri M, Fazio F, Blennow K, Zetterberg H, Di Rosa M. Sex, Age, and Regional Differences in CHRM1 and CHRM3 Genes Expression Levels in the Human Brain Biopsies: Potential Targets for Alzheimer's Disease-related Sleep Disturbances. Curr Neuro pharmacol. 2023;21(3):740-760. doi:10.2174/1570159X21666221207091209 202. D'Andrea MR, Nagele RG. MAP-2 i mmunolabeling can distinguish diffuse from dense-core amyloid plaques in brains with Alzheimer's disease. Biotech Histochem. 2002;77(2):95-103. 203. Henderson MX, Sengupta M, Trojanowski JQ, Lee VMY. Alzheimer's disease tau is a prominent pathology in LRRK2 Parkinson's disease. Acta Neuropathol Commun. 2019;7(1):183. doi: 10.1186/s40478- 019-0836-x 204. C a i B , S h a o N , Y e T , Z h o u P , S i W , S o n g H , W a n g G , K o u J . Phosphorylation of MAP 1A regulates hyperphosphorylation of Tau in Alzheimer's disease model. Ne uropathol Appl Neurobiol. 2023;49(5):e12934. doi:10.1111/nan.12934 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 205. Yao J, Chen SRW. RyR2-dependent modulation of neuronal hyperactivity: A potential therapeutic target for treating Alzheimer's disease. J Physiol. 2024;602(8):1509-1518. doi:10.1113/JP283824 206. Martínez-Drudis L, Bérard M, Musiol D, Rivest S, Oueslati A. Pharmacological inhibition of PLK2 kinase activity mitigates cognitive decline but aggravates APP pathology in a sex-dependent manner in APP/PS1 mouse model of Alzheimer's disease. Heliyon. 2024;10(20):e39571. doi:10.1016/j.heliyon.2024.e39571 207. Shu L, Sun Q, Zhang Y, Xu Q, Guo J, Yan X, Tang B. The Association between C9orf72 Repeats and Risk of Alzheimer's Disease and Amyotrophic Lateral Sclerosis: A Meta-Analysis. Parkinsons Dis. 2016;2016:5731734. doi:10.1155/2016/5731734 208. S e v l e v e r D , Z o u F , M a L , C a r r asquillo S, Crump MG, Culley OJ, Hunter TA, Bisceglio GD, Younkin L, Allen M, et al. Genetically-controlled Vesicle-Associated Membrane Protein 1 expression may contribute to Alzheimer's pathophysiology and susceptibility. Mol Neurodegener. 2015;10:18. doi:10.1186/s13024-015-0015-x 209. Almeida VN. Somatostatin and the pathophysiology of Alzheimer's disease. Ageing Res Rev. 2024;96:102270. doi:10.1016/j.arr.2024.102270 210. Kumar P, Goettemoeller AM, Espinosa-Garcia C, Tobin BR, Tfaily A, Nelson RS, Natu A, Dammer EB, Santiago JV, Malepati S, et al. Native- state proteomics of Parvalbumin interneurons identifies unique molecular signatures and vulnerabilities to early Alzheimer's pathology. Nat Commun. 2024;15(1):2823. doi:10.1038/s41467-024-47028-7 211. Zhu M, Tang M, Du Y. Identification of TAC1 Associated with Alzheimer's Disease Using a Robust Rank Aggregation Approach. J Alzheimers Dis. 2023;91(4):1339-1349. doi:10.3233/JAD-220950 212. Seddighi S, Varma VR, An Y, Varma S, Beason-Held LL, Tanaka T, Kitner-Triolo MH, Kraut MA, Davatzikos C, Thambisetty M. SPARCL1 Accelerates Symptom Onset in Alzheimer's Disease and Influences Brain Structure and Function During Aging. J Alzheimers Dis. 2018;61(1):401- 414. doi:10.3233/JAD-170557 213. Ouellette AR, Neuner SM, Dumitrescu L, Anderson LC, Gatti DM, Mahoney ER, Bubier JA, Churchill G, Peters L, Huentelman MJ, et al. Cross-Species Analyses Identify Dlgap2 as a Regulator of Age-Related (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Cognitive Decline and Alzheimer's Dementia. Cell Rep. 2020;32(9):108091. doi:10.1016/j.celrep.2020.108091 214. Di Maio A, De Rosa A, Pelucchi S, Garofalo M, Marciano B, Nuzzo T, Gardoni F, Isidori AM, Di Luca M, Errico F, et al. Analysis of mRNA and Protein Levels of CAP2, DLG1 and ADAM10 Genes in Post-Mortem Brain of Schizophrenia, Parkinson's and Alzheimer's Disease Patients. Int J Mol Sci. 2022;23(3):1539. doi:10.3390/ijms23031539 215. Detrait E, Maurice T, Hanon E, Leclercq K, Lamberty Y. Lack of synaptic vesicle protein SV2B protects against amyloid- β/i2/i2/i2/i2/i2 -induced oxidative stress, cholinergic deficit and cognitive impairment in mice. Behav Brain Res. 2014;271:277-285. doi:10.1016/j.bbr.2014.06.013 216. Deng Y, Bi M, Delerue F, Forrest SL, Chan G, van der Hoven J, van Hummel A, Feiten AF, Lee S, Martinez-Valbuena I, et al. Loss of LAMP5 interneurons drives neuronal network dysfunction in Alzheimer's disease. Acta Neuropathol. 2022;144(4):637-650. doi:10.1007/s00401-022-02457-w 217. Davidsson P, Bogdanovic N, La nnfelt L, Blennow K. Reduced expression of amyloid precursor protein, presenilin-1 and rab3a in cortical brain regions in Alzheimer's disease. Dement Geriatr Cogn Disord. 2001;12(4):243-250. doi:10.1159/000051266 218. Lin CW, Chang LC, Tseng GC, Kirkwood CM, Sibille EL, Sweet RA. VSNL1 Co-Expression Networks in Aging Include Calcium Signaling, Synaptic Plasticity, and Alzheimer's Disease Pathways. Front Psychiatry. 2015;6:30. doi:10.3389/fpsyt.2015.00030 219. Zhuang X, Xia Y, Liu Y, Guo T, Xia Z, Wang Z, Zhang G. SCG5 and MITF may be novel markers of copper metabolism immunorelevance in Alzheimer's disease. Sc i Rep. 2024;14(1):13619. doi: 10.1038/s41598-024- 64599-z 220. Soosanabadi M, Bayat H, Kamali K, Saliminejad K, Banan M, Khorram Khorshid HR. Association Study of IL-4 -590 C/T and DDX39B - 22 G/C Polymorphisms with the Risk of Late-Onset Alzheimer's Disease in Iranian Population. Curr Aging Sci. 2015;8(3):276-281. doi:10.2174/187460980803151027125919 221. Zhu X, Rottkamp CA, Raina AK, Brewer GJ, Ghanbari HA, Boux H, Smith MA. Neuronal CDK7 in hippo campus is related to aging and (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Alzheimer disease. Neurobiol Aging. 2000;21(6):807-813. doi:10.1016/s0197-4580(00)00217-7 222. Zho u X, Wu X, Wang R, Han L , Li H, Zhao W. Mechanisms o f 3- Hydroxyl 3-Methylglutaryl CoA Reductase in Alzheimer's Disease. Int J Mol Sci. 2023;25(1):170. doi:10.3390/ijms25010170 223. Fu Y, Hsiao JH, Paxinos G, Halliday GM, Kim WS. ABCA5 regulates amyloid- β peptide production and is associated with Alzheimer's disease neuropathology. J Alzheimers Dis. 2015;43(3):857-869. doi:10.3233/JAD-141320 224. Wang J, Chen L, Wang Z, Zhang S, Ding D, Lin G, Zhang H, Boda VK, Kong D, Ortyl TC, et al. TRPC 3 suppression amel iorates synaptic dysfunctions and memory deficits in Al zheimer's disease. Preprint. bioRxiv. 2024;2024.09.16.611061. doi:10.1101/2024.09.16.611061 225. Dulewicz M, Kulczy ń ska-Przybik A, Słowik A, Borawska R, Mroczko B. Fatty Acid Binding Protein 3 (FABP3) and Apolipoprotein E4 (ApoE4) as Lipid Metabolism-Related Biomarkers of Alzheimer's Disease. J Clin Med. 2021;10(14):3009. doi:10.3390/jcm10143009 226. Zuo Y, Dang R, Peng H, Hu P, Yang Y. LL37-mtDNA regulates viability, apoptosis, inflammation, and autophagy in lipopolysaccharide- treated RLE-6TN cells by targeting Hsp90aa1. Open Life Sci. 2024;19(1):20220943. doi:10.1515/biol-2022-0943 227. Yu W, Ye H, Li Y, Bao X, Ni Y, Chen X, Sun Y, Chen A, Zhou W, Li J. Pneumocystis carinii infection drives upregulation of Fn1 expression that causes pulmonary fibrosis with an inflammatory response. Rev Iberoam Micol. 2024;41(1):17-26. doi:10.1016/j.riam.2024.04.002 228. Xu M, Li XY, Song L, Tao C, Fang J, Tao L. miR-484 targeting of Yap1-induced LPS-inhibited proliferat ion, and promoted apoptosis and inflammation in cardiomyocyte. Biosci Biotechnol Biochem. 2021;85(2):378-385. doi:10.1093/bbb/zbaa009 229. Qin WD, Mi SH, Li C, Wang GX, Zhang JN, Wang H, Zhang F, Ma Y, Wu DW, Zhang M. Low shear stress induced HMGB1 translocation and release via PECAM-1/PARP-1 pathway to induce inflammation response. PLoS One. 2015;10(3):e0120586. doi:10.1371/journal.pone.0120586 230. Mueller M, Zwinger L, Klaassen S, Poller W, Monserrat Iglesias L, Pablo Ochoa J, Klingel K, Landmesser U, Heidecker B. Severe heart failure (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint in the setting of inflammatory cardiom yopathy with likely pathogenic titin variant. Int J Cardiol Heart Vasc. 2022;39:100969. doi:10.1016/j.ijcha.2022.100969 231. S t o l f i C , T r o n c o n e E , M a r a f i n i I , M o n t e l e o n e G . R o l e o f T G F - B e t a and Smad7 in Gut Inflammation, Fi brosis and Cancer. Biomolecules. 2020;11(1):17. doi:10.3390/biom11010017 232. Zhao P, Sun L, Zhao C. TCF1/LEF1 triggers Wnt-dependent chemokine/cytokine-induced inflammation and cadherin pathways to drive T-ALL cell migration. Bioche m Biophys Rep. 2023;34:101457. doi:10.1016/j.bbrep.2023.101457 233. Park CJ, Lin PC, Zhou S, Barakat R, Bashir ST, Choi JM, Cacioppo JA, Oakley OR, Duffy DM, Lydon JP, et al. Progesterone Receptor Serves the Ovary as a Trigger of Ovulation and a Terminator of Inflammation. Cell Rep. 2020;31(2):107496. doi:10.1016/j.celrep.2020.03.060 234. Overstreet AC, Burge M, Bellar A, McMullen M, Czarnecki D, Huang E, Pathak V, Finney C, Vij R, Dasarathy S, et al. Evidence that extracellular HSPB1 contributes to inflammation in alcohol-associated hepatitis. Preprint. medRxiv. 2024;2024.09.06.24313193. doi:10.1101/2024.09.06.24313193 235. Yoo SA, Yoon HJ, Kim HS, Chae CB, De Falco S, Cho CS, Kim WU. Role of placenta growth factor and its receptor flt-1 in rheumatoid inflammation: a link between angiogenesis and inflammation. Arthritis Rheum. 2009;60(2):345-354. doi:10.1002/art.24289 236. Chawla M, Mukherjee T, Deka A, Chatterjee B, Sarkar UA, Singh AK, Kedia S, Lum J, Dhillon MK, Banoth B, et al. An epithelial Nfkb2 pathway exacerbates intestinal inflamma tion by supplementing latent RelA dimers to the canonical NF- κ B module. Proc Natl Acad Sci U S A. 2021;118(25):e2024828118. doi:10.1073/pnas.2024828118 237. Liu KL, Yang YC, Yao HT, Chia TW, Lu CY, Li CC, Tsai HJ, Lii CK, Chen HW. Docosahexaenoic acid inhibits inflammation via free fatty acid receptor FFA4, disruption of TAB2 interaction with TAK1/TAB1 and downregulation of ERK-dependent Egr-1 expression in EA.hy926 cells. Mol Nutr Food Res. 2016;60(2):430-443. doi:10.1002/mnfr.201500178 238. Knyazev E, Maltseva D, Raygorodskaya M, Shkurnikov M. HIF- Dependent NFATC1 Activation Upregulates ITGA5 and PLAUR in (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Intestinal Epithelium in Inflammatory Bowel Disease. Front Genet. 2021;12:791640. doi:10.3389/fgene.2021.791640 239. Larson KC, Lipko M, Dabrowski M, Draper MP. Gng12 is a novel negative regulator of LPS-induced inflammation in the microglial cell line BV-2. Inflamm Res. 2010;59(1):15-22. doi:10.1007/s00011-009-0062-2 240. Fu W, Hu W, Shi L, Mundra JJ, Xiao G, Dustin ML, Liu CJ. Foxo4- and Stat3-dependent IL-10 production by progranulin in regulatory T cells restrains inflammatory arthritis. FASEB J. 2017;31(4):1354-1367. doi:10.1096/fj.201601134R 241. Han W, Allam SA, Elsawa SF. GLI2-Mediated Inflammation in the Tumor Microenvironment. Adv Exp Med Biol. 2020;1263:55-65. doi:10.1007/978-3-030-44518-8_5 242. Baba H, Kimura N, Kanegane H, Miya F, Kosaki K, Morio T, Koike R. GATA2 deficiency of a novel missense variant with multiorgan inflammation. Rheumatology (Oxford). 2024;63(8):e226-e228. doi:10.1093/rheumatology/keae062 243. Chen J, Liu Y, Xia S, Ye X, Chen L. Annexin A2 (ANXA2) regulates the transcription and alternative splicing of inflammatory genes in renal tubular epithelial cells. BMC Genomics. 2022;23(1):544. doi:10.1186/s12864-022-08748-6 244. Kyoreva M, Li Y, Hoosenally M, Hardman-Smart J, Morrison K, Tosi I, Tolaini M, Barinaga G, Stockinger B, Mrowietz U, Nestle FO, et al. CYP1A1 Enzymatic Activity Influences Skin Inflammation Via Regulation of the AHR Pathway. J Invest Dermatol. 2021;141(6):1553-1563.e3. doi:10.1016/j.jid.2020.11.024 245. Wang X, Zheng Z, Caviglia JM, Corey KE, Herfel TM, Cai B, Masia R, Chung RT, Lefkowitch JH, Schwabe RF, et al. Hepatocyte TAZ/WWTR1 Promotes Inflammation and Fibrosis in Nonalcoholic Steatohepatitis. Cell Metab. 2016;24(6):848-862. doi:10.1016/j.cmet.2016.09.01 246. Lamkanfi M, Kanneganti TD. Caspase-7: a protease involved in apoptosis and inflammation. Int J Bi ochem Cell Biol. 2010;42(1):21-24. doi:10.1016/j.biocel.2009.09.013 247. Khan S, Mentrup HL, Novak EA, Siow VS, Wang Q, Crawford EC, Schneider C, Comerford TE 4th, Firek B, Rogers MB, Loughran P, et al. Cyclic GMP-AMP synthase contributes to epithelial homeostasis in (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint intestinal inflammation via Beclin-1-mediated autophagy. FASEB J. 2022;36(5):e22282. doi:10.1096/fj.202200138R 248. Hazell GG, Peachey AM, Teasdale JE, Sala-Newby GB, Angelini GD, Newby AC, White SJ. PI16 is a shear stress and inflammation-regulated inhibitor of MMP2. Sci Rep. 2016;6:39553. doi:10.1038/srep39553 249. Yamamura K, Uruno T, Shiraish i A, Tanaka Y, Ushijima M, Nakahara T, Watanabe M, Kido-Nakahara M, Tsuge I, Furue M, et al. The transcription factor EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induc tion. Nat Commun. 2017;8:13946. doi:10.1038/ncomms13946 250. Zhang T, Wu J, Ungvijanpunya N, Jackson-Weaver O, Gou Y, Feng J, Ho TV, Shen Y, Liu J, Richard S, et al. Smad6 Methylation Represses NFκ B Activation and Periodontal Inflammation. J Dent Res. 2018;97(7):810-819. doi:10.1177/0022034518755688 251. Chen Z, Liang Y, Lu Q, Nazar M, Mao Y, Aboragah A, Yang Z, Loor JJ. Cadmium promotes apoptosis and inflammation via the circ08409/miR- 133a/TGFB2 axis in bovine mammary epithelial cells and mouse mammary gland. Ecotoxicol Environ Saf. 2021;222:112477. doi:10.1016/j.ecoenv.2021.112477 252. Liu L, Huang S, Du Y, Zhou H, Zhang K, He J. Lats2 deficiency protects the heart against myocardial infarction by reducing inflammation and inhibiting mitochondrial fission and STING/p65 signaling. Int J Biol Sci. 2023;19(11):3428-3440. doi:10.7150/ijbs.84426 253. Zeng X, Tian G, Zhu J, Yang F, Zhang R, Li H, An Z, Li J, Song J, Jiang J, et al. Air pollution associated acute respiratory inflammation and modification by GSTM1 and GSTT1 gene polymorphisms: a panel study of healthy undergraduates. Environ Health. 2023;22(1):14. doi:10.1186/s12940-022-00954-9 254. Zhang K, Li Z, Lu Y, Xiang L, Sun J, Zhang H. Silencing of Vangl2 attenuates the inflammation promoted by Wnt5a via MAPK and NF- κ B pathway in chondrocytes. J Orthop Surg Res. 2021;16(1):136. doi:10.1186/s13018-021-02268-x 255. Lotem J, Levanon D, Negreanu V, Ba uer O, Hantisteanu S, Dicken J, Groner Y. Runx3 in Immunity, Infl ammation and Cancer. Adv Exp Med Biol. 2017;962:369-393. doi:10.1007/978-981-10-3233-2_23 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 256. Krause K, Sabat R, Witte-Händel E, Schulze A, Puhl V, Maurer M, Wolk K. Association of CCL2 with systemic inflammation in Schnitzler syndrome. Br J Dermatol. 2019;180(4):859-868. doi:10.1111/bjd.17334 257. Artym J, Zimecki M, Kruzel ML. Lactoferrin for Prevention and Treatment of Anemia and Inflammation in Pregnant Women: A Comprehensive Review. Biom edicines. 2021;9(8):898. doi:10.3390/biomedicines9080898 258. Yildirim S, Sengul E, Aksu EH, Cinar İ , Gelen V, Tekin S, Dag Y. Selenium reduces acrylamide-induced testicular toxicity in rats by regulating HSD17B1, StAR, and CYP17A1 expression, oxidative stress, inflammation, apoptosis, autophagy, and DNA damage. Environ Toxicol. 2024;39(3):1402- 1414. doi:10.1002/tox.23996 259. Portig I, Sandmoeller A, Kreilinger S, Maisch B. HLA-DQB1* polymorphism and associations with dilated cardiomyopathy, inflammatory dilated cardiomyopathy and myocarditis. Autoimmunity. 2009;42(1):33-40. doi:10.1080/08916930802258651 260. Mori T, Maeda N, Inoue K, Sekimo to R, Tsushima Y, Matsuda K, Yamaoka M, Suganami T, Nishizawa H, Ogawa Y, et al. A novel role for adipose ephrin-B1 in inflammatory response. PLoS One. 2013;8(10):e76199. doi:10.1371/journal.pone.0076199 261. Khadir A, Kavalakatt S, Dehbi M, Alarouj M, Bennakhi A, Tiss A, Elkum N. DUSP1 Is a Potential Marker of Chronic Inflammation in Arabs with Cardiovascular Diseases . Dis Markers. 2018;2018:9529621. doi:10.1155/2018/9529621 262. Huang MT, Chen YL, Lien CI, Liu WL, Hsu LC, Yagita H, Chiang BL. Notch Ligand DLL4 Alleviates Allergic Airway Inflammation via Induction of a Homeostatic Regulatory Pathway. Sci Rep. 2017;7:43535. doi:10.1038/srep43535 263. Verhamme FM, De Smet EG, Van Hooste W, Delanghe J, Verleden SE, Joos GF, Brusselle GG, Bracke KR. Bone morphogenetic protein 6 (BMP-6) modulates lung function, pul monary iron levels and cigarette smoke-induced inflammation. Muco sal Immunol. 2019;12(2):340-351. doi:10.1038/s41385-018-0116-2 264. Liu M, Zhang L, Marsboom G, Jambusaria A, Xiong S, Toth PT, Benevolenskaya EV, Rehman J, Malik AB. Sox17 is required for endothelial (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint regeneration following inflammation-induced vascular injury. Nat Commun. 2019;10(1):2126. doi:10.1038/s41467-019-10134-y 265. Baumgart S, Chen NM, Siveke JT, König A, Zhang JS, Singh SK, Wolf E, Bartkuhn M, Esposito I, Heßmann E, et al. Inflammation-induced NFATc1-STAT3 transcription comple x promotes pancreatic cancer initiation by KrasG12D. Cancer Discov. 2014;4(6):688-701. doi:10.1158/2159-8290.CD-13-0593 266. Xu H, Du X, Liu G, Huang S, Du W, Zou S, Tang D, Fan C, Xie Y, Wei Y, et al. The pseudokinase MLKL regulates hepatic insulin sensitivity independently of inflammati on. Mol Metab. 2019;23:14-23. doi:10.1016/j.molmet.2019.02.003 267. Jingjing H, Tongqian W, Shirong Y, Lan M, Jing L, Shihui M, Haijian Y, Fang Y. S100A4 promotes experime ntal autoimmune encephalomyelitis by impacting microglial inflammation through TLR4/NF- κ B signaling pathway. Int Immunopharmacol. 2024;142(Pt A):112849. doi:10.1016/j.intimp.2024.112849 268. Kubo T, Sato S, Hida T, Minowa T, Hirohashi Y, Tsukahara T, Kanaseki T, Murata K, Uhara H, Torigoe T. IL-13 modulates ∆ Np63 levels causing altered expression of barrier- and inflammation-related molecules in human keratinocytes: A possible explanation for chronicity of atopic dermatitis. Immun Inflamm Dis. 2021;9(3):734-745. doi:10.1002/iid3.427 269. Gao T, Zhu L, Liu H, Zhang X, Wang T, Fu Y, Li H, Dong Q, Hu Y, Zhang Z, et al. Highly pathogenic coronavirus N protein aggravates inflammation by MASP-2-mediated lectin complement pathway overactivation. Signal Transduct Target Ther. 2022;7(1):318. doi:10.1038/s41392-022-01133-5 270. Du J, Wei X, Ge X, Chen Y, Li YC. Microbiota-Dependent Induction of Colonic Cyp27b1 Is Associated With Colonic Inflammation: Implications of Locally Produced 1,25-Dihydroxyvitamin D3 in Inflammatory Regulation in the Colon. Endocrinology. 2017;158(11):4064-4075. doi:10.1210/en.2017-00578 271. Stoeltje L, Luc JK, Haddad T, Schrankel CS. The roles of ABCB1/P- glycoprotein drug transporters in regulating gut microbes and inflammation: insights from animal models, old and new. Philos Trans R Soc Lond B Biol Sci. 2024;379(1901):20230074. doi:10.1098/rstb.2023.0074 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 272. Brodzikowska A, Gondek A, Rak B, Paskal W, Pełka K, Cudnoch- Ję drzejewska A, Włodarski P. Metalloproteinase 14 (MMP-14) and hsa- miR-410-3p expression in human inflam ed dental pulp and odontoblasts. Histochem Cell Biol. 2019;152(5):345-353. doi:10.1007/s00418-019-01811- 6 273. Xu J, Jiang C, Cai Y, Guo Y, Wang X, Zhang J, Xu J, Xu K, Zhu W, Wang S, et al. Intervening upregulated SLC7A5 could mitigate inflammatory mediator by mTOR-P70S6K signal in rheumatoid arthritis synoviocytes. Arthritis Res Ther. 2020;22(1):200. doi: 10.1186/s13075-020- 02296-8 274. Mazrouei S, Ziaei A, Tanhaee AP, Keyhanian K, Esmaeili M, Baradaran A, Salehi M. Apoptosis inhibition or inflammation: the role of NAIP protein expression in Hodg kin and non-Hodgkin lymphomas compared to non-neoplastic lymph node. J Inflamm (Lond). 2012;9(1):4. doi:10.1186/1476-9255-9-4 275. Hsieh PC, Huang KL, Peng CK, Wu YK, Liu GT, Kuo CY, Wang MC, Lan CC. Aqueous extract of Descuraniae Semen attenuates lipopolysaccharide-induced inflammatio n by inhibiting ER stress and WNK4-SPAK-NKCC1 pathway. J Cell Mol Med. 2024;28(15):e18589. doi:10.1111/jcmm.18589 276. Zhang BS, Zhang XM, Ito M, Yajima S, Yoshida K, Ohno M, Nishi E, Wang H, Li SY, Kubota M, et al. JMJD6 Autoantibodies as a Potential Biomarker for Inflammation-Related Diseases. Int J Mol Sci. 2024;25(9):4935. doi:10.3390/ijms25094935 277. Lin L, Spoor MS, Gerth AJ, Brody SL, Peng SL. Modulation of Th1 activation and inflammation by the NF -kappaB repressor Foxj1. Science. 2004;303(5660):1017-1020. doi:10.1126/science.1093889 278. Jia Y, Pan J. CKLF1, transcriptionally activated by FOXC1, promotes hypoxia/reoxygenation/i2 induced oxidative stress and inflammation in H9c2 cells by NLRP3 inflammasome activation. Exp Ther Med. 2023;27(2):59. doi:10.3892/etm.2023.12347 279. Kalin TV, Meliton L, Meliton AY, Zhu X, Whitsett JA, Kalinichenko VV. Pulmonary mastocytosis and enhanced lung inflammation in mice heterozygous null for the Foxf1 gene. Am J Respir Cell Mol Biol. 2008;39(4):390-399. doi:10.1165/rcmb.2008-0044OC (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 280. Lin W, Xu D, Austin CD, Caplazi P, Senger K, Sun Y, Jeet S, Young J, Delarosa D, Suto E, et al. Func tion of CSF1 and IL34 in Macrophage Homeostasis, Inflammation, and Ca ncer. Front Immunol. 2019;10:2019. doi:10.3389/fimmu.2019.02019 281. Na YR, Jung D, Stakenborg M, Jang H, Gu GJ, Jeong MR, Suh SY, Kim HJ, Kwon YH, Sung TS, et al. Prostaglandin E2 receptor PTGER4- expressing macrophages promote intes tinal epithelial barrier regeneration upon inflammation. Gut. 2021;70(12):2249-2260. doi: 10.1136/gutjnl-2020- 322146 282. Meurer SK, Weiskirchen R. Endoglin: An 'Accessory' Receptor Regulating Blood Cell Development and Inflammation. Int J Mol Sci. 2020;21(23):9247. doi:10.3390/ijms21239247 283. L o n g C , L i u H , Z h a n W , C h e n L , W u A , Y a n g L , C h e n S . N u l l Function of Npr1 Disturbs Immune Response in Colonic Inflammation During Early Postnatal Stage. Inflammation. 2022;45(6):2419-2432. doi:10.1007/s10753-022-01702-4 284. Korhonen EA, Lampinen A, Giri H, Anisimov A, Kim M, Allen B, Fang S, D'Amico G, Sipilä TJ, Lohela M, et al. Tie1 controls angiopoietin function in vascular remodeling and inflammation. J Clin Invest. 2016;126(9):3495-3510. doi:10.1172/JCI84923 285. X u G , G o n g Y , L u F , W a n g B , Y a n g Z , C h e n L , M i n J , C h e n g C , Jiang T. Endothelin receptor B enhances liver injury and pro-inflammatory responses by increasing G-protein-coupled receptor kinase-2 expression in primary biliary cholangitis. Sci Rep. 2022;12(1):19772. doi:10.1038/s41598- 022-21816-x 286. Ahmad S, Wrennall JA, Goriounova AS, Sekhri M, Iskarpatyoti JA, Ghosh A, Abdelwahab SH, Voeller A, Rai M, Mahida RY, et al. pecific Inhibition of Orai1-mediated Calcium Signalling Resolves Inflammation and Clears Bacteria in an Acute Respiratory Distress Syndrome Model. Am J Respir Crit Care Med. 2024;209(6):703-715. doi: 10.1164/rccm.202308- 1393OC 287. Yin J, Wang C, Vogel U, Ma Y, Zhang Y, Wang H, Sun Z, Du S. Common variants of pro-inflammatory gene IL1B and interactions with PPP1R13L and POLR1G in relation to lung cancer among Northeast Chinese. Sci Rep. 2023;13(1):7352. doi:10.1038/s41598-023-34069-z (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 288. Lian X, Zhang X, Chen W, Xue F, Wang G. Dexmedetomidine mitigates neuroinflammation in an Alzheimer's disease mouse model via the miR-204-3p/FBXL7 signaling axis. Brain Res. 2024;1822:148612. doi:10.1016/j.brainres.2023.148612 289. Tu F, Wang X, Zhang X, Ha T, Wang Y, Fan M, Yang K, Gill PS, Ozment TR, Dai Y, et al. Novel Role of Endothelial Derived Exosomal HSPA12B in Regulating Macropha ge Inflammatory Responses in Polymicrobial Sepsis. Front Immunol. 2020;11:825. doi:10.3389/fimmu.2020.00825 290. Fairbanks CA, Peterson CD, Speltz RH, Riedl MS, Kitto KF, Dykstra JA, Braun PD, Sadahiro M, Salton SR, Vulchanova L. The VGF-derived peptide TLQP-21 contributes to infl ammatory and nerve injury-induced hypersensitivity. Pain. 2014;155(7):1229-1237. doi:10.1016/j.pain.2014.03.012 291. Kato N, Nemoto K, Arino H, Fujikawa K. Influence of peripheral inflammation on growth-associated phosphoprotein (GAP-43) expression in dorsal root ganglia and on nerve recove ry after crush injury. Neurosci Res. 2003;45(3):297-303. doi:10.1016/s0168-0102(02)00234-1 292. Yan S, Ju X, Lao J, et al. Overexpression of the Mas1 gene mitigated LPS-induced inflammatory injury in mammary epithelial cells by inhibiting the NF- κ B/MAPKs signaling pathways. Front Vet Sci. 2024;11:1446366. doi:10.3389/fvets.2024.1446366 293. J ó s v a y K , W i n t e r Z , K a t o n a R L , P e c z e L , M a r t o n A , B u h a l a A , Szakonyi G, Oláh Z, Vizler C. Besides neuro-imaging, the Thy1-YFP mouse could serve for visualizing experiment al tumours, inflammation and wound- healing. Sci Rep. 2014;4:6776. doi:10.1038/srep06776 294. Alrashdi B, Dawod B, Tacke S, Kuerten S, Côté PD, Marshall JS. Mice Heterozygous for the Sodium Ch annel Scn8a (Nav1.6) Have Reduced Inflammatory Responses During EAE and Following LPS Challenge. Front Immunol. 2021;12:533423. doi:10.3389/fimmu.2021.533423 295. Wang L, Li X, Song Y, Zhang L, Ye L, Zhou X, Song D, Huang D. NELL1 augments osteoge nesis and inhibits in flammation of human periodontal ligament stem cells induced by BMP9. J Periodontol. 2022;93(7):977-987. doi:10.1002/JPER.20-0517 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 296. Xie Z, Chan EC, Druey KM. R4 Regulator of G Protein Signaling (RGS) Proteins in Inflammation and Immunity. AAPS J. 2016;18(2):294- 304. doi:10.1208/s12248-015-9847-0 297. Leoncini S, De Felice C, Signorini C, Zollo G, Cortelazzo A, Durand T , G a l a n o J M , G u e r r a n t i R , R o s s i M , C i c c o l i L , e t a l . C y t o k i n e Dysregulation in MECP2- and CDKL5-Related Rett Syndrome: Relationships with Aberrant Redo x Homeostasis, Inflammation, and ω -3 PUFAs. Oxid Med Cell Longev. 2015;2015:421624. doi:10.1155/2015/421624 298. Mulder DJ, Pacheco I, Hurlbut DJ, Mak N, Furuta GT, MacLeod RJ, Justinich CJ. FGF9-induced prolifer ative response to eosinophilic inflammation in oesophagitis. Gut. 2009;58(2):166-173. doi:10.1136/gut.2008.157628 299. Duan XL, Guo Z, He YT, Li YX, Liu YN, Bai HH, Li HL, Hu XD, Suo ZW. SNAP25/syntaxin4/VAMP2/M unc18-1 Complexes in Spinal Dorsal Horn Contributed to Inflammatory Pain. Neuroscience. 2020;429:203-212. doi:10.1016/j.neuroscience.2020.01.003 300. Yang X, Lu L, Wu C, Zhang F. ATP2B1-AS1 exacerbates sepsis- induced cell apoptosis and inflamma tion by regulating miR-23a-3p/TLR4 axis. Allergol Immunopathol (Madr). 2023;51(2):17-26. doi:10.15586/aei.v51i2.782 301. Arnaud L, Benech P, Greetham L, Stephan D, Jimenez A, Jullien N, García-González L, Tsvetkov PO, Devred F, Sancho-Martinez I, et al. APOE4 drives inflammation in human astrocytes via TAGLN3 repression and NF- κ B activation. Cell Rep. 2022;40(7):111200. doi:10.1016/j.celrep.2022.111200 302. Ho TC, Yeh SI, Chen SL, Tsao YP. Integrin α v and Vitronectin Prime Macrophage-Related Inflammation and Contribute the Development of Dry Eye Disease. Int J Mol Sci. 2021;22(16):8410. doi:10.3390/ijms22168410 303. Wang D, Qian W, Wu D, Wu Y, Lu K, Zou G. METTL3 promotes microglial inflammation via MEF2C in spinal cord injury. Cell Tissue Res. 2024;395(2):189-197. doi:10.1007/s00441-023-03855-6 304. Sui J, Zhan L, Ji S, Wu W, Chen Y, Yun F, Liang W, Wang J, Cao M, Shen D, et al. Differential inflammation responses determine the variable (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint phenotypes of epilepsy induced by GABRG2 mutations. CNS Neurosci Ther. 2024;30(2):e14583. doi:10.1111/cns.14583 305. Acosta C, McMullan S, Djouhri L, Gao L, Watkins R, Berry C, Dempsey K, Lawson SN. HCN1 and HCN2 in Rat DRG neurons: levels in nociceptors and non-nociceptors, NT3-dependence and influence of CFA- induced skin inflammation on HCN2 and NT3 expression. PLoS One. 2012;7(12):e50442. doi:10.1371/journal.pone.0050442 306. Bencsics M, Bányai B, Ke H, Csépányi-Kömi R, Sasvári P, Dantzer F, Hanini N, Benk ő R, Horváth EM. PARP2 downregulation in T cells ameliorates lipopolysaccharide-induced in flammation of the large intestine. Front Immunol. 2023;14:1135410. doi:10.3389/fimmu.2023.1135410 307. Xia Q, Zhan G, Mao M, Zhao Y, Li X. TRIM45 causes neuronal damage by aggravating microglia-mediated neuroinflammation upon cerebral ischemia and reperfusion injury. Exp Mol Med. 2022;54(2):180- 193. doi:10.1038/s12276-022-00734-y 308. Chen M, Pan L, Chen D, Wu Y, Ye J, Li K, Zhang N, Xu J. PAK1 Promotes Inflammation Induced by Sepsis through the Snail/CXCL2 Signaling Pathway. ACS Inf ect Dis. 2024;10(4):1370-1378. doi:10.1021/acsinfecdis.4c00052 309. Chen Y, Wang B, Chen Y, Wu Q, Lai WF, Wei L, Nandakumar KS, Liu D. HAPLN1 Affects Cell Viability and Promotes the Pro-Inflammatory Phenotype of Fibroblast-Like Synoviocytes. Front Immunol. 2022;13:888612. doi:10.3389/fimmu.2022.888612 310. Zhang Q, Zhou L, Xie H, Zhang H, Gao X. HAGLR aggravates neuropathic pain and promotes infla mmatory response and apoptosis of lipopolysaccharide-treated SH-SY5Y cells by sequestering miR-182-5p from ATAT1 and activating NLRP3 inflammasome. Neurochem Int. 2021;145:105001. doi:10.1016/j.neuint.2021.105001 311. Tuysuz EC, Mourati E, Rosberg R, Moskal A, Gialeli C, Johansson E, Governa V, Belting M, Pietras A, Blom AM. Tumor suppressor role of the complement inhibitor CSMD1 and its role in TNF-induced neuroinflammation in gliomas. J Exp Clin Cancer Res. 2024;43(1):98. doi:10.1186/s13046-024-03019-6 312. Yi J, Bergstrom K, Fu J, Shan X, McDaniel JM, McGee S, Qu D, Houchen CW, Liu X, Xia L. Dclk1 in tuft cells promotes inflammation- (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint driven epithelial restitution and mitigates chronic colitis. Cell Death Differ. 2019;26(9):1656-1669. doi:10.1038/s41418-018-0237-x 313. Yun JH, Lee C, Liu T, Liu S, Kim EY, Xu S, Curtis JL, Pinello L, Bowler RP, Silverman EK, et al. Hedg ehog interacting protein-expressing lung fibroblasts s uppress lymphocytic inflammation in mice. JCI Insight. 2021;6(17):e144575. doi:10.1172/jci.insight.144575 314. Sun H, Li Z, Fan C, Liu S, Yan K, Huang G, Li S. Slit guidance ligand 2 promotes the inflammatory response of periodontitis through activation of the NF- κ B signaling pathway. J Periodontal Res. 2022;57(3):578-586. doi:10.1111/jre.12987 315. Zhang S, Cheng L, Su Y, Qian Z, Wang Z, Chen C, Li R, Zhang A, He J, Mao J, et al. AGBL4 promotes malignant progression of glioblastoma via modulation of MMP-1 and inflammatory pathways. Front Immunol. 2024;15:1420182. Published 2024 Jun 28. doi:10.3389/fimmu.2024.1420182 316. Rienks M, Carai P, Bitsch N, Schellings M, Vanhaverbeke M, Verjans J, Cuijpers I, Heymans S, Papageorgiou A. Sema3A promotes the resolution of cardiac inflammation after myocardial infarction. Basic Res Cardiol. 2017;112(4):42. doi:10.1007/s00395-017-0630-5 317. Zhang Z, Liu N, Chen X, Zhang F, Kong T, Tang X, Yang Q, Chen W, Xiong X, Chen X. UCHL1 regulates inflammation via MAPK and NF- κ B pathways in LPS-activated macrophages. Cell Biol Int. 2021;45(10):2107-2117. doi:10.1002/cbin.11662 318. Lehman CW, Smith A, Kelly J, Jacobs JL, Dinman JD, Kehn-Hall K. EGR1 Upregulation during Encephalitic Viral Infections Contributes to Inflammation and Cell Death. Viruses. 2022;14(6):1210. doi:10.3390/v14061210 319. Isidro-Hernández M, Mayado A, Casado-García A, Martínez-Cano J, Palmi C, Fazio G, Orfao A, Ribera J, Ribera JM, Zamora L, et al. Inhibition of inflammatory signaling in Pax5 mutant cells mitigates B-cell leukemogenesis. Sci Rep. 2020;10(1):19189. doi: 10.1038/s41598-020- 76206-y 320. Zhang X, Chen W, Liu W, Li D, Shen W. CITED2 alleviates lipopolysaccharide-induced inflammation and pyroptosis in - human lung (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint fibroblast by inhibition of NF- κ B pathway. Allergol Immunopathol (Madr). 2022;50(4):64-70. doi:10.15586/aei.v50i4.628 321. Huan Z, Tang Y, Xu C, Cai J, Yao H, Wang Y, Bu F, Ge X. PTPRO knockdown protects against inflammation in hemorrhage shock-induced lung injury involving the NF- κ B signaling pathway. Respir Res. 2022;23(1):195. doi:10.1186/s12931-022-02118-2 322. Cabezudo D, Baekelandt V, Lobbestael E. Multiple-Hit Hypothesis in Parkinson's Disease: LRRK2 and Inflammation. Front Neurosci. 2020;14:376. doi:10.3389/fnins.2020.00376 323. Marchese E, Valentini M, Di Sante G, Cesari E, Adinolfi A, Corvino V, Ria F, Sette C, Geloso MC. Alternative splicing of neurexins 1-3 is modulated by neuroinflammation in the prefrontal cortex of a murine model of multiple sclerosis. Exp Neurol. 2021;335:113497. doi:10.1016/j.expneurol.2020.113497 324. Luo Q, Jahangir A, He J, Huang C, Xia Y, Jia L, Wei X, Pan T, Du Y, Mu B, et al. Ameliorating Effects of TRIM67 against Intestinal Inflammation and Barrier Dysfunction Induced by High Fat Diet in Obese Mice. Int J Mol Sci. 2022;23(14):7650. doi:10.3390/ijms23147650 325. Panda S, Gekara NO. The deubi quitinase MYSM1 dampens NOD2- mediated inflammation and tissue damage by inactivating the RIP2 complex. Nat Commun. 2018;9(1):4654. doi:10.1038/s41467-018-07016-0 326. Karki P, Ke Y, Zhang CO, Li Y, Tian Y, Son S, Yoshimura A, Kaibuchi K, Birukov KG, Birukova AA. SOCS3-microtubule interaction via CLIP-170 and CLASP2 is critical for modulation of endothelial inflammation and lung injury. J Biol Chem. 2021;296:100239. doi:10.1074/jbc.RA120.014232 327. Kim DE, Byeon HE, Kim DH, Kim SG, Yim H. Plk2-mediated phosphorylation and translocalization of Nrf2 activates anti-inflammation through p53/Plk2/p21cip1 signaling in acute kidney injury. Cell Biol Toxicol. 2023;39(4):1509-1529. doi:10.1007/s10565-022-09741-1 328. Pang W, Hu F. C9ORF72 s uppresses JAK-STAT mediated inflammation. iScience. 2023;26(5):106579. doi:10.1016/j.isci.2023.106579 329. Hernández C, Arroba AI, Bogdanov P, Ramos H, Simó-Servat O, Simó R, Valverde AM. Effect of Topical Administration of Somatostatin on (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Retinal Inflammation and Neurodegenerat ion in an Experimental Model of Diabetes. J Clin Med. 2020;9(8):2579. doi:10.3390/jcm9082579 330. Miao Y, Wu S, Gong Z, Chen Y, Xue F, Liu K, Zou J, Feng Y, Li G. SPARCL1 promotes chondrocytes extracellular matrix degradation and inflammation in osteoarthritis via TNF/NF- κ B pathway. J Orthop Translat. 2024;46:116-128. doi:10.1016/j.jot.2024.02.009 331. Yang C, Blaize G, Marrocco R, Rouquié N, Bories C, Gador M, Mélique S, Joulia E, Benamar M, Dejean AS, et al. THEMIS enhances the magnitude of normal and neuroinflamma tory type 1 immune responses by promoting TCR-independent signals. Sci Signal. 2022;15(742):eabl5343. doi:10.1126/scisignal.abl5343 332. Tang W, Dong M, Teng F, Cui J, Zhu X, Wang W, Wuniqiemu T, Q i n J , Y i L , W a n g S , e t a l . T M T -based quantitative proteomics reveals suppression of SLC3A2 and ATP1A3 expression contributes to the inhibitory role of acupuncture on airw ay inflammation in an OVA-induced mouse asthma model. Biomed Pharmacother. 2021;134:111001. doi:10.1016/j.biopha.2020.111001 333. Shen C, Kuang Y, Xu S, Li R, Wang J, Zou Y, Wang C, Xu S, Liang L, Lin C, et al. Nitidine chloride inhibits fibroblast like synoviocytes- mediated rheumatoid synovial inflammation and joint destruction by targeting KCNH1. Int Immunopharmacol. 2021;101(Pt A):108273. doi:10.1016/j.intimp.2021.108273 334. Deng S, Guo A, Huang Z, Guan K, Zhu Y, Chan C, Gui J, Song C, Li X. The exploration of neuroinflammatory mechanism by which CRHR2 deficiency induced anxiety disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2024;128:110844. doi:10.1016/j.pnpbp.2023.110844 335. Zeng J, Wang Y, Luo Z, Chang LC, Yoo JS, Yan H, Choi Y, Xie X, Deverman BE, Gradinaru V, et al. TRIM9-Mediated Resolution of Neuroinflammation Confers Neuroprotection upon Ischemic Stroke in Mice. Cell Rep. 2023;42(8):113050. doi:10.1016/j.celrep.2023.113050 336. Yang X, He Z, Dong Q, Nai S, Duan X, Yu J, Zhao N, Du X, Chen L. Btbd8 deficiency reduces susceptibility to colitis by enhancing intestinal barrier function and suppressing inflammation. Front Immunol. 2024;15:1382661. doi:10.3389/fimmu.2024.1382661 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 337. Gracia-Maldonado G, Clark J, Burwinkel M, Greenslade B, Wunderlich M, Salomonis N, Leone D, Ga tti E, Pierre P, Kumar AR, et al. LAMP-5 is an essential inflammatory-signaling regulator and novel immunotherapy target for mixed lineage leukemia-rearranged acute leukemia. Haematologica. 2022;107(4):803-815. doi:10.3324/haematol.2020.257451 338. Sheng M, Huo S, Jia L, Weng Y, Liu W, Lin Y, Yu W. NUAK1 promotes metabolic dysfunction-associat ed steatohepatitis progression by activating Caspase 6-driven pyroptosis and inflammation. Hepatol Commun. 2024;8(7):e0479. doi:10.1097/HC9.0000000000000479 339. Xu Y, Zhan Y, Lew AM, Naik SH, Kershaw MH. Differential development of murine dendritic cells by GM-CSF versus Flt3 ligand has implications for inflammation and trafficking. J Immunol. 2007;179(11):7577-7584. doi:10.4049/jimmunol.179.11.7577 340. Chen TT, Wu SM, Ho SC, Chuang HC, Liu CY, Chan YF, Kuo LW, Feng PH, Liu WT, Chen KY, et al. Reduction Is Implicated in Abnormal Inflammation in COPD. Sci Rep. 2017;7:46667. doi:10.1038/srep46667 341. Huang J, Tang D, Cao Y, Wang Y, Long J, Wei L, Song H. Inhibition of PDE10A-Rescued TBI-Induced Neuroinflammation and Apoptosis through the cAMP/PKA/NLRP3 Pathway. Evid Based Complement Alternat Med. 2022;2022:3311250. doi:10.1155/2022/3311250 342. Zheng K, Zhang Y, Zhang C, Ye W, Ye C, Tan X, Xiong Y. PRMT8 Attenuates Cerebral Ischemia/Reperfusion Injury via Modulating Microglia Activation and Polarization to Suppress Neuroinflammation by Upregulating Lin28a. ACS Chem Neurosci. 2022;13(7):1096-1104. doi:10.1021/acschemneuro.2c00096 343. Zhang YX, Zhang XT, Li HJ, Zhou TF, Zhou AC, Zhong ZL, Liu YH, Yuan LL, Zhu HY, Luan D, et al. Antidepressant-like effects of helicid on a chronic unpredictable mild stre ss-induced depressi on rat model: Inhibiting the IKK/I κ Bα /NF-κ B pathway through NCALD to reduce inflammation. Int Immunopharmacol. 2021;93:107165. doi:10.1016/j.intimp.2020.107165 344. Hong H, Zeng Y, Jian W, Li L, Lin L, Mo Y, Liu M, Fang S, Xia Y. CDK7 inhibition suppresses rheumatoid arthritis inflammation via blockage (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint of NF- κ B activation and IL-1 β /IL-6 secretion. J Cell Mol Med. 2018;22(2):1292-1301. doi:10.1111/jcmm.13414 345. C h e n Y , K u H , Z h a o L , W h e e l e r D C , L i L C , L i Q , V a r g h e s e Z , Moorhead JF, Powis SH, Huang A, et al. Inflammatory stress induces statin resistance by disrupting 3-hydroxy- 3-methylglutaryl-CoA reductase feedback regulation. Arterioscler Thromb Vasc Biol. 2014;34(2):365-376. doi:10.1161/ATVBAHA.113.301301 346. Feng X, Lu J, Wu Y, Xu H. MiR-18a-3p improves cartilage matrix remodeling and inhibits inflammation in osteoarthritis by suppressing PDP1. J Physiol Sci. 2022;72(1):3. doi:10.1186/s12576-022-00827-3 347. Belgath AA, Emam AM, Taujanskas J, Bryce RA, Freeman S, Stratford IJ. Discovery of Potent Benzothiazole Inhibitors of Oxidoreductase NQO2, a Target for Inflammation and Cancer. Int J Mol Sci. 2024;25(22):12025. doi:10.3390/ijms252212025 348. Hua J, Gao Z, Zhong S, Wei B, Zhu J, Ying R. CISD1 protects against atherosclerosis by suppr essing lipid accumulation and inflammation via mediating Drp1. Biochem Biop hys Res Commun. 2021;577:80-88. doi:10.1016/j.bbrc.2021.08.023 349. Tubau-Juni N, Hontecillas R, Leber A, Maturavongsadit P, Chauhan J, Bassaganya-Riera J. First-in-class topical therapeutic omilancor ameliorates disease severity and inflammation through activation of LANCL2 pathway in psoriasi s. Sci Rep. 2021;11(1):19827. doi:10.1038/s41598-021-99349-y 350. J i n g C , D o n g m i n g Z , H o n g C , Q u a n N , S i s h i L , C a i x i a L . T R P C 3 Overexpression Promotes the Progression of Inflammation-Induced Preterm Labor and Inhibits T Cell Activation. Cell Physiol Biochem. 2018;45(1):378-388. doi:10.1159/000486912 351. Nguyen HC, Bu S, Nikfarjam S, Ra sheed B, Michels DCR, Singh A, Singh S, Marszal C, McGuire JJ, Feng Q, et al. Loss of fatty acid binding protein 3 ameliorates lipopolysaccharide-induced inflammation and endothelial dysfunction. J Biol Chem. 2023;299(3):102921. doi:10.1016/j.jbc.2023.102921 352. Zhu WS, Guo W, Zhu JN, Tang CM, Fu YH, Lin QX, Tan N, Shan ZX. Hsp90aa1: a novel target gene of miR-1 in cardiac ischemia/reperfusion injury. Sci Rep. 2016;6:24498. doi:10.1038/srep24498 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 353. Page MM, Ellis KL, Chan DC, Pang J, Hooper AJ, Bell DA, Burnett JR, Moses EK, Watts GF. A variant in the fibronectin (FN1) gene, rs1250229-T, is associated with decreased risk of coronary artery disease in familial hypercholesterolaemia. J Clin Lipidol. 2022;16(4):525-529. doi:10.1016/j.jacl.2022.05.065 354. Li TY, Su W, Li LL, Zhao XG, Yang N, Gai JX, Lv X, Zhang J, Huang MQ, Zhang Q, et al. Critical role of PAFR/YAP1 positive feedback loop in cardiac fibrosis. Acta Pharmacol Sin. 2022;43(11):2862-2872. doi:10.1038/s41401-022-00903-9 355. Elrayess MA, Talmud PJ. Platelet endothelial cell adhesion molecule- 1 (PECAM-1) & coronary heart diseas e. Indian J Med Res. 2005;121(2):77- 79. 356. Yuan J, Chen H, Ge D, Xu Y, Xu H, Yang Y, Gu M, Zhou Y, Zhu J, Ge T, et al. Mir-21 Promotes Cardiac Fibrosis After Myocardial Infarction Via Targeting Smad7. Cell Phys iol Biochem. 2017;42(6):2207-2219. doi:10.1159/000479995 357. Cho HM, Lee KH, Shen YM, Shin TJ, Ryu PD, Choi MC, Kang KS, Cho JY. Transplantation of hMSCs Genome Edited with LEF1 Improves Cardio-Protective Effects in Myocardial Infarction. Mol Ther Nucleic Acids. 2020;19:1186-1197. doi:10.1016/j.omtn.2020.01.007 358. Tian D, Qin Q, Liu R, Wang Z, Li X, Xu Q, Lv Q. Diagnostic Value of Circulating Progranulin and It s Receptor EphA2 in Predicting the Atheroma Burden in Patients with Coronary Artery Disease. Dis Markers. 2021;2021:6653501. doi:10.1155/2021/6653501 359. Wang Z, Li C, Sun X, Li Z, Li J, Wang L, Sun Y. Hypermethylation of miR-181b in monocytes is associated with coronary artery disease and promotes M1 polarized phenotype via PIAS1-KLF4 axis. Cardiovasc Diagn Ther. 2020;10(4):738-751. doi:10.21037/cdt-20-407 360. Bowers SLK, Meng Q, Kuwabara Y, Huo J, Minerath R, York AJ, Sargent MA, Prasad V, Saviola AJ, Galindo DC, et al. Col1a2-Deleted Mice Have Defective Type I Collagen and Secondary Reactive Cardiac Fibrosis with Altered Hypertrophic Dyna mics. Cells. 2023;12(17):2174. doi:10.3390/cells12172174 361. Kraemer BF, Mannell H, Lamkemeyer T, Franz-Wachtel M, Lindemann S. Heat-Shock Protein 27 (HSPB1) Is Upregulated and (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Phosphorylated in Human Platelets during ST-Elevation Myocardial Infarction. Int J Mol Sci. 2019;20(23):5968. doi:10.3390/ijms20235968 362. Mauricio R, Singh K, Sangha vi M, Ayers CR, Rohatgi A, Vongpatanasin W, de Lemos JA, Khera A. Soluble Fms-like tyrosine kinase- 1 (sFlt-1) is associated with subclinical and clinical atherosclerotic cardiovascular disease: The Dallas Heart Study. Atherosclerosis. 2022;346:46-52. doi:10.1016/j.atherosclerosis.2022.02.026 363. Deng Q, Wang X, Gao J, Xia X, Wang Y, Zhang Y, Chen Y. Growth restriction and congenital heart disease caused by a novel TAB2 mutation: A case report. Exp Ther Med. 2023;25(6):258. doi:10.3892/etm.2023.11957 364. Monaghan RM, Naylor RW, Flatman D, Kasher PR, Williams SG, Keavney BD. FLT4 causes developmental disorders of the cardiovascular and lymphovascular systems via pleiotropic molecular mechanisms. Cardiovasc Res. 2024;120(10):1164-1176. doi:10.1093/cvr/cvae104 365. Muiya NP, Wakil S, Al-Najai M, Tahir AI, Baz B, Andres E, Al- Boudari O, Al-Tassan N, Al-Shahid M, Meyer BF, et al. A study of the role of GATA2 gene polymorphism in corona ry artery disease risk traits. Gene. 2014;544(2):152-158. doi:10.1016/j.gene.2014.04.064 366. Ji Z, Guo J, Zhang R, Zuo W, Xu Y, Qu Y, Tao Z, Li X, Li Y, Yao Y, et al. ADAM8 deficiency in macropha ges promotes cardiac repair after myocardial infarction via ANXA2-mTOR-autophagy pathway. J Adv Res. 2024. doi:10.1016/j.jare.2024.07.037 367. Eskandari M, Awsat Mellati A, Mahmoodi K, Kamali K, Soltanpour MS. Association of the CYP1A1 rs4646903 polymorphism with susceptibility and severity of coronary artery disease. Mol Biol Res Commun. 2021;10(2):22-61. doi:10.22099/mbrc.2021.39141.1574 368. Zhang W, Zhang Y, Han L, Bo T, Qi Z, Zhong H, Xu H, Hu L, Chen S, Zhang S. Double-stranded DNA enhances platelet activation, thrombosis, and myocardial injury via cyclic GMP-AMP synthase. Cardiovasc Res. 2024. doi:10.1093/cvr/cvae218 369. Wang LY, Tan CS, Lai MKP, Hilal S. Factors Associated with RANTES, EMMPIRIN, MMP2 and MMP9, and the Association of These Biomarkers with Cardiovascular Disease in a Multi-Ethnic Population. J Clin Med. 2022;11(24):7281. doi:10.3390/jcm11247281 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 370. Sluimer JC. Metabolic and Shear Stress Regulate Endothelial Epas1 in Atherosclerosis. Circ Res. 2024;135(8):838-840. doi:10.1161/CIRCRESAHA.124.325131 371. Niu HM, Liu CL. The aberrant expression of Smad6 and TGF- β in obesity linked cardiac disease. Eur Rev Med Pharmacol Sci. 2017;21(1):138-142. 372. Rusu-Nastase EG, Lupan AM, Marinescu CI, Neculachi CA, Preda MB, Burlacu A. MiR-29a Increase in Aging May Function as a Compensatory Mechanism Against Cardiac Fibrosis Through SERPINH1 Downregulation. Front Card iovasc Med. 2022;8:810241. doi:10.3389/fcvm.2021.810241 373. Sobha SP, Kesavarao KE. Progonostic effect of GSTM1/GSTT1 polymorphism in determining cardiovascular diseases risk among type 2 diabetes patients in South Indi an population. Mol Biol Rep. 2023;50(8):6415-6423. doi:10.1007/s11033-023-08514-1 374. Su Z, Lu H, Jiang H, Zhu H, Li Z, Zhang P, Ni P, Shen H, Xu W, Xu H. IFN- γ -producing Th17 cells bias by HMGB1-T-bet/RUNX3 axis might contribute to progression of coronary artery atherosclerosis. Atherosclerosis. 2015;243(2):421-428. doi:10.1016/j.atherosclerosis.2015.09.037 375. Rodríguez I, Coto E, Reguero JR, González P, Andrés V, Lozano I, Martín M, Alvarez V, Morís C. Role of the CDKN1A/p21, CDKN1C/p57, and CDKN2A/p16 genes in the risk of atherosclerosis and myocardial infarction. Cell Cycle. 2007;6(5):620-625. doi:10.4161/cc.6.5.3927 376. Gholamalizadeh H, Ensan B, Sukhorukov VN, Sahebkar A. Targeting the CCL2-CCR2 signaling pathway: potential implications of statins beyond cardiovascular diseases. J Pharm Pharmacol. 2024;76(2):138-153. doi:10.1093/jpp/rgad112 377. Videm V, Dahl H, Wålberg LE, Wise th R. Functional polymorphisms in the LTF gene and risk of coronary artery stenosis. Hum Immunol. 2012;73(5):554-559. doi:10.1016/j.humimm.2012.02.014 378. W a n g W , M u r r a y B , T i c h n e l l C , G i l o t r a N A , Z i m m e r m a n S L , Gasperetti A, Scheel P, Tandri H, Calkins H, James CA. Clinical characteristics and risk stratification of desmoplakin cardiomyopathy. Europace. 2022;24(2):268-277. doi:10.1093/europace/euab183 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 379. Tulay P, Temel SG, Ergoren MC. Investigation of KCNQ1 polymorphisms as biomarkers for cardi ovascular diseases in the Turkish Cypriots for establishi ng preventative medical measures. Int J Biol Macromol. 2019;124:537-540. doi:10.1016/j.ijbiomac.2018.11.227 380. Cong L, Zhao L, Shi Y, Bai Y, Guo Z. Circ_0006476 modulates macrophage apoptosis through the miR-3074-5p/DLL4 axis: implications for Notch signalling pathway regulation in cardiovascular disease. Aging (Albany NY). 2024;16(16):11857-11876. doi:10.18632/aging.206049 381. Banach J, Gilewski W, Słomka A, Buszko K, Bła ż ejewski J, Karasek D, Rogowicz D, Ż ekanowska E, Sinkiewicz W. Bone morphogenetic protein 6-a possible new player in pathophysiology of heart failure. Clin Exp Pharmacol Physiol. 2016;43(12):1247-1250. doi:10.1111/1440-1681.12665 382. Lee JW, Lee CS, Son H, Lee J, Kang M, Chai J, Cho HJ, Kim HS. SOX17-mediated LPAR4 expression plays a pivotal role in cardiac development and regeneration after myocardial infarction. Exp Mol Med. 2023;55(7):1424-1436. doi:10.1038/s12276-023-01025-w 383. Rasheed A, Robichaud S, Nguyen MA, Geoffrion M, Wyatt H, Cottee ML, Dennison T, Pietrangelo A, Lee R, Lagace TA, et al. Loss of MLKL (Mixed Lineage Kinase Domain-Like Protein) Decreases Necrotic Core but Increases Macrophage Lipid Accumulation in Atherosclerosis. Arterioscler Thromb Vasc Biol. 2020;40(5):1155-1167. doi:10.1161/ATVBAHA.119.313640 384. Martínez-Campelo L, Blanco-Verea A, López-Fernández T, Martínez- Monzonís A, Buño A, Mazón P, Zamora P, Norton N, Reddy JS, Velasco- Ruiz A, et al. Meta-analysis of genome-wide association studies for cancer therapy-related cardiovascular dysfunction and functional mapping highlight an intergenic region close to TP63. Sci Rep. 2024;14(1):18413. doi:10.1038/s41598-024-69064-5 385. Catarino SJ, Boldt AB, Beltrame MH, Nisihara RM, Schafranski MD, de Messias-Reason IJ. Association of MASP2 polymorphisms and protein levels with rheumatic fever and rheumatic heart disease. Hum Immunol. 2014;75(12):1197-1202. doi:10.1016/j.humimm.2014.10.003 386. Li FF, Han Y, Shi S, Li X, Zhu XD, Zhou J, Shao QL, Li XQ, Liu SL. Characterization of Transcriptional Re pressor Gene MSX1 Variations for (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Possible Associations with Congenital Heart Diseases. PLoS One. 2015;10(11):e0142666. doi:10.1371/journal.pone.0142666 387. Zhai YJ, Liu P, He HR, Zheng XW, Wang Y, Yang QT, Dong YL, Lu J.The association of ADORA2A and ADORA2B polymorphisms with the risk and severity of chronic heart fail ure: a case-control study of a northern Chinese population. Int J Mol Sci. 2015;16(2):2732-2746. doi:10.3390/ijms16022732 388. Wilke RA, Simpson RU, Mukesh BN, Bhupathi SV, Dart RA, Ghebranious NR, McCarty CA. Genetic variation in CYP27B1 is associated with congestive heart failure in patients with hypertension. Pharmacogenomics. 2009;10(11):1789-1797. doi:10.2217/pgs.09.101 389. Bharath G, Vishnuprabu DP, Preethi L, Nagappan AS, Dhianeshwaran Isravanya RT, Bhaskar LV, Swaminathan N, Munirajan AK. SLCO1B1 and ABCB1 variants synergis tically influence the atorvastatin treatment response in South Indian coronary artery disease patients. Pharmacogenomics. 2022;23(12):683-694. doi:10.2217/pgs-2022-0044 390. Ray BK, Shakya A, Turk JR, Apte SS, Ray A. Induction of the MMP- 14 gene in macrophages of the atherosc lerotic plaque: role of SAF-1 in the induction process. Circ Res. 2004;95(11):1082-1090. doi:10.1161/01.RES.0000150046.48115.80 391. Zhang K, Wu M, Qin X, Wen P, Wu Y, Zhuang J. Asporin is a Potential Promising Biomarker for Common Heart Failure. DNA Cell Biol. 2021;40(2):303-315. doi:10.1089/dna.2020.5995 392. Guo Z, Hu YH, Feng GS, Valenzuela Ripoll C, Li ZZ, Cai SD, Wang QQ, Luo WW, Li Q, Liang LY, et al. JMJD6 protects against isoproterenol- induced cardiac hypertrophy via inhibition of NF- κ B activation by demethylating R149 of the p65 subunit. Acta Pharmacol Sin. 2023;44(9):1777-1789. doi:10.1038/s41401-023-01086-7 393. Chaptal MC, Maraninchi M, Musto G, Mancini J, Chtioui H, Dupont- Roussel J, Marlinge M, Fromonot J, Lalevee N, Mourre F, et al. Low Density Lipoprotein Cholesterol Decreases the Expression of Adenosine A2A Receptor and Lipid Rafts-Protein Flotillin-1: Insights on Cardiovascular Risk of Hyperchole sterolemia. Cells. 2024;13(6):488. doi:10.3390/cells13060488 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 394. Padua MB, Helm BM, Wells JR, Smith AM, Bellchambers HM, Sridhar A, Ware SM. Congenital hear t defects caused by FOXJ1. Hum Mol Genet. 2023;32(14):2335-2346. doi:10.1093/hmg/ddad065 395. Wei W, L i B, L i F , Sun K, Jiang X, Xu R. Variants in F OXC1 and FOXC2 identified in patients with conotruncal heart defects. Genomics. 2024;116(3):110840. doi:10.1016/j.ygeno.2024.110840 396. Jin D, Han F. FOXF1 ameliorates angiotensin II-induced cardiac fibrosis in cardiac fibroblasts through inhibiting the TGF- β 1/Smad3 signaling pathway. J Recept Signal Transduct Res. 2020;40(6):493-500. doi:10.1080/10799893.2020.1772299 397. Wang MX, Liu X, Li JM, Liu L, Lu W, Chen GC. Inhibition of CACNA1H can alleviate endoplasmic reticulum stress and reduce myocardial cell apoptosis caused by myocardial infarction. Eur Rev Med Pharmacol Sci. 2020;24(24):12887-12895. doi:10.26355/eurrev_202012_24192 398. Sjaarda J, Gerstein H, Chong M, Yusuf S, Meyre D, Anand SS, Hess S, Paré G. Blood CSF1 and CXCL12 as Causal Mediators of Coronary Artery Disease. J Am Coll Cardiol. 2018;72(3):300-310. doi:10.1016/j.jacc.2018.04.067 399. Vicen M, Igreja Sá IC, Tripská K, Vitverová B, Najmanová I, Eissazadeh S, Micuda S, Nachtigal P. Membrane and soluble endoglin role in cardiovascular and metabolic disorders related to metabolic syndrome. Cell Mol Life Sci. 2021;78(6):2405-2418. doi:10.1007/s00018-020-03701-w 400. Theis JL, Niaz T, Sundsbak RS, Fo garty ZC, Bamlet WR, Hagler DJ, Olson TM. CELSR1 Risk Alleles in Familial Bicuspid Aortic Valve and Hypoplastic Left Heart Syndrome. Circ Genom Precis Med. 2022;15(2):e003523. doi:10.1161/CIRCGEN.121.003523 401. Alaei Z, Zamani N, Rabbani B, Mahdieh N. TCAP gene is not a common cause of cardiomyopathy in Iranian patients. Eur J Med Res. 2023;28(1):376. doi:10.1186/s40001-023-01019-4 402. Huang Y, Li T, Gao S, Li S, Zhu X, Li Y, Liu D, Li W, Yang L, Liu K, et al. Investigating the role of NPR1 in dilated cardiomyopathy and its potential as a therapeutic target for glucocorticoid therapy. Front Pharmacol. 2023;14:1290253. doi:10.3389/fphar.2023.1290253 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 403. Fonseca J, Tomada N, Magalhães A, Rodrigues AR, Gouveia AM, Neves D. Effect of aging and cardiovascular risk factors on receptor Tie1 expression in human erectile tissu e. J Sex Med. 2015;12(4):876-886. doi:10.1111/jsm.12794 404. Scotland RL, Allen L, Hennings LJ, Post GR, Post SR. The ral exchange factor rgl2 promotes cardiomyocyte survival and inhibits cardiac fibrosis. PLoS One. 2013;8(9):e73599. doi:10.1371/journal.pone.0073599 405. Accornero F, van Berlo JH, Benard MJ, Lorenz JN, Carmeliet P, Molkentin JD. Placental growth factor regulates cardiac adaptation and hypertrophy through a paracrine mechanism. Circ Res. 2011;109(3):272- 280. doi:10.1161/CIRCRESAHA.111.240820 406. Edin ML, Hamedani BG, Gruzdev A, Graves JP, Lih FB, Arbes SJ 3rd, Singh R, Orjuela Leon AC, Bra dbury JA, DeGraff LM, et al. Epoxide hydrolase 1 (EPHX1) hydrolyzes epox yeicosanoids and impairs cardiac recovery after ischemia. J Biol Chem. 2018;293(9):3281-3292. doi:10.1074/jbc.RA117.000298 407. Bartoli F, Sabourin J. Cardiac Remodeling and Disease: Current Understanding of STIM1/Orai1-Mediated Store-Operated Ca2+ Entry in Cardiac Function and Pathology. Adv Exp Med Biol. 2017;993:523-534. doi:10.1007/978-3-319-57732-6_26 408. Zhou JJ, Li H, Qian YL, Quan RL, Chen XX, Li L, Li Y, Wang PH, Meng XM, Jing XL, et al. Nestin represents a potential marker of pulmonary vascular remodeling in pulmonary arterial hypertension associated with congenital heart disease. J Mol Cell Cardiol. 2020;149:41-53. doi:10.1016/j.yjmcc.2020.09.005 409. Mavroidis M, Athanasiadis NC, Rigas P, Kostavasili I, Kloukina I, Te Rijdt WP, Kavantzas N, Chaniotis D, van Tintelen JP, Skaliora I, et al.Desmin is essential for the structur e and function of the sinoatrial node: implications for increased arrhythm ogenesis. Am J Physiol Heart Circ Physiol. 2020;319(3):H557-H570. doi:10.1152/ajpheart.00594.2019 410. Wu Y, Huang T, Li X, Shen C, Ren H, Wang H, Wu T, Fu X, Deng S, Feng Z, et al. Retinol dehydrogenase 10 reduction mediated retinol metabolism disorder promotes diabetic cardiomyopathy in male mice. Nat Commun. 2023;14(1):1181. doi:10.1038/s41467-023-36837-x (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 411. Tulbah S, Alruwaili N, Alhashem A, Aljohany A, Alhadeq F, Brotons DCA, Alwadai A, Al-Hassnan ZN. Variable phenotype of a null PPP1R13L allele in children with dilated cardiomyopathy. Am J Med Genet A. 2024;194(1):59-63. doi:10.1002/ajmg.a.63402 412. Fan M, Yang K, Wang X, Wang Y, Tu F, Ha T, Liu L, Williams DL, Li C. Endothelial cell HSPA12B and yes-associated protein cooperatively regulate angiogenesis following myocardial infarction. JCI Insight. 2020;5(18):e139640. doi:10.1172/jci.insight.139640 413. Wei X, Ma X, Lu R, Bai G, Zhang J, Deng R, Gu N, Feng N, Guo X. Genetic variants in PCSK1 gene are associated with the risk of coronary artery disease in type 2 diabetes in a Chinese Han population: a case control study. PLoS One. 2014;9(1):e87168. doi:10.1371/journal.pone.0087168 414. Bai S, Wang X, Hou Y, Cui Y, Song Q, Du J, Zhang Y, Xu J. ncRNA-056298 Regulates GAP43 and Promotes Cardiac Intrinsic Autonomic Nerve Remodelling in a Canine Model of Atrial Fibrillation Induction after Ganglionated Plexus Ablation. Curr Med Chem. 2024. doi:10.2174/0109298673289298240129103537 415. Zhou G, Fan L, Li Z, Li J, Kou X, Xiao M, Gao M, Qu X. G protein- coupled receptor MAS1 induces an inhibitory effect on myocardial infarction-induced myocardial injury. Int J Biol Macromol. 2022;207:72-80. doi:10.1016/j.ijbiomac.2022.02.163 416. Li Y, Song D, Mao L, Abraham DM, Bursac N. Lack of Thy1 defines a pathogenic fraction of cardiac fibroblasts in heart failure. Biomaterials. 2020;236:119824. doi:10.1016/j.biomaterials.2020.119824 417. Frasier CR, Wagnon JL, Bao YO, McVeigh LG, Lopez-Santiago LF, Meisler MH, Isom LL. Cardiac arrhythmia in a mouse model of sodium channel SCN8A epileptic encephalopathy. Proc Natl Acad Sci U S A. 2016;113(45):12838-12843. doi:10.1073/pnas.1612746113 418. Borges JI, Suster MS, Lymperopou los A. Cardiac RGS Proteins in Human Heart Failure and Atrial Fibrillation: Focus on RGS4. Int J Mol Sci. 2023;24(7):6136. doi:10.3390/ijms24076136 419. Wingert J, Meinhardt E, Sasipong N, Pott M, Lederer C, de la Torre C , S t i c h t C , M o s t P , K a t u s H A , F r e y N , e t a l . C a r d i o m y o c y t e - s p e c i f i c RXFP1 overexpression protects against pressure overload-induced cardiac (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint dysfunction independently of relaxin. Biochem Pharmacol. 2024;225:116305. doi:10.1016/j.bcp.2024.116305 420. L o i M , B a s t i a n i n i S , C a n d i n i G , R i z z a r d i N , M e d i c i G , P a p a V , Gennaccaro L, Mottolese N, Tassinari M, Uguagliati B, et al. Cardiac Functional and Structural Abnormalities in a Mouse Model of CDKL5 Deficiency Disorder. Int J Mol Sci. 2023;24(6):5552. doi:10.3390/ijms24065552 421. Duong T, Austin TR, Brody JA, Shojaie A, Battle A, Bader JS, Hong YS, Ballantyne CM, Coresh J, Gerszten RE, et al. Circulating Blood Plasma Profiling Reveals Proteomic Signature and a Causal Role for SVEP1 in Sudden Cardiac Death. Circ Geno m Precis Med. 2024;17(5):e004494. doi:10.1161/CIRCGEN.123.004494 422. Lu QB, Fu X, Liu Y, Wang ZC, Liu SY, Li YC, Sun HJ. Disrupted cardiac fibroblast BCAA catabolism contributes to diabetic cardiomyopathy via a periostin/NAP1L2/SIRT3 axis. Ce ll Mol Biol Lett. 2023;28(1):93. doi:10.1186/s11658-023-00510-4 423. Accornero F, Schips TG, Petrosino JM, Gu SQ, Kanisicak O, van Berlo JH, Molkentin JD. BEX1 is an RNA-dependent mediator of cardiomyopathy. Nat Commun. 2017;8(1):1875. doi:10.1038/s41467-017- 02005-1 424. Shi HJ, Wang MW, Sun JT, Wang H, Li YF, Chen BR, Fan Y, Wang SB, Wang ZM, Wang QM, et al. A novel long noncoding RNA FAF inhibits apoptosis via upregulating FGF9 through PI3K/AKT signaling pathway in ischemia-hypoxia cardiomyocytes. J Cell Physiol. 2019;234(12):21973-21987. doi:10.1002/jcp.28760 425. Kulkarni S, Lenin M, Ramesh R, De lphine SCW, Velu K. Evaluation of Single-Nucleotide Polymorphisms of Transcription Factor 7-Like 2 and ATP2B1 Genes as Cardi ovascular Risk Predictors in Chronic Kidney Disease. Int J Appl Basic Med Res. 2019;9(4):221-225. doi:10.4103/ijabmr.IJABMR_92_19 426. P a n g Y , X u Y , C h e n Q , C h e n g K , L i n g Y , J a n g J , G e J , Z h u W . FLRT3 and TGF-β /SMAD4 signalling: Impacts on apoptosis, autophagy and ion channels in supraventricular tachycardia. J Cell Mol Med. 2024;28(7):e18237. doi:10.1111/jcmm.18237 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 427. Li Q, Zhao Y, Wu G, Chen S, Zhou Y, Li S, Zhou M, Fan Q, Pu J, Hong K, et al. De Novo FGF12 (Fibro blast Growth Factor 12) Functional Variation Is Potentially Associated With Idiopathic Ventricular Tachycardia. J Am Heart Assoc. 2017;6(8):e006130. doi:10.1161/JAHA.117.006130 428. Pereira AHM, Cardoso AC, Consonni SR, Oliveira RR, Saito A, Vaggione MLB, Matos-Souza JR, Carazzolle MF, Gonçalves A, Fernandes JL, et al. MEF2C repressor variant deregulation leads to cell cycle re-entry and development of heart failure. EBioMedicine. 2020;51:102571. doi:10.1016/j.ebiom.2019.11.032 429. Huang C, Zhang X, Wang S, Shen A, Xu T, Hou Y, Gao S, Xie Y, Zeng Y, Chen J, et al. PARP-2 mediates cardiomyocyte aging and damage induced by doxorubicin through SIRT1 Inhibition. Apoptosis. 2024;29(5- 6):816-834. doi:10.1007/s10495-023-01929-y 430. Wang Y, Wang S, Lei M, Boyett M, Tsui H, Liu W, Wang X. The p21-activated kinase 1 (Pak1) signalli ng pathway in cardiac disease: from mechanistic study to therapeutic exploration. Br J Pharmacol. 2018;175(8):1362-1374. doi:10.1111/bph.13872 431. Yan T, Song S, Sun W, Ge Y. HAPLN1 knockdown inhibits heart failure development via activating the PKA signaling pathway. BMC Cardiovasc Disord. 2024;24(1):197. doi:10.1186/s12872-024-03861-8 432. Hermida A, Jedraszak G, Ader F, Denjoy I, Fressart V, Maury P, Beyls C, Bloch A, Clerici G, Daire E, et al. Systematic analysis of SCN5A variants associated with inherited cardiac diseases. Heart Rhythm. 2024. doi:10.1016/j.hrthm.2024.08.018 433. Yang B, Zhao Y, Luo W, Zhu W, Jin L, Wang M, Ye L, Wang Y, Liang G. Macrophage DCLK1 promot es obesity-induced cardiomyopathy via activating RIP2/TAK1 signaling pathway. Cell Death Dis. 2023;14(7):419. doi:10.1038/s41419-023-05960-4 434. Shen J, Shentu J, Zhong C, Huang Q, Duan S. RNA splicing factor RBFOX2 is a key factor in the progression of cancer and cardiomyopathy. Clin Transl Med. 2024;14(9):e1788. doi:10.1002/ctm2.1788 435. Li X, Zheng S, Tan W, Chen H, Li X, Wu J, Luo T, Ren X, Pyle WG, Wang L, et al. Slit2 Protects Hearts Against Ischemia-Reperfusion Injury by Inhibiting Inflammatory Responses and Maintaining Myofilament (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Contractile Properties. Front Physiol. 2020;11:228. doi:10.3389/fphys.2020.00228 436. Ruiz-Velasco A, Raja R, Chen X, Ganenthiran H, Kaur N, Alatawi NHO, Miller JM, Abouleisa RRE, Ou Q, Zhao X, et al. Restored autophagy is protective against PAK3-induced cardiac dysfunction. iScience. 2023;26(6):106970. doi:10.1016/j.isci.2023.106970 437. Geng B, Wang X, Park KH, Lee KE, Kim J, Chen P, Zhou X, Tan T, Yang C, Zou X, et al. UCHL1 protects against ischemic heart injury via activating HIF-1 α signal pathway. Re dox Biol. 2022;52:102295. doi:10.1016/j.redox.2022.102295 438. Xiang M, Luo H, Wu J, Ren L, Ding X, Wu C, Chen J, Chen S, Zhang H, Yu L, et al. ADAM23 in Cardiomyocyte Inhibits Cardiac Hypertrophy by Targeting FAK - AKT Signaling. J Am Heart Assoc. 2018;7(18):e008604. doi:10.1161/JAHA.118.008604 439. Xie Y, Li Y, Chen J, Ding H, Zhang X. Early growth response-1: Key mediators of cell death and novel targets for cardiovascular disease therapy. Front Cardiovasc Med. 2023;10:1162662. doi:10.3389/fcvm.2023.1162662 440. Wang X, Guan Z, Tang W, Wang X, Xu C, Shan E, Wang W, Gao Y. PAX5/ITGAX Contributed to the Progression of Atherosclerosis by Regulation of B Differentiation via TNF- α Signaling Pathway. DNA Cell Biol. 2023;42(2):97-104. doi:10.1089/dna.2022.0461 441. Yaqoob H, Ahmad H, Ali SI, Patel N, Arif A. Missense mutations in the CITED2 gene may contribute to congenital heart disease. BMC Cardiovasc Disord. 2024;24(1):516. doi:10.1186/s12872-024-04035-2 442. Barefield DY, Yamakawa S, Tahtah I, Sell JJ, Broman M, Laforest B, Harris S, Alvarez-Arce A, Araujo KN, Puckelwartz MJ, et al. Partial and complete loss of myosin binding protein H-like cause cardiac conduction defects. J Mol Cell Cardiol. 2022;169:28-40. doi:10.1016/j.yjmcc.2022.04.012 443. Liu Y, Chen L, Gao L, Pei X, Tao Z, Xu Y, Li R. LRRK2 deficiency protects the heart against myocardial infarction injury in mice via the P53/HMGB1 pathway. Free Radi c Biol Med. 2022;191:119-127. doi:10.1016/j.freeradbiomed.2022.08.035 444. Lin YJ, Chang JS, Liu X, Tsang H, Chien WK, Chen JH, Hsieh HY, Hsueh KC, Shiao YT, Li JP, et al. Genetic variants in PLCB4/PLCB1 as (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint susceptibility loci for coronary artery aneurysm formation in Kawasaki disease in Han Chinese in Taiwan. Sci Rep. 2015;5:14762. doi:10.1038/srep14762 445. Dobrev D, Wehrens XH. Role of RyR2 phosphorylation in heart failure and arrhythmias: Controve rsies around ryanodine receptor phosphorylation in cardiac disease. Circ Res. 2014;114(8):1311-1319. doi:10.1161/CIRCRESAHA.114.300568 446. Künzel SR, Hoffmann M, Weber S, Künzel K, Kämmerer S, Günscht M, Klapproth E, Rausch JSE, Sadek MS, Kolanowski T, et al. Diminished PLK2 Induces Cardiac Fibrosis and Promotes Atrial Fibrillation. Circ Res. 2021;129(8):804-820. doi:10.1161/CIRCRESAHA.121.319425 447. Cheng X, Chen X, Zhang M, Wan Y, Ge S, Cheng X. Sparcl1 and Atherosclerosis. J Inflamm Re s. 2023;16:2121-2127. doi:10.2147/JIR.S406907 448. Moya-Mendez ME, Ogbonna C, Ezekian JE, Rosamilia MB, Prange L, de la Uz C, Kim JJ, Howard T, Garcia J, Nussbaum R, et al. ATP1A3- Encoded Sodium-Potassi um ATPase Subunit Alpha 3 D801N Variant Is Associated With Shortened QT Interval and Predisposition to Ventricular Fibrillation Preceded by Brad ycardia. J Am Heart Assoc. 2021;10(17):e019887. doi:10.1161/JAHA.120.019887 449. Noori MR, Zhang B, Pan L. Is KCNH1 mutation related to coronary artery ectasia. BMC Cardi ovasc Disord. 2019;19(1):296. doi:10.1186/s12872-019-01276-4 450. Calvert JW, Gundewar S, Yamakuchi M, Park PC, Baldwin WM 3rd, Lefer DJ, Lowenstein CJ. Inhibition of N-ethylmaleimide-sensitive factor protects against myocardial ischemia/reperfusion injury. Circ Res. 2007;101(12):1247-1254. doi:10.1161/CIRCRESAHA.107.162610 451. Gurunathan S, Sebastian J, Baker J, Abdel-Hamid HZ, West SC, Feingold B, Peche V, Reyes-Múgica M, Madan-Khetarpal S, Field J. A homozygous CAP2 pathogenic variant in a neonate presenting with rapidly progressive cardiomyopathy and ne maline rods. Am J Med Genet A. 2022;188(3):970-977. doi:10.1002/ajmg.a.62590 452. Golimbet VE, Volel' BA, Dolzhikov AV, Korovaitseva GI, Isaeva MI. Association of 5-HTR2A and 5-HT R2C serotonin receptor gene (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint polymorphisms with depression risk in patients with coronary heart disease. Bull Exp Biol Med. 2014;156(5):680-683. doi:10.1007/s10517-014-2424-1 453. Kang K, Li J, Li R, Xu X, Liu J, Qin L, Huang T, Wu J, Jiao M, Wei M, et al. Potentially Critical Roles of NDUFB5, TIMMDC1, and VDAC3 in the Progression of Septic Cardiomyopathy Through Integrated Bioinformatics Analysis. DNA Cell Biol. 2020;39(1):105-117. doi:10.1089/dna.2019.4859 454. Kušíková K, Feichtinger RG, Csillag B, Kalev OK, Weis S, Duba HC, Mayr JA, Weis D. Case Report and Review of the Literature: A New and a Recurrent Variant in the VARS2 Gene Are Associated With Isolated Lethal Hypertrophic Cardiomyopathy, Hyperlactatemia, and Pulmonary Hypertension in Early Infancy. Front Pediatr. 2021;9:660076. doi:10.3389/fped.2021.660076 455. Pfister O, Lorenz V, Oikonomopo ulos A, Xu L, Häuselmann SP, Mbah C, Kaufmann BA, Liao R, Wodnar-Filipowicz A, Kuster GM. FLT3 activation improves post-myocardial infarction remodeling involving a cytoprotective effect on cardiomyocytes. J Am Coll Cardiol. 2014;63(10):1011-1019. doi:10.1016/j.jacc.2013.08.1647 456. Xiong F, Mao R, Zhao R, Zhang L, Tan K, Liu C, Wang S, Xu M, Li Y, et al. Plasma Exosomal S1PR5 a nd CARNS1 as Potential Non-invasive Screening Biomarkers of Coronary Heart Disease. Front Cardiovasc Med. 2022;9:845673. doi:10.3389/fcvm.2022.845673 457. Shen JF, Fan ZB, Wu CW, Qi GX, Cao QY, Xu F. Sacubitril Valsartan Enhances Cardiac Function a nd Alleviates Myocardial Infarction in Rats through a SUV39H1/SPP1 Axis. Oxid Med Cell Longev. 2022;2022:5009289. doi:10.1155/2022/5009289 458. Chen S, Zhang Y, Lighthouse JK, Mickelsen DM, Wu J, Yao P, Small EM, Yan C. A Novel Role of Cyclic Nucleotide Phosphodiesterase 10A in Pathological Cardiac Remodeling and Dysfunction. Circulation. 2020;141(3):217-233. doi:10.1161/CIRCULATIONAHA.119.042178 459. Lu Z, Cui Y, Wei X, Gao P, Zhang H, Wei X, Li Q, Sun F, Yan Z, Zheng H, et al. Deficiency of PKD2L1 (TRPP3) Exacerbates Pathological Cardiac Hypertrophy by Augmenting NCX1-Mediated Mitochondrial Calcium Overload. Cell Rep. 2018;24(6):1639-1652. doi:10.1016/j.celrep.2018.07.022 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 460. Zhuo C, Jiang R, Lin X, Shao M. LncRNA H19 inhibits autophagy by epigenetically silencing of DIRAS3 in diabetic cardiomyopathy. Oncotarget. 2017;8(1):1429-1437. doi:10.18632/oncotarget.13637 461. Hayderi A, Kumawat AK, Shavva VS, Dreifaldt M, Sigvant B, Petri MH, Kragsterman B, Olofsson PS, Sirsjö A, Ljungberg LU. RSAD2 is abundant in atherosclerotic plaque s and promotes interferon-induced CXCR3-chemokines in human smooth muscle cells. Sci Rep. 2024;14(1):8196. doi:10.1038/s41598-024-58592-9 462. Mayer O Jr, Seidlerová J, Č erná V, Ku č erová A, Bruthans J, Vágovič ová P, Van ě k J, Timoracká K, Wohlfahrt P, Filipovský J, et al. The DRD2/ANKK1 Taq1A polymorphism is associated with smoking cessation failure in patients with coronary heart disease. Per Med. 2015;12(5):463- 473. doi:10.2217/pme.15.16 463. Li H, Lewis A, Brodsky S, Rieger R, Iden C, Goligorsky MS. Homocysteine induces 3-hydroxy-3-methylglutaryl coenzyme a reductase in vascular endothelial cells: a mechanism for development of atherosclerosis?. Circulation. 2002;105(9):1037-1043. doi:10.1161/hc0902.104713 464. Du Z, Kuang S, Li Y, Han P, Liu J, Wang Z, Huang Y, Guan Y, Xu X, Liu X, et al. Family-Based Whole Genome Sequencing Identified Novel Variants in ABCA5 Gene in a Patient with Idiopathic Ventricular Tachycardia. Pediatr Cardiol. 2020;41(8):1783-1794. doi: 10.1007/s00246- 020-02446-4 465. Ma T, Lin S, Wang B, Wang Q, Xia W, Zhang H, Cui Y, He C, Wu H, Sun F, et al. TRPC3 deficiency attenuates high salt-induced cardiac hypertrophy by alleviating cardiac mitochondrial dysfunction. Biochem Biophys Res Commun. 2019;519(4):674-681. doi:10.1016/j.bbrc.2019.09.018 466. Li B, Syed MH, Khan H, Singh KK, Qadura M. The Role of Fatty Acid Binding Protein 3 in Cardi ovascular Diseases. Biomedicines. 2022;10(9):2283. doi:10.3390/biomedicines10092283 467. Tam CHT, Lim CKP, Luk AOY, Shi M, Man Cheung H, Ng ACW, Lee HM, Lau ESH, Fan B, Jiang G, et al. Identification of a Common Variant for Coronary Heart Disease at PDE1A Contributes to Individualized Treatment Goals and Risk Stratification of Cardiovascular Complications in (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Chinese Patients With Type 2 Diab etes. Diabetes Care. 2023;46(6):1271- 1281. doi:10.2337/dc22-2331 468. Lei W, Yiming S, Qiang P, Xin C, Peng G, Baofeng Z. Unleashing the Neurotherapeutic Potential: The Crucial Role of miR-206-3p in Facilitating Hsp90aa1-Mediated Central Nervous System Injuries During Heat Stroke. Mol Neurobiol. 2024. doi:10.1007/s12035-024-04342-x 469. Li D, Ji JX, Xu YT, Ni HB, Rui Q, Liu HX, Jiang F, Gao R, Chen G. Inhibition of Lats1/p-YAP1 pathway mitigates neuronal apoptosis and neurological deficits in a rat model of traumatic brain injury. CNS Neurosci Ther. 2018;24(10):906-916. doi:10.1111/cns.12833 470. Z h a n g Z , Z h a n g X , W u X , Z h a n g Y , L u J , L i D . S i r t 1 a t t e n u a t e s astrocyte activation via modulating Dnajb1 and chaperone-mediated autophagy after closed head inju ry. Cereb Cortex. 2022;32(22):5191-5205. doi:10.1093/cercor/bhac007 471. Amirkhosravi L, Khaksari M, Sheibani V, Shahrokhi N, Ebrahimi MN, Amiresmaili S, Salmani N. Improved spatial memory, neurobehavioral outcomes, and neuroprotective effect after progesterone administration in ovariectomized rats with trauma tic brain injury: Role of RU486 progesterone receptor antagonist. Iran J Basic Med Sci. 2021;24(3):349-359. doi:10.22038/ijbms.2021.50973.11591 472. Thundyil J, Manzanero S, Pavlovski D, Cully TR, Lok KZ, Widiapradja A, Chunduri P, Jo DG, Naruse C, Asano M, et al. Evidence that the EphA2 receptor exacerbates ischemic brain injury. PLoS One. 2013;8(1):e53528. doi:10.1371/journal.pone.0053528 473. Huang Z, Liu J, Xu J, Dai L, Wang H. Downregulation of miR-26b attenuates early brain injury induced by subarachnoid hemorrhage via mediating the KLF4/STAT3/HMGB1 axis. Exp Neurol. 2023;359:114270. doi:10.1016/j.expneurol.2022.114270 474. Dai Y, Hu L. HSPB1 overexpression improves hypoxic-ischemic brain damage by attenuating ferroptosis in rats through promoting G6PD expression. J Neurophysiol. 2022;128(6):1507-1517. doi:10.1152/jn.00306.2022 475. Krum JM, Mani N, Rosenstein JM. Roles of the endogenous VEGF receptors flt-1 and flk-1 in astroglia l and vascular remodeling after brain (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint injury. Exp Neurol. 2008;212(1):108-117. doi:10.1016/j.expneurol.2008.03.019 476. Luo J, Wu X, Liu H, Cui W, Guo W, Guo K, Guo H, Tao K, Li F, Shi Y, et al. Antagonism of Protease-Activated Receptor 4 Protects Against Traumatic Brain Injury by Suppressing Neuroinflammation via Inhibition of Tab2/NF-κ B Signaling. Neurosci Bull. 2021;37(2):242-254. doi:10.1007/s12264-020-00601-8 477. Li Y, Liu C, Fan H, Du Y, Zhang R, Zhan S, Zhang G, Bu N. Gli2- induced lncRNA Peg13 alleviates cerebral ischemia-reperfusion injury by suppressing Yy1 transcription in a PRC2 complex-dependent manner. Metab Brain Dis. 2023;38(4):1389-1404. doi:10.1007/s11011-023-01159-w 478. Zhang AQ, Wang L, Wang YX, Hong SS, Zhong YS, Yu RY, Wu XL, Zhou BB, Yu QM, Fu HF, et al. Silencing miRNA-324-3p protects against cerebral ischemic injury via regulation of the GATA2/A1R axis. Neural Regen Res. 2022;17(11):2504-2511. doi:10.4103/1673-5374.339009 479. Liu N, Han J, Li Y, Jiang Y, Shi SX, Lok J, Whalen M, Dumont AS, Wang X. Recombinant annexin A2 inhibits peripheral leukocyte activation and brain infiltration after traumatic brain injury. J Neuroinflammation. 2021;18(1):173. doi:10.1186/s12974-021-02219-7 480. Li S, Qu X, Qin Z, Gao J, Li J, Liu J. lncfos/miR-212-5p/CASP7 Axis-Regulated miR-212-5p Protects th e Brain Against Ischemic Damage. Mol Neurobiol. 2023;60(5):2767-2785. doi:10.1007/s12035-023-03216-y 481. Kumari D, Kaur S, Dandekar MP. Intricate Role of the Cyclic Guanosine Monophosphate Adenosine Monophosphate Synthase-Stimulator of Interferon Genes (cGAS-STING) Pathway in Traumatic Brain Injury- Generated Neuroinflammation and Neuronal Death. ACS Pharmacol Transl Sci. 2024;7(10):2936-2950. doi:10.1021/acsptsci.4c00310 482. Mao W, Yi X, Qin J, Tian M, Jin G. CXCL12/CXCR4 Axis Improves Migration of Neuroblasts Along Corpus Callosum by Stimulating MMP-2 Secretion After Traumatic Brain Injury in Rats. Neurochem Res. 2016;41(6):1315-1322. doi:10.1007/s11064-016-1831-2 483. Chen Z, Hu Y, Lu R, Ge M, Zhang L. MicroRNA-374a-5p inhibits neuroinflammation in neonatal hypoxic-ischemic encephalopathy via regulating NLRP3 inflammasome targeted Smad6. Life Sci. 2020;252:117664. doi:10.1016/j.lfs.2020.117664 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 484. Niu LJ, Xu RX, Zhang P, Du MX, Jiang XD. Suppression of Frizzled- 2-mediated Wnt/Ca²/i2 signaling significantly attenuates intracellular calcium accumulation in vitro and in a rat model of traumatic brain injury. Neuroscience. 2012;213:19-28. doi:10.1016/j.neuroscience.2012.03.057 485. Chernyak YI, Itskovich VB, D'yakovich OA, Kolesnikov SI. Role of cytochrome P450-dependent monooxygen ases and polymor phic variants of GSTT1 and GSTM1 genes in the formatio n of brain lesions in individuals chronically exposed to mercury. Bu ll Exp Biol Med. 2013;156(1):15-18. doi:10.1007/s10517-013-2266-2 486. Chen Y, Wang Y, Xu J, Hou T, Zhu J, Jiang Y, Sun L, Huang C, Sun L, Liu S. Multiplex Assessment of Serum Chemokines CCL2, CCL5, CXCL1, CXCL10, and CXCL13 Following Traumatic Brain Injury. Inflammation. 2023;46(1):244-255. doi:10.1007/s10753-022-01729-7 487. Li HY, Li P, Yang HG, Yao QQ, Huang SN, Wang JQ, Zheng N. Investigation and comparison of the protective activities of three functional proteins-lactoferrin, α -lactalbumin, and β -lactoglobulin-in cerebral ischemia reperfusion injury. J Dair y Sci. 2020;103(6):4895-4906. doi:10.3168/jds.2019-17725 488. Jiao W, Jiang L, Zhang Y. SNHG1 alleviates the oxidative stress and inflammatory response in traumatic brain injury through regulating miR- 377-3p/DUSP1 axis. Neuroreport. 2023;34(1):17-29. doi:10.1097/WNR.0000000000001852 489. Zhang Z, Trautmann K, Artelt M, Burnet M, Schluesener HJ. Bone morphogenetic protein-6 is expressed early by activated astrocytes in lesions of rat traumatic brain injury. Neuroscience. 2006;138(1):47-53. doi:10.1016/j.neuroscience.2005.11.036 490. W a n g Y , F a n g M , R e n Q , Q i W , B a i X , A m i n N , Z h a n g X , L i Z , Zhang L. Sox17 protects human brain microvascular endothelial cells from AngII-induced injury by regulating autophagy and apoptosis. Mol Cell Biochem. 2024;479(9):2337-2350. doi:10.1007/s11010-023-04838-5 491. Wu Q, Liu G, Xu L, Wen X, Cai Y, Fan W, Yao X, Huang H, Li Q. Repair of Neurological Function in Response to FK506 Through CaN/NFATc1 Pathway Following Traumatic Brain Injury in Rats. Neurochem Res. 2016;41(10):2810-2818. doi:10.1007/s11064-016-1997-7 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 492. Zhou Y, Zhou B, Tu H, Tang Y, Xu C, Chen Y, Zhao Z, Miao Z. he degradation of mixed lineage kinase domain-like protein promotes neuroprotection after ischemic brai n injury. Oncotarget. 2017;8(40):68393- 68401. doi:10.18632/oncotarget.19416 493. Lipponen A, Paananen J, Puhakka N, Pitkänen A. Analysis of Post- Traumatic Brain Injury Gene Expre ssion Signature Reveals Tubulins, Nfe2l2, Nfkb, Cd44, and S100a4 as Treatment Targets. Sci Rep. 2016;6:31570. doi:10.1038/srep31570 494. Mercurio D, Oggioni M, Fumagalli S, Lynch NJ, Roscher S, Minuta D, Perego C, Ippati S, Wallis R, Schwaeble WJ, et al. Targeted deletions of complement lectin pathway genes improve outcome in traumatic brain injury, with MASP-2 playing a major role. Acta Neuropathol Commun. 2020;8(1):174. doi:10.1186/s40478-020-01041-1 495. Zhao Y, Zhou YG, Chen JF. Targ eting the adenosine A2A receptor for neuroprotection and cognitive improvement in traumatic brain injury and Parkinson's disease. Chin J Traumatol. 2024;27(3):125-133. doi:10.1016/j.cjtee.2023.08.003 496. Willyerd FA, Empey PE, Philbrick A, Ikonomovic MD, Puccio AM, Kochanek PM, Okonkwo DO, Clark RS. Expression of ATP-Binding Cassette Transporters B1 and C1 after Severe Traumatic Brain Injury in Humans. J Neurotrauma. 2016;33(2):226-231. doi:10.1089/neu.2015.3879 497. Cui G, Yu Z, Li Z, Wang W, Lu T, Qian C, Li J, Ding Y. Increased expression of Foxj1 after trauma tic brain injury. J Mol Neurosci. 2011;45(2):145-153. doi:10.1007/s12031-011-9504-8 498. He T, Shang J, Gao C, Guan X, Chen Y, Zhu L, Zhang L, Zhang C, Zhang J, Pang T. A novel SIRT6 activator ameliorates neuroinflammation and ischemic brain injury via EZH2/FOXC1 axis. Acta Pharm Sin B. 2021;11(3):708-726. doi:10.1016/j.apsb.2020.11.002 499. Li L, Yerra L, Chang B, Mathur V, Nguyen A, Luo J. Acute and late administration of colony stimulating factor 1 attenuates chronic cognitive impairment following mild traumatic brain injury in mice. Brain Behav Immun. 2021;94:274-288. doi:10.1016/j.bbi.2021.01.022 500. Wang LH, Zhang GL, Liu XY, et al. CELSR1 Promotes Neuroprotection in Cerebral Ischemic Injury Mainly Through the Wnt/PKC (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Signaling Pathway. Int J Mol Sci. 2020;21(4):1267. doi:10.3390/ijms21041267 501. Michinaga S, Hishinuma S, Koyama Y. Roles of Astrocytic Endothelin ETB Receptor in Traumatic Brain Injury. Cells. 2023;12(5):719. doi:10.3390/cells12050719 502. Frisén J, Johansson CB, Török C, Risling M, Lendahl U. Rapid, widespread, and longlasting induction of nestin contributes to the generation of glial scar tissue after CNS inju ry. J Cell Biol. 1995;131(2):453-464. doi:10.1083/jcb.131.2.453 503. Li HL, Guo RJ, Ai ZR, Han S, Guan Y, Li JF, Wang Y. Upregulation of Spinal MDGA1 in Rats After Nerve Injury Alters Interactions Between Neuroligin-2 and Postsynaptic Scaffo lding Proteins and Increases GluR1 Subunit Surface Delivery in the Spinal Cord Dorsal Horn. Neurochem Res. 2024;49(2):507-518. doi:10.1007/s11064-023-04049-w 504. Ma Y, Lu C, Li C, Li R, Zhang Y, Ma H, Zhang X, Ding Z, Liu L. Overexpression of HSPA12B protects against cerebral ischemia/reperfusion injury via a PI3K/Akt-dependent mechanism. Biochim Biophys Acta. 2013;1832(1):57-66. doi:10.1016/j.bbadis.2012.10.003 505. Dan QQ, Ma Z, Tan YX, Visar B, Chen L. AQP4 knockout promotes neurite outgrowth via upregulating GAP43 expression in infant rats with hypoxic-ischemic brain injury. Ibrain. 2022;8(3):324-337. doi:10.1002/ibra.12062 506. Richter M, Negro-Demontel ML, Blanco-Ocampo D, Taranto E, Lago N, Peluffo H. Thy1-YFP-H Mice and the Parallel Rod Floor Test to Evaluate Short- and Long-Term Progression of Traumatic Brain Injury. Curr Protoc Immunol. 2018;120:24.1.1-24.1.25. doi:10.1002/cpim.42 507. Lin C, Zhao P, Sun G, Liu N, Ji J. SCG2 mediates blood-brain barrier dysfunction and schizophrenia-like behaviors after traumatic brain injury. FASEB J. 2024;38(17):e70016. doi:10.1096/fj.202401117R 508. Qiu L, He J, Chen H, Xu X, Tao Y. CircDLGAP4 overexpression relieves oxygen-glucose deprivation-i nduced neuronal injury by elevating NEGR1 through sponging miR-503-3p. J Mol Histol. 2022;53(2):321-332. doi:10.1007/s10735-021-10036-8 509. Zhang J, Liang L, Miao X, Wu S, Cao J, Tao B, Mao Q, Mo K, Xiong M, et al. Contribution of the Suppre ssor of Variegation 3-9 Homolog 1 in (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Dorsal Root Ganglia and Spinal Cord Dorsal Horn to Nerve Injury-induced Nociceptive Hypersensitivity. Anesthesiology. 2016;125(4):765-778. doi:10.1097/ALN.0000000000001261 510. Si W, Sun B, Luo J, Li Z, Do u Y, Wang Q. Snap25 attenuates neuronal injury via reducing ferroptosis in acute ischemic stroke. Exp Neurol. 2023;367:114476. doi:10.1016/j.expneurol.2023.114476 511. Wang L, Tan Y, Zhu Z, Chen J, Sun Q, Ai Z, Ai C, Xing Y, He G, Liu Y. ATP2B1-AS1 Promotes Cerebral Ischemia/Reperfusion Injury Through Regulating the miR-330-5p/TLR4-MyD88-NF- κ B Signaling Pathway. Front Cell Dev Biol. 2021;9:720468. doi:10.3389/fcell.2021.720468 512. Xu J, Huang X, Liu S, Chen D, Xie Y, Zhao Z. The protective effects of lncRNA ZFAS1/miR-421-3p/MEF2C axis on cereb ral ischemia- reperfusion injury. Cell Cycle. 2022;21(18):1915-1931. doi:10.1080/15384101.2022.2060627 513. Kofler J, Otsuka T, Zhang Z, Noppens R, Grafe MR, Koh DW, Dawson VL, de Murcia JM, Hurn PD, Tr aystman RJ. Differential effect of PARP-2 deletion on brain injury after focal and global cerebral ischemia. J Cereb Blood Flow Metab. 2006;26(1):135-141. doi:10.1038/sj.jcbfm.9600173 514. Huang M, Zhang J, Li M, Cao H, Zhu Q, Yang D. PAK1 contributes to cerebral ischemia/reperfusion injury by regulating the blood-brain barrier integrity. iScience. 2023;26(8):107333. doi:10.1016/j.isci.2023.107333 515. Gu X, Ni H, Kan X, Chen C, Zhou Z, Ding Z, Li D, Liu B. Nicotinamide Mononucleotide Adenylyl Transferase 2 Inhibition Aggravates Neurological Damage after Traumatic Brain Injury in a Rat Model. J Korean Neurosurg Soc. 2023;66(4):400-408. doi:10.3340/jkns.2022.0115 516. Zhang N, Yang L, Meng L, Cui H. Inhibition of miR-200b-3p alleviates hypoxia-ischemic brain damage via targeting Slit2 in neonatal rats. Biochem Biophys Res Co mmun. 2020;523(4):931-938. doi:10.1016/j.bbrc.2020.01.029 517. Yang M, Wang X, Fan Y, Chen Y, Sun D, Xu X, Wang J, Gu G, Peng R , S h e n T , e t a l . S e m a p h o r i n 3 A Contributes to Secondary Blood-Brain (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Barrier Damage After Traumatic Brain Injury. Front Cell Neurosci. 2019;13:117. doi:10.3389/fncel.2019.00117 518. Mi Z, Graham SH. Role of UCHL1 in the pathogenesis of neurodegenerative diseases and brain injury. Ageing Res Rev. 2023;86:101856. doi:10.1016/j.arr.2023.101856 519. Zhu J, Chen Z, Yu B, Zhang L, Ai F. MicroRNA-375-3p Alleviates Salicylate-Induced Neuronal Injury by Targeting ELAVL4 in Tinnitus. J Neurol Surg B Skull Base. 2023;85(3):227-233. doi: 10.1055/s-0043- 1764379 520. Li YY, Guo JH, Liu YQ, Dong JH, Zhu CH. PPAR γ Activation- Mediated Egr-1 Inhibition Benefits Agai nst Brain Injury in an Experimental Ischaemic Stroke Model. J Stroke Cerebrovasc Dis. 2020;29(12):105255. doi:10.1016/j.jstrokecerebrovasdis.2020.105255 521. Zhu G, Fang Y, Cui X, Jia R, Kang X, Zhao R. Magnolol upregulates CHRM1 to attenuate Amyloid- β -triggered neuronal injury through regulating the cAMP/PKA/CREB pathway. J Nat Med. 2022;76(1):188-199. doi:10.1007/s11418-021-01574-2 522. Mondello S, Gabrielli A, Catani S, D'Ippolito M, Jeromin A, Ciaramella A, Bossù P, Schmid K, Tortella F, Wang KK, et al. Increased levels of serum MAP-2 at 6-months correlate with improved outcome in survivors of severe traumatic brain injury. Brain Inj. 2012;26(13-14):1629- 1635. doi:10.3109/02699052.2012.700083 523. An J, Yang H, Park SM, Chwae YJ, Joe EH. The LRRK2-G2019S mutation attenuates repair of brain injury partially by reducing the release of osteopontin-containing monocytic exosome-like vesicles. Neurobiol Dis. 2024;197:106528. doi:10.1016/j.nbd.2024.106528 524. Q i J , M e n g C , M o J , S h o u T , D i n g L , Z h i T . C i r c A F F 2 P r o m o t e s Neuronal Cell Injury in Intracerebral Hemorrhage by Regulating the miR- 488/CLSTN3 Axis. Neuros cience. 2023;535:75-87. doi:10.1016/j.neuroscience.2023.10.014 525. Yu Y, Xia Q, Zhan G, Gao S, Han T, Mao M, Li X, Wang Y. TRIM67 alleviates cerebral ischemia /i2 reperfusion injury by protecting neurons and inhibiting neuroinflammation via targeting Iκ Bα for K63-linked polyubiquitination. Cell Biosci. 2023;13(1):99. doi: 10.1186/s13578-023- 01056-w (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 526. Kahriman A, Bouley J, Tuncali I, Dogan EO, Pereira M, Luu T, Bosco DA, Jaber S, Peters OM, Brown RH Jr, et al. Repeated mild traumatic brain injury triggers pathology in as ymptomatic C9ORF72 transgenic mice. Brain. 2023;146(12):5139-5152. doi:10.1093/brain/awad264 527. Jacobsson G, Piehl F, Meister B. VAMP-1 and VAMP-2 gene expression in rat spinal motoneurones: differential regulation after neuronal injury. Eur J Neurosci. 1998;10(1):301-316. doi: 10.1046/j.1460- 9568.1998.00050.x 528. Ihbe N, Le Prieult F, Wang Q, Dist ler U, Sielaff M, Tenzer S, Thal SC, Mittmann T. Adaptive Mechanisms of Somatostatin-Positive Interneurons after Traumatic Brain Injury through a Switch of α Subunits in L-Type Voltage-Gated Calcium Channels. Cereb Cortex. 2022;32(5):1093- 1109. doi:10.1093/cercor/bhab268 529. Hiltunen J, Ndode-Ekane XE, Lipponen A, Drexel M, Sperk G, Puhakka N, Pitkänen A. Regulation of Parvalbumin Interactome in the Perilesional Cortex after Experimental Traumatic Brain Injury. Neuroscience. 2021;475:52-72. doi:10.1016/j.neuroscience.2021.08.018 530. Huang HB, Yang SB, Shen LJ, Lv QW, Guo M, Zhou J, Li Z, Yang CS, Wang LY, Zhang H. A prospective study on serum secreted protein acidic and rich in cysteine-like 1 as a prognostic marker for severe traumatic brain injury. Clin Chim Acta. 2019;491:19-23. doi:10.1016/j.cca.2019.01.005 531. Qiu M, Zhao X, Guo T, He H, Deng Y. N-ethylmaleimide-sensitive factor elicits a neuroprotection against ischemic neuronal injury by restoring autophagic/lysosomal dysfunction. Cell Death Discov. 2024;10(1):368. doi:10.1038/s41420-024-02144-7 532. Fronczak KM, Li Y, Henchir J, Dixon CE, Carlson SW. Reductions in Synaptic Vesicle Glycoprotein 2 Isoforms in the Cortex and Hippocampus in a Rat Model of Traumatic Brain Injury. Mol Neurobiol. 2021;58(11):6006- 6019. doi:10.1007/s12035-021-02534-3 533. Liu Z, Gao W, Xu Y. Eleutheroside E alleviates cerebral ischemia- reperfusion injury in a 5-hydroxytrypt amine receptor 2C (Htr2c)-dependent manner in rats. Bioengineered. 2022;13(5):11718-11731. doi:10.1080/21655979.2022.2071009 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 534. Zhu X, Li H, You W, Yu Z, Wang Z, Shen H, Li X, Yu H, Wang Z, Chen G. Role of Rph3A in brain injury induced by experimental cerebral ischemia-reperfusion model in rats. CNS Neurosci Ther. 2022;28(7):1124- 1138. doi:10.1111/cns.13850 535. Zhang J, Liang L, Miao X, Wu S, Cao J, Tao B, Mao Q, Mo K, Xiong M, Lutz BM, et al. Contribution of the Suppressor of Variegation 3-9 Homolog 1 in Dorsal Root Ganglia and Spinal Cord Dorsal Horn to Nerve Injury-induced Nociceptive Hypersensitivity. Anesthesiology. 2016;125(4):765-778. doi:10.1097/ALN.0000000000001261 536. Beker MC, Altintas MO, Dogan E, Bayraktaroglu C, Balaban B, Ozpinar A, Sengun N, Altunay S, Kilic E. Inhibition of phosphodiesterase 10A mitigates neuronal injury by modulating apoptotic pathways in cold- induced traumatic brain injury. Mol Cell Neurosci. 2024. doi:10.1016/j.mcn.2024.103977 537. Jiang W, Stingelin L, Zhang P, Tian X, Kang N, Liu J, Aihemaiti Y, Zhou D, Tu H. Enolase2 and enolase1 cooperate against neuronal injury in stroke model. Neurosci Lett. 2021;747:135662. doi:10.1016/j.neulet.2021.135662 538. Snider S, Albano L, Gagliardi F, Comai S, Roncelli F, De Domenico P, Pompeo E, Panni P, Bens N, Calvi MR, et al. Substantially elevated serum glutamate and CSF GOT-1 levels associated with cerebral ischemia and poor neurological outcomes in subarachnoid hemorrhage patients. Sci Rep. 2023;13(1):5246. doi:10.1038/s41598-023-32302-3 539. Yue JK, Pronger AM, Ferguson AR, Temkin NR, Sharma S, Rosand J, Sorani MD, McAllister TW, Barber J, Winkler EA, et al. Association of a common genetic variant within ANKK1 with six-month cognitive performance after traumatic brain injury. Neurogenetics. 2015;16(3):169- 180. doi:10.1007/s10048-015-0437-1 540. C h e n X , L u M , H e X , M a L , B i r n b a u m e r L , L i a o Y . T R P C 3 / 6 / 7 Knockdown Protects the Brain from Cerebral Ischemia Injury via Astrocyte Apoptosis Inhibition and Effects on NF- к B Translocation. Mol Neurobiol. 2017;54(10):7555-7566. doi:10.1007/s12035-016-0227-2 541. Zhong FF, Wei B, Bao GX, Lou YP, Wei ME, Wang XY, Xiao X, Tian JJ. FABP3 Induces Mitochondrial Autophagy to Promote Neuronal (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Cell Apoptosis in Brain Ischemia-Reperfusion Injury. Neurotox Res. 2024;42(4):35. doi:10.1007/s12640-024-00712-4 542. Winneberger J, Schöls S, Lessmann K, Rández-Garbayo J, Bauer AT, Mohamud Yusuf A, Hermann DM, Gunzer M, Schneider SW, Fiehler J, et al. Platelet endothelial cell adhesion molecule-1 is a gatekeeper of neutrophil transendothelial migration in ischemic stroke. Brain Behav Immun. 2021;93:277-287. doi:10.1016/j.bbi.2020.12.026 543. Rankinen T, Rice T, Boudreau A, Leon AS, Skinner JS, Wilmore JH, Rao DC, Bouchard C. Titin is a candida te gene for stroke volume response to endurance training: the HERITAGE Family Study. Physiol Genomics. 2003;15(1):27-33. doi:10.1152/physiolgenomics.00147.2002 544. Stetskaya TA, Krapiva AB, Kobzeva KA, Gurtovoy DE, Komkova GV, Polonikov AV, Bushueva OY. Po lymorphism in Genes Encoding Adaptor Proteins ST13 and STIP1 and the Risk of Ischemic Stroke: a Pilot Study. Bull Exp Biol Med. 2024;176(4):477-480. doi: 10.1007/s10517-024- 06050-x 545. Wang C, Li L. The critical role of KLF4 in regulating the activation of A1/A2 reactive astrocytes following ischemic stroke. J Neuroinflammation. 2023;20(1):44. doi:10.1186/s12974-023-02742-9 546. Lindahl K, Rubin CJ, Brändström H, Karlsson MK, Holmberg A, Ohlsson C, Mellström D, Orwoll E, Mallmin H, Kindmark A, et al. Heterozygosity for a coding SNP in COL1A2 confers a lower BMD and an increased stroke risk. Biochem Biophys Res Commun. 2009;384(4):501- 505. doi:10.1016/j.bbrc.2009.05.006 547. Li Z, Liu B, Lambertsen KL, Clausen BH, Zhu Z, Du X, Xu Y, Poulsen FR, Halle B, Bonde C, et al . USP25 Inhibits Neuroinflammatory Responses After Cerebral Ischemic Stroke by Deubiquitinating TAB2. Adv Sci (Weinh). 2023;10(28):e2301641. doi:10.1002/advs.202301641 548. Bierman-Chow S, Holland SM, Hsu AP , Palmer C, Lynch J, Mina Y, Joo Sophie Cho H. Clinical, Imaging, and Laboratory Findings in Patients With GATA2 Deficiency Presenting With Early-Onset Ischemic Stroke. Neurology. 2023;100(7):338-341. doi:10.1212/WNL.0000000000201569 549. Liu B, Xing Z, Song F, Li D, Zhao B, Xu C, Xia W, Ji H. METTL3- mediated ANXA2 inhibition confers neuroprotection in ischemic stroke: (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Evidence from in vivo and in vitro studies. FASEB J. 2023;37(7):e22974. doi:10.1096/fj.202300246R 550. Karimian M, Karimnia F. CYP1A1 common gene polymorphisms and ischemic stroke risk: a meta-analysis and a structural examination. Per Med. 2023;20(3):271-281. doi:10.2217/pme-2022-0113 551. Z h e n g Z , L i u S , W a n g C , W a n g C , T a n g D , S h i Y , H a n X . Association of genetic polymorphisms in CASP7 with risk of ischaemic stroke. Sci Rep. 2019;9(1):18627. doi:10.1038/s41598-019-55201-y 552. Chauhan C, Kaundal RK. The role of cGAS-STING signaling in ischemic stroke: From immune response to therapeutic targeting. Drug Discov Today. 2023;28(11):103792. doi:10.1016/j.drudis.2023.103792 553. Li S, Yang S, Zhang X, Zhang Y, Zhang J, Zhang X, Li W, Niu X, Shi W, Zhang G, et al. Impact of MMP2 rs243849 and rs14070 genetic polymorphisms on the ischemic stroke susceptibility in Chinese Shaanxi population. Front Neurol. 2022;13:931437. doi:10.3389/fneur.2022.931437 554. Wang R, Wang Y, Wang J, Yang K. Association of glutathione S- transferase T1 and M1 gene polymorphisms with ischemic stroke risk in the Chinese Han population. Neural Regen Res. 2012;7(18):1420-1427. doi:10.3969/j.issn.1673-5374.2012.18.009 555. L i J , Z h a n g L , X u e S , Y u C , L i Y , L i S , Y e Q , D u a n X , P e n g D . Exploration of the mechanism of Taohong Siwu Decoction for the treatment of ischemic stroke based on CCL2/CCR2 axis. Front Pharmacol. 2024;15:1428572. doi:10.3389/fphar.2024.1428572 556. Xiao Z, Shen D, Lan T, Wei C, Wu W, Sun Q, Luo Z, Chen W, Zhang Y, Hu L, et al. Reduction of lactoferrin aggravates neuronal ferroptosis after intracerebral hemorrhagic stroke in hyperglycemic mice. Redox Biol. 2022;50:102256. doi:10.1016/j.redox.2022.102256 557. Janicki PK, Eyileten C, Ruiz-Velasco V, Pordzik J, Czlonkowska A, Kurkowska-Jastrzebska I, Sugino S, Imamura Kawasawa Y, Mirowska- Guzel D, Postula M. Increased burden of rare deleterious variants of the KCNQ1 gene in patients with large /i2 vessel ischemic stroke. Mol Med Rep. 2019;19(4):3263-3272. doi:10.3892/mmr.2019.9987 558. Murali V, Rathika C, Ramgopal S, Padma Malini R, Arun Kumar MJ, Neethi Arasu V, Jeyaram Illiayaraja K, Balakrishnan K. Susceptible and protective associations of HLA DRB1*/ DQB1* alleles and haplotypes with (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint ischaemic stroke. Int J Immunogenet. 2016;43(3):159-165. doi:10.1111/iji.12266 559. Fan J, Cao S, Chen M, Yao Q, Zhang X, Du S, Qu H, Cheng Y, Ma S, Zhang M, et al. Investigating th e AC079305/DUSP1 Axis as Oxidative Stress-Related Signatures and Immune Infiltration Characteristics in Ischemic Stroke. Oxid Med Cell Longev. 2022;2022:8432352. doi:10.1155/2022/8432352 560. Zhou YF, Chen AQ, Wu JH, Mao L, Xia YP, Jin HJ, He QW, Miao QR, Yue ZY, Liu XL, et al. Sema 3E/PlexinD1 signaling inhibits postischemic angiogenesis by regulati ng endothelial DLL4 and filopodia formation in a rat model of ischemic stroke. FASEB J. 2019;33(4):4947- 4961. doi:10.1096/fj.201801706RR 561. Xu L, Wang Y. Combined influence of ABCB1 genetic polymorphism and DNA methylation on aspirin resistance in Chinese ischemic stroke patients. Acta Neurol Belg. 2022;122(4):1057-1064. doi:10.1007/s13760-021-01714-1 562. Yin Y, Zhang Y, Zhang X, Zhang Q, Wang J, Yang T, Liang C, Li W, Liu J, Ma X, et al. Association of MMP3, MMP14, and MMP25 gene polymorphisms with cerebral stroke risk: a case-control study. BMC Med Genomics. 2023;16(1):297. doi:10.1186/s12920-023-01734-1 563. Muthusamy N, Brumm A, Zhang X, Carmichael ST, Ghashghaei HT. Foxj1 expressing ependymal cells do not contribute new cells to sites of injury or stroke in the mouse forebrain. Sci Rep. 2018;8(1):1766. doi:10.1038/s41598-018-19913-x 564. Haarmann A, Zimmermann L, Bieber M, Silwedel C, Stoll G, Schuhmann MK. Regulation and Release of Vasoactive Endoglin by Brain Endothelium in Response to Hypoxia/Reoxygenation in Stroke. Int J Mol Sci. 2022;23(13):7085. doi:10.3390/ijms23137085 565. Zhang Z, Su G, Guo J, et al. Pooled genetic analysis reveals an association of SNPs of only a few genes with risk predisposition to ischemic stroke in a Chinese population. IUBMB Life. 2015;67(3):170-174. doi:10.1002/iub.1359 566. Zhang L, Sui R. Effect of SNP polymorphisms of EDN1, EDNRA, and EDNRB gene on ischemic stroke. Cell Biochem Biophys. 2014;70(1):233-239. doi:10.1007/s12013-014-9887-6 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 567. Can Demirdö ğ en B, Miçoo ğ ulları Y, Türkano ğ lu Özçelik A, Adalı O. Missense Genetic Polymorphisms of Microsomal (EPHX1) and Soluble Epoxide Hydrolase (EPHX2) and Their Relation to the Risk of Large Artery Atherosclerotic Ischemic Stroke in a Turkish Population. Neuropsychiatr Dis Treat. 2021;16:3251-3265. doi:10.2147/NDT.S233992 568. Secondo A, Petrozziello T, Tedesc hi V, Boscia F, Vinciguerra A, Ciccone R, Pannaccione A, Molinaro P, Pignataro G, Annunziato L. ORAI1/STIM1 Interaction Intervenes in Stroke and in Neuroprotection Induced by Ischemic Preconditioning Through Store-Operated Calcium Entry. Stroke. 2019;50(5):1240-1249. doi:10.1161/STROKEAHA.118.024115 569. Nishie H, Nakano-Doi A, Sawano T, Nakagomi T. Establishment of a Reproducible Ischemic Stroke Model in Nestin-GFP Mice with High Survival Rates. Int J Mol Sci. 2021;22(23):12997. doi:10.3390/ijms222312997 570. C h i W , M e n g F , L i Y , W a n g Q , W a n g G , H a n S , W a n g P , L i J . Downregulation of miRNA-134 protects neural cells against ischemic injury in N2A cells and mouse brain with ischemic stroke by targeting HSPA12B. Neuroscience. 2014;277:111-122. doi:10.1016/j.neuroscience.2014.06.062 571. Gillis HL, Kalinina A, Xue Y, Yan K, Turcotte-Cardin V, Todd MAM, Young KG, Lagace D, Picketts DJ. VGF is required for recovery after focal stroke. Exp Neurol. 2023;362:114326. doi:10.1016/j.expneurol.2023.114326 572. Sandelius Å, Cullen NC, Källén Å, Rosengren L, Jensen C, Kostanjevecki V, Vandijck M, Zetterberg H, Blennow K. Transient increase in CSF GAP-43 concentration after ischemic stroke. BMC Neurol. 2018;18(1):202. doi:10.1186/s12883-018-1210-5 573. Wang PR, Masuda Y, Kitamura H, Yamanaka N. Tubulointerstitial injury of Thy-1 nephritis in uninephrectomized stroke-prone spontaneously hypertensive rats. J Nippon Med Sch. 2001;68(4):301-309. doi:10.1272/jnms.68.301 574. Gao XZ, Ma RH, Zhang ZX. miR-339 Promotes Hypoxia-Induced Neuronal Apoptosis and Impairs Cell Viability by Targeting FGF9/CACNG2 and Mediating MAPK Pathway in Ischemic Stroke. Front Neurol. 2020;11:436. doi:10.3389/fneur.2020.00436 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 575. Jia C, Lovins C, Malone HM, Keasey MP, Hagg T. Female-specific neuroprotection after ischemic stroke by vitronectin-focal adhesion kinase inhibition. J Cereb Blood Flow Metab. 2022;42(10):1961-1974. doi:10.1177/0271678X221107871 576. Ma M, Zhao J, Xie D, Chen J. Association between GABRG2 Gene Single Nucleotide Polymorphisms and Susceptibility to Ischemic Stroke in a Chinese Population. J Integr Neurosci. 2023;22(6):151. doi:10.31083/j.jin2206151 577. Bu F, Min JW, Munshi Y, Lai YJ , Qi L, Urayama A, McCullough LD, Li J. Activation of endothelial ras-related C3 botulinum toxin substrate 1 (Rac1) improves post-stroke recovery and angiogenesis via activating Pak1 in mice. Exp Neurol. 2019;322:113059. doi:10.1016/j.expneurol.2019.113059 578. Schulz A, Wagner F, Ungelenk M, Kurth I, Redecker C. Stroke-like onset of brain stem degeneration presents with unique MRI sign and heterozygous NMNAT2 variant: a case report. Transl Neurodegener. 2016;5:23. doi:10.1186/s40035-016-0069-x 579. Zhao L, Zhang M, Yan F, Cong Y. Knockdown of RMST Impedes Neuronal Apoptosis and Oxidative Stress in OGD/R-Induced Ischemic Stroke Via Depending on the miR-377/SEMA3A Signal Network. Neurochem Res. 2021;46(3):584-594. doi:10.1007/s11064-020-03194-w 580. Ren C, Kobeissy F, Alawieh A, Li N, Li N, Zibara K, Zoltewicz S, Guingab-Cagmat J, Larner SF, Ding Y, et al. Assessment of Serum UCH-L1 and GFAP in Acute Stroke Pa tients. Sci Rep. 2016;6:24588. doi:10.1038/srep24588 581. Hu Y, Cao X, Zhao Y, Jin Y, Li F, Xu B, Zhao M, Chen Y, Du B, Sun Y, et al. The Function of Spag6 to Repair Brain Edema Damage After Cerebral Ischemic Stroke-reperfu sion. Neuroscience. 2023;522:132-149. doi:10.1016/j.neuroscience.2023.04.014 582. Mages B, Fuhs T, Aleithe S, Blietz A, Hobusch C, Härtig W, Schob S, Krueger M, Michalski D. The Cytoskeletal Elements MAP2 and NF-L Show Substantial Alterations in Different Stroke Models While Elevated Serum Levels Highlight Especially MAP2 as a Sensitive Biomarker in Stroke Patients. Mol Neurobiol. 2021;58(8):4051-4069. doi: 10.1007/s12035-021- 02372-3 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 583. Lu M, Liu Y, Xian Z, Yu X, Chen J, Tan S, Zhang P, Guo Y. VEGF to CITED2 ratio predicts the collateral circulation of acute ischemic stroke. Front Neurol. 2022;13:1000992. doi:10.3389/fneur.2022.1000992 584. Hwang JA, Choi SK, Kim SH, Kim DW. Pharmacological Inhibition of LRRK2 Exhibits Neuroprotective Activity in Mouse Photothrombotic Stroke Model. Exp Neurobiol. 2024;33(1):36-45. doi:10.5607/en23023 585. Fırtına ÖB, Salt Ö, Sayhan MB, Dibirdik I, Yucal A. Value of plasma alpha- and beta-synuclein levels in the diagnosis, severity, and functional outcome of acute ischemic stroke. Turk J Emerg Med. 2024;24(4):238-244. doi:10.4103/tjem.tjem_17_24 586. McCrory M, Murphy DF, Morris RC, Noad RF. Evaluating the GAD- 2 to screen for post-stroke anxiety on an acute stroke unit. Neuropsychol Rehabil. 2023;33(3):480-496. doi:10.1080/09602011.2022.2030366 587. Sharifulina S, Dzreyan V, Guzenko V, Demyanenko S. Histone Methyltransferases SUV39H1 and G9a and DNA Methyltransferase DNMT1 in Penumbra Neurons and Astrocytes after Photothrombotic Stroke. Int J Mol Sci. 2021;22(22):12483. doi:10.3390/ijms222212483 588. Birjandi SZ, Abduljawad N, Nair S, Dehghani M, Suzuki K, Kimura H, Carmichael ST. Phosphodiesterase 10A Inhibition Leads to Brain Region-Specific Recovery Based on Stroke Type. Transl Stroke Res. 2021;12(2):303-315. doi:10.1007/s12975-020-00819-8 589. Deng ZH, Chen YX, Xue-Gao, Yang JY, Wei XY, Zhang GX, Qian JX. Mesenchymal stem cell-derived exosomes ameliorate hypoxic pulmonary hypertension by inhibiti ng the Hsp90aa1/ERK/pERK pathway. Biochem Pharmacol. 2024;226:116382. doi:10.1016/j.bcp.2024.116382 590. Chen YX, Deng ZH, Xue-Gao, Qiang-Du, Juan-Yin, Chen GH, Li JG, Zhao YM, Zhang HT, Zhang GX, et al. Exosomes derived from mesenchymal stromal cells exert a therapeutic effect on hypoxia-induced pulmonary hypertension by modulatin g the YAP1/SPP1 signaling pathway. Biomed Pharmacother. 2023;168:115816. doi:10.1016/j.biopha.2023.115816 591. Clapham KR, Rao Y, Sahay S, Sauler M, Lee PJ, Psotka MA, Fares WH, Ahmad T. PECAM-1 is Associated WithOutcomes and Response to Treatment in Pulmonary Arterial Hypertension. Am J Cardiol. 2020;127:198-199. doi:10.1016/j.amjcard.2020.04.031 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 592. Li Y, Li H, Xing W, Li J, Du R, Cao D, Wang Y, Yang X, Zhong G, Zhao Y, et al. Vascular smooth muscle cell-specific miRNA-214 knockout inhibits angiotensin II-induced hypertension through upregulation of Smad7. FASEB J. 2021;35(11):e21947. doi:10.1096/fj.202100766RR 593. Barberis MC, Veronese S, Baue r D, De Juli E, Harari S. Immunocytochemical detection of progesterone receptors. A study in a patient with primary pulmonary hypertension. Chest. 1995;107(3):869-872. doi:10.1378/chest.107.3.869 594. Murakoshi M, Iwasawa T, Koshida T, Suzuki Y, Gohda T, Kato K. Development of an In-House EphA2 ELISA for Human Serum and Measurement of Circulating Levels of EphA2 in Hypertensive Patients with Renal Dysfunction. Diagnostic s (Basel). 2022;12(12):3023. doi:10.3390/diagnostics12123023 595. Han X, Li W, Chen C, Liu J, Sun J, Wang F, Wang C, Mu J, Gu X, Liu F, et al. Genetic variants and mRNA expression of KLF4 and KLF5 with hypertension: A combination of case-control study and cohort study. J Biomed Res. 2024. doi:10.7555/JBR.38.20240208 596. Tian DZ, Wei W, Dong YJ. Influence of COL1A2 gene variants on the incidence of hypertensive intr acerebral hemorrhage in a Chinese population. Genet Mol Res. 2016;15(1):10.4238/gmr.15017369. doi:10.4238/gmr.15017369 597. Morris BJ, Chen R, Donlon TA, Kallianpur KJ, Masaki KH, Willcox BJ. Vascular endothelial growth factor receptor 1 gene (FLT1) longevity variant increases lifespan by reducing mortality risk posed by hypertension. Aging (Albany NY). 2023;15(10):3967-3983. doi:10.18632/aging.204722 598. Nagata T, Nakagawa K, Tsurumi F, Watanabe K, Endo T, Hata A. A case of novel NFKB2 variant with hy pertensive emergency and nephrotic syndrome leading to CKD 5D. Pediatr Nephrol. 2024;39(9):2637-2640. doi:10.1007/s00467-024-06334-4 599. Jouneau S, Ballerie A, Kerjouan M, Demant X, Blanchard E, Lederlin M. Haemodynamically proven pulmonary hypertension in a patient with GATA2 deficiency-associated pulmonary alveolar pr oteinosis and fibrosis. Eur Respir J. 2017;49(5):1700407. doi:10.1183/13993003.00407-2017 600. Fähling M, Paliege A, Jönsson S, Becirovic-Agic M, Melville JM, Skogstrand T, Hultström M. NFAT5 re gulates renal gene expression in (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint response to angiotensin II through A nnexin-A2-mediated posttranscriptional regulation in hypertensive rats. Am J Physiol Renal Physiol. 2019;316(1):F101-F112. doi:10.1152/ajprenal.00361.2018 601. Perepechaeva ML, Stefanova NA, Grishanova AY, Kolosova NG. The Expression of Genes CYP1A1, CYP1B1, and CYP2J3 in Distinct Regions of the Heart and Its Possible Contribution to the Development of Hypertension. Biomedicines. 2024;12(10):2374. doi:10.3390/biomedicines12102374 602. Yan X, Huang J, Zeng Y, Zhong X, Fu Y, Xiao H, Wang X, Lian H, Luo H, Li D, et al. CGRP attenuates pulmonary vascular remodeling by inhibiting the cGAS-STING-NF κ B pathway in pulmonary arterial hypertension. Biochem Pharmacol. 2024;222:116093. doi:10.1016/j.bcp.2024.116093 603. Wetzl V, Tiede SL, Faerber L, Weissmann N, Schermuly RT, Ghofrani HA, Gall H. Plasma MMP2/TIMP4 Ratio at Follow-up Assessment Predicts Disease Progression of Idiopathic Pulmonary Arterial Hypertension. Lung. 2017;195(4):489-496. doi:10.1007/s00408-017-0014-5 604. Wang N, Hua J, Fu Y, An J, Chen X, Wang C, Zheng Y, Wang F, Ji Y, Li Q. Updated perspective of EPAS1 and the role in pulmonary hypertension. Front Ce ll Dev Biol. 2023;11:1125723. doi:10.3389/fcell.2023.1125723 605. Li Y, Cai H, Wei J, Zhu L, Yao Y, Xie M, Song L, Zhang C, Huang X, et al. Dihydroartemisinin Attenuates Hypoxic Pulmonary Hypertension via the Downregulation of miR-335 Targeting Vangl2. DNA Cell Biol. 2022;41(8):750-767. doi:10.1089/dna.2021.1113 606. Alsheikh AJ, Dasinger JH, Abais-Battad JM, Fehrenbach DJ, Yang C, Cowley AW Jr, Mattson DL. CCL2 mediates early renal leukocyte infiltration during salt-sensitive hypertension. Am J Physiol Renal Physiol. 2020;318(4):F982-F993. doi:10.1152/ajprenal.00521.2019 607. Singh A, Zapata RC, Pezeshki A, Knight CG, Tuor UI, Chelikani PK. Whey Protein and Its Components L actalbumin and Lactoferrin Affect Energy Balance and Protect against Stroke Onset and Renal Damage in Salt- Loaded, High-Fat Fed Male Spontaneously Hypertensive Stroke-Prone Rats. J Nutr. 2020;150(4):763-774. doi:10.1093/jn/nxz312 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 608. Huang KC, Li TM, Liu X, Chen JH, Chien WK, Shiao YT, Tsang H, Lin TH, Liao CC, Huang SM, et al.KCNQ1 variants associate with hypertension in type 2 diabetes and affect smooth muscle contractility in vitro. J Cell Physiol. 2017;232(12):3309-3316. doi:10.1002/jcp.25775 609. Zhu F, Sun Y, Wang M, Ma S, Chen X, Cao A, Chen F, Qiu Y, Liao Y. Correlation between HLA-DRB1, HLA-DQB1 polymorphism and autoantibodies against angiotensin AT(1) receptors in Chinese patients with essential hypertension. Clin Cardiol. 2011;34(5):302-308. doi:10.1002/clc.20852 610. Chen Y, Ye C, Chen J, Lin D, Wang H, Wang S. Association of the gene polymorphisms of BMPR2, ACVR L1, SMAD9 and their interactions with the risk of essential hypertension in the Chinese Han population. Biosci Rep. 2019;39(1):BSR20181217. doi:10.1042/BSR20181217 611. Wu T, Zhang BQ, Raelson J, Yao YM, Wu HD, Xu ZX, Marois- Blanchet FC, et al. Analysis of the association of EPHB6, EFNB1 and EFNB3 variants with hypertension ri sks in males with hypogonadism. Sci Rep. 2018;8(1):14497. doi:10.1038/s41598-018-32836-x 612. Pan Z, Yao Y, Liu X, Wang Y, Zhang X, Zha S, Hu K. Nr1d1 inhibition mitigates intermittent hypoxia-induced pulmonary hypertension via Dusp1-mediated Erk1/2 deactivation and mitochondrial fission attenuation. Cell Death Discov. 2024;10(1):459. doi: 10.1038/s41420-024- 02219-5 613. Z h a n g X , Z h a n g C , L i Q , P i a o C , Z h a n g H , G u H . C l i n i c a l characteristics and prognosis analys is of idiopathic and hereditary pulmonary hypertension patients with ACVRL1 gene mutations. Pulm Circ. 2021;11(4):20458940211044577. doi:10.1177/20458940211044577 614. Tan G, Juan C, Mao Y, Xue G, Fang Z. Inhibition of DLL4/Notch Signaling Pathway Promotes M2 Polarization and Cell Proliferation in Pulmonary Arterial Hypertension. ACS Omega. 2024;9(36):37923-37933. doi:10.1021/acsomega.4c04307 615. Gallego-Zazo N, Miranda-Alcaraz L, Cruz-Utrilla A, Del Cerro Marín MJ, Álvarez-Fuente M, Del Mar Rodríguez Vázquez Del Rey M, Guillén Rodríguez I, Becerra-Munoz VM, Moya-Bonora A, Ochoa Parra N, et al. Seven Additional Patients with SOX17 Related Pulmonary Arterial (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Hypertension and Review of the Literature. Genes (Basel). 2023;14(10):1965. doi:10.3390/genes14101965 616. Du M, Kou L, Li S. Water-soluble chitosan regulates vascular remodeling in hypertension via NFAT c1. Eur Heart J Suppl. 2016;18(Suppl F):F38. doi:10.1093/eurheartj/suw037 617. Laggner M, Hacker P, Oberndorfer F, Bauer J, Raunegger T, Gerges C, Szerafin T, Thanner J, Lang I, Skoro-Sajer N, et al. The Roles of S100A4 and the EGF/EGFR Signaling Axis in Pulmonary Hypertension with Right Ventricular Hypertrophy. Biol ogy (Basel). 2022;11(1):118. doi:10.3390/biology11010118 618. Sychev D, Shikh N, Morozova T, Grishina E, Ryzhikova K, Malova E. Effects of ABCB1 rs1045642 polymorphisms on the efficacy and safety of amlodipine therapy in Caucasian patients with stage I-II hypertension. Pharmgenomics Pers Med. 2018;11:157-165. doi:10.2147/PGPM.S158401 619. Hong J, Medzikovic L, Sun W, Wong B, Ruffenach G, Rhodes CJ, Brownstein A, Liang LL, Aryan L, Li M, et al. Integrative Multiomics in the Lung Reveals a Protective Role of Asporin in Pulmonary Arterial Hypertension. Circulation. 2024;150(16):1268-1287. doi:10.1161/CIRCULATIONAHA.124.069864 620. Guo XG, Ding J, Xu H, Xuan TM, Jin WQ, Yin X, Shang YP, Zhang FR, Zhu JH, et al. Comprehensive assessment of the association of WNK4 polymorphisms with hypertension: evid ence from a meta-analysis. Sci Rep. 2014;4:6507. doi:10.1038/srep06507 621. Yang L, Liang H, Shen L, Guan Z, Meng X. LncRNA Tug1 involves in the pulmonary vascular remodeling in mice with hypoxic pulmonary hypertension via the microRNA- 374c-mediated Foxc1. Life Sci. 2019;237:116769. doi:10.1016/j.lfs.2019.116769 622. Isobe S, Nair RV, Kang HY, Wang L, Moonen JR, Shinohara T, Cao A, Taylor S, Otsuki S, Marciano DP, et al. Reduced FOXF1 links unrepaired DNA damage to pulmonary arterial hypertension. Nat Commun. 2023;14(1):7578. doi:10.1038/s41467-023-43039-y 623. Seidel E, Schewe J, Zhang J, Dinh HA, Forslund SK, Markó L, Hellmig N, Peters J, Muller DN, Lifton RP, et al. Enhanced Ca2+ signaling, mild primary aldosteronism, and hypertension in a familial (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint hyperaldosteronism mouse model (Cacna1hM1560V/+ ). Proc Natl Acad Sci U S A. 2021;118(17):e2014876118. doi:10.1073/pnas.2014876118 624. Gallardo-Vara E, Gamella-Pozuelo L, Perez-Roque L, Bartha JL, Garcia-Palmero I, Casal JI, López-Novoa JM, Pericacho M, Bernabeu C. Potential Role of Circulating Endoglin in Hypertension via the Upregulated Expression of BMP4. Cells. 2020;9(4):988. doi:10.3390/cells9040988 625. Nakano N, Hori H, Abe M, Shibata H, Arimura T, Sasaoka T, Sawabe M, Chida K, Arai T, Nakahara K, et al. Interaction of BMP10 with Tcap may modulate the course of hypertensive cardiac hypertrophy. Am J Physiol Heart Circ Physiol. 2007;293(6):H3396-H3403. doi:10.1152/ajpheart.00311.2007 626. Capri Y, Kwon T, Boyer O, Bourmance L, Testa N, Baudouin V, Bonnefoy R, Couderc A, Meziane C, Tour nier-Lasserve E, et al. Biallelic NPR1 loss of function variants are responsible for neonatal systemic hypertension. J Med Gene t. 2023;60(10):993-998. doi: 10.1136/jmg-2023- 109176 627. Huang CC, Chung CM, Yang CY, Leu HB, Huang PH, Lin LY, Wu TC, Lin SJ, Pan WH, Chen JW. SLC12A3 Variation and Renal Function in Chinese Patients With Hypertension. Front Med (Lausanne). 2022;9:863275. doi:10.3389/fmed.2022.863275 628. Masson B, Le Ribeuz H, Sabourin J, Laubry L, Woodhouse E, Foster R, Ruchon Y, Dutheil M, Boët A, Ghigna MR, et al. Orai1 Inhibitors as Potential Treatments for Pulmonary Arterial Hypertension. Circ Res. 2022;131(9):e102-e119. doi:10.1161/CIRCRESAHA.122.321041 629. Li XM, Ling Y, Lu DR, Lu ZQ, Liu Y, Chen HY, Gao X. The obesity-related polymorphism PCSK1 rs6235 is associated with essential hypertension in the Han Chinese population. Hypertens Res. 2012;35(10):994-999. doi:10.1038/hr.2012.79 630. Fargali S, Garcia AL, Sadahiro M, Jiang C, Janssen WG, Lin WJ, Cogliani V, Elste A, Mortillo S, Cero C, et al. The granin VGF promotes genesis of secretory vesicles, and regulates circulating catecholamine levels and blood pressure. FASEB J. 2014;28(5):2120-2133. doi: 10.1096/fj.13- 239509 631. C h e n Y , L i S , X u Z , Z h a n g Y , Z h a n g H , S h i L . A e r o b i c t r a i n i n g - mediated DNA hypermethylation of Agtr1a and Mas1 genes ameliorate (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint mesenteric arterial function in spontaneously hypertensive rats. Mol Biol Rep. 2021;48(12):8033-8044. doi:10.1007/s11033-021-06929-2 632. Li Q, Wong JH, Lu G, Antonio GE, Yeung DK, Ng TB, Forster LE, Yew DT. Gene expression of synaptosomal-associated protein 25 (SNAP- 25) in the prefrontal cortex of the spontaneously hypert ensive rat (SHR). Biochim Biophys Acta. 2009;1792(8):766-776. doi:10.1016/j.bbadis.2009.05.006 633. Kobayashi Y, Yatsu K, Haruna A, Kawano R, Ozawa M, Haze T, Komiya S, Suzuki S, Ohki Y, Fujiwara A, et al. ATP2B1 gene polymorphisms associated with resistant hypertension in the Japanese population. J Clin Hypertens (Greenwich). 2024;26(4):355-362. doi:10.1111/jch.14785 634. Yeo Y, Yi ES, Kim JM, Jo EK, Seo S, Kim RI, Kim KL, Sung JH, Park SG, Suh W. et al. FGF12 (Fibro blast Growth Factor 12) Inhibits Vascular Smooth Muscle Cell Remodeling in Pulmonary Arterial Hypertension. Hyperten sion. 2020;76(6):1778-1786. doi:10.1161/HYPERTENSIONAHA.120.15068 635. Sahoo S, Meijles DN, Al Ghouleh I, Tandon M, Cifuentes-Pagano E, Sembrat J, Rojas M, Goncharova E, Pagano PJ. MEF2C-MYOCD and Leiomodin1 Suppression by miRNA-214 Promotes Smooth Muscle Cell Phenotype Switching in Pulmonary Arterial Hypertension. PLoS One. 2016;11(5):e0153780. doi:10.1371/journal.pone.0153780 636. Hong KW, Go MJ, Jin HS, Lim JE, Lee JY, Han BG, Hwang SY, Lee SH, Park HK, Cho YS, et al. Genetic variations in ATP2B1, CSK, ARSG and CSMD1 loci are related to blood pr essure and/or hype rtension in two Korean cohorts. J Hum Hypertens. 2010;24(6):367-372. doi:10.1038/jhh.2009.86 637. Zhang QY, Guo Y, Jiang XL, Liu X, Zhao SG, Zhou XL, Yang ZW. Intestinal Cckbr-specific knockout mouse as a novel model of salt-sensitive hypertension via sodium over-absorption. J Geriatr Cardiol. 2023;20(7):538- 547. doi:10.26599/1671-5411.2023.07.001 638. Agrud A, Subburaju S, Goel P, Ren J, Kumar AS, Caldarone BJ, Dai W, Chavez J, Fukumura D, Jain RK, et al. Gabrb3 endothelial cell-specific knockout mice display abnormal blood flow, hypertension, and behavioral dysfunction. Sci Rep. 2022;12(1):4922. doi:10.1038/s41598-022-08806-9 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 639. Olinger E, Phakdeekitcharoen P, Caliskan Y, Orr S, Mabillard H, Pickles C, Tse Y, Wood K; Genomics England Research Consortium; Sayer JA. Biallelic variants in TTC21B as a rare cause of early-onset arterial hypertension and tubuloglomerular kidney disease. Am J Med Genet C Semin Med Genet. 2022;190(1):109-120. doi:10.1002/ajmg.c.31964 640. Viazzi F, Ramesh G, Jayakumar C, Leoncini G, Garneri D, Pontremoli R. Increased urine semapho rin-3A is associated with renal damage in hypertensive patients with chronic kidney disease: a nested case- control study. J Nephrol. 2015;28(3):315-320. doi: 10.1007/s40620-014- 0097-5 641. Tang H, Gupta A, Morrisroe SA, Bao C, Schwantes-An TH, Gupta G, Liang S, Sun Y, Chu A, et al. Deficiency of the Deubiquitinase UCHL1 Attenuates Pulmonary Arterial Hypert ension. Circulation. 2024;150(4):302- 316. doi:10.1161/CIRCULATIONAHA.123.065304 642. Laggner M, Oberndorfer F, Golabi B, Bauer J, Zuckermann A, Hacker P, Lang I, Skoro-Sajer N, Gerges C, Taghavi S, et al. EGR1 Is Implicated in Right Ventricular Cardiac Remodeling Associated with Pulmonary Hypertension. Biology (Basel). 2022;11(5):677. doi:10.3390/biology11050677 643. L i D , S h a o N Y , M o o n e n J R , Z h a o Z , S h i M , O t s u k i S , W a n g L , Nguyen T, Yan E, Marciano DP, et al. ALDH1A3 Coordi nates Metabolism With Gene Regulation in Pulmonary Arterial Hypertension. Circulation. 2021;143(21):2074-2090. doi:10.1161/CIRCULATIONAHA.120.048845 644. Liang J, Zhang X, Xia W, Tong X, Qiu Y, Qiu Y, He J, Yu B, Huang H, Tao J. Promotion of Aerobic Exercise Induced Angiogenesis Is Associated With Decline in Blood Pr essure in Hypertension: Result of EXCAVATION-CHN1. Hypertension. 2021;77(4):1141-1153. doi:10.1161/HYPERTENSIONAHA.120.16107 645. Tanaka S, Yamamoto T, Mikawa M, Nawata J, Fujii S, Nakamura Y, Kato T, Fukuda M, Suetomi T, Uchinoumi H, et al. Stabilization of RyR2 maintains right ventricular function, reduces the development of ventricular arrhythmias, and improves prognosis in pulmonary hypertension. Heart Rhythm. 2022;19(6):986-997. doi:10.1016/j.hrthm.2022.02.003 646. Schinagl C, Melum GR, Rødningen OK, Bjørgo K, Andresen JH. Severe persistent pulmonary hyperten sion of the newborn and dysmorphic (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint features in neonate with a deletion involving TWIST1 and PHF14: a case report. J Med Case Rep. 2017;11(1):226. doi:10.1186/s13256-017-1402-4 647. Zhu H, Zhu L, Fang Z, Yang S, Chen Y, Jin Y, Zhao X, Shen C, Yao Y. Common variants at somatostatin are significantly associated with hypertension incidence in smoking and drinking populations. J Am Soc Hypertens. 2018;12(3):230-237.e12. doi:10.1016/j.jash.2017.12.009 648. K e r a n o v S , D ö r r O , J a f a r i L , L i e b e t r a u C , K e l l e r T , T r o i d l C , Kriechbaum S, Voss S, Richter M, Tello K, et al. SPARCL1 as a biomarker of maladaptive right ventricular remodelling in pulmonary hypertension. Biomarkers. 2020;25(3):290-295. doi:10.1080/1354750X.2020.1745889 649. Zhang HL, Liu ZH, Luo Q, Wang Y, Zhao ZH. Abnormal expression of NSF, α -SNAP and SNAP23 in pulmonary arterial hypertension in rats treated with monocrotaline. Int J Clin Exp Med. 2015;8(2):1834-1843. 650. Wang LA, Nguyen DH, Mifflin SW. CRHR2 (Corticotropin- Releasing Hormone Receptor 2) in th e Nucleus of the Solitary Tract Contributes to Intermittent Hypoxia- Induced Hypertension. Hypertension. 2018;72(4):994-1001. doi:10.1161/HYPERTENSIONAHA.118.11497 651. Faruque MU, Chen G, Doumatey A, Huang H, Zhou J, Dunston GM, Rotimi CN, Adeyemo AA. Association of ATP1B1, RGS5 and SELE polymorphisms with hypertension and blood pressure in African-Americans. J Hypertens. 2011;29(10):1906-1912. doi:10.1097/HJH.0b013e32834b000d 652. Herrera VL, Pasion KA, Moran AM, Zaninello R, Ortu MF, Fresu G, Piras DA, Argiolas G, Troffa C, Glorioso V, et al. A functional 12T- insertion polymorphism in the AT P1A1 promoter confers decreased susceptibility to hypertension in a male Sardinian population. PLoS One. 2015;10(1):e0116724. doi:10.1371/journal.pone.0116724 653. Takahashi Y, Yamazaki K, Kamatani Y, Kubo M, Matsuda K, Asai S. A genome-wide association study identifies a novel candidate locus at the DLGAP1 gene with susceptibility to resi stant hypertension in the Japanese population. Sci Rep. 2021;11(1):19497. doi:10.1038/s41598-021-98144-z 654. Huang YY, Yu YF, Zhang C, Chen Y, Zhou Q, Li Z, Zhou S, Li Z, Guo L, Wu D, et al. Validation of Phosphodiesterase-10 as a Novel Target for Pulmonary Arterial Hypertension via Highly Selective and Subnanomolar Inhibitors. J Med Chem. 2019;62(7):3707-3721. doi:10.1021/acs.jmedchem.9b00224 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 655. Hu Y, Xia W, Li Y, Wang Q, Lin S, Wang B, Zhou C, Cui Y, Jiang Y, Pu X, et al. High-salt intake increases TRPC3 expression and enhances TRPC3-mediated calcium influx and systolic blood pressure in hypertensive patients. Hypertens Res. 2020;43(7):679-687. doi: 10.1038/s41440-020- 0409-1 656. Xiang X, You XM, Li LQ. Expression of HSP90AA1/HSPA8 in hepatocellular carcinoma patients with depression. Onco Targets Ther. 2018;11:3013-3023. doi:10.2147/OTT.S159432 657. Ma F, Bian H, Jiao W, Zhang N. Single-cell RNA-seq reveals the role of YAP1 in prefrontal cortex micr oglia in depression. BMC Neurol. 2024;24(1):191. doi:10.1186/s12883-024-03685-1 658. Huang K, Zhang X, Duan J, Wang R, Wu Z, Yang C, Yang L. STAT4 and COL1A2 are potential diagnostic biomarkers and therapeutic targets for heart failure comorbided with depression. Brain Res Bull. 2022;184:68-75. doi:10.1016/j.brainresbull.2022.03.014 659. Choi M, Wang SE, Ko SY, Kang HJ, Chae SY, Lee SH, Kim YS, Duman RS, Son H. Overexpression of human GATA-1 and GATA-2 interferes with spine formation and produces depressive behavior in rats. PLoS One. 2014;9(10):e109253. doi:10.1371/journal.pone.0109253 660. Dai Y, Wei T, Huang Y, Bei Y, Lin H, Shen Z, Yu L, Yang M, Xu H, He W, et al. Upregulation of HDAC9 in hippocampal neurons mediates depression-like behaviours by inhibiting ANXA2 degradation. Cell Mol Life Sci. 2023;80(10):289. doi:10.1007/s00018-023-04945-y 661. Chen S, Li J, Yan L, Zhang X, Huang J, Zhou P. Electroacupuncture alleviates the symptom of depression in mice by regulating the cGAS- STING-NLRP3 signaling. Aging (Albany NY). 2024;16(8):6731-6744. doi:10.18632/aging.205596 662. Bobiń ska K, Szemraj J, Czarny P, Gałecki P. Role of MMP-2, MMP- 7, MMP-9 and TIMP-2 in the development of recurrent depressive disorder. J Affect Disord. 2016;205:119-129. doi:10.1016/j.jad.2016.03.068 663. Curzytek K, Le ś kiewicz M. Targeting the CCL2-CCR2 axis in depressive disorders. Pharmacol Rep. 2021;73(4):1052-1062. doi:10.1007/s43440-021-00280-w 664. Zhang J, Xin H, Wang W, Li Y, Wu R, Wei L, Su S, Wang X, Wang X, Wang X, et al. Investigating the modulatory effects of lactoferrin on (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint depressed rats through 16S rDNA gene sequencing and LC-MS metabolomics analysis. Sci Rep. 2024;14(1):22111. doi: 10.1038/s41598- 024-72793-2 665. Chen MX, Oh YS, Kim Y. S100A10 and its binding partners in depression and antidepressant actions. Front Mol Neurosci. 2022;15:953066. doi:10.3389/fnmol.2022.953066 666. Zhao Y, Wang S, Chu Z, Dang Y, Zhu J, Su X. MicroRNA-101 in the ventrolateral orbital cortex (VLO) mo dulates depressive-like behaviors in rats and targets dual-specificity ph osphatase 1 (DUSP1). Brain Res. 2017;1669:55-62. doi:10.1016/j.brainres.2017.05.020 667. Oliveira S, Ardais AP, Bastos CR, Gazal M, Jansen K, de Mattos Souza L, da Silva RA, Kaster MP, Lara DR, Ghisleni G. Impact of genetic variations in ADORA2A gene on depression and symptoms: a cross- sectional population-based study. Pu rinergic Signal. 2019;15(1):37-44. doi:10.1007/s11302-018-9635-2 668. Brückl TM, Uhr M. ABCB1 genotyping in the treatment of depression. Pharmacogenom ics. 2016;17(18):2039-2069. doi:10.2217/pgs.16.18 669. Z h o ng J, L i S , Z en g W , L i X , G u C , L iu J, L u o X J. I n teg r at i o n o f GWAS and brain eQTL identifies FLOT1 as a risk gene for major depressive disorder. Neuropsych opharmacology. 2019;44(9):1542-1551. doi:10.1038/s41386-019-0345-4 670. Wohleb ES, Terwilliger R, Duman CH, Duman RS. Stress-Induced Neuronal Colony Stimulating Factor 1 Provokes Microglia-Mediated Neuronal Remodeling and Depressive-like Behavior. Biol Psychiatry. 2018;83(1):38-49. doi:10.1016/j.biopsych.2017.05.026 671. Yun S, Donovan MH, Ross MN, Richardson DR, Reister R, Farnbauch LA, Fischer SJ, Riethmacher D, Gershenfeld HK, Lagace DC, et al. Stress-Induced Anxiety- and Depressive-Like Phenotype Associated with Transient Reduction in Neurogenesis in Adult Nestin-CreERT2/Diphtheria Toxin Fragment A Transgenic Mice. PLoS One. 2016;11(1):e0147256. doi:10.1371/journal.pone.0147256 672. Li YJ, Kresock E, Kuplicki R, Savitz J, McKinney BA. Differential expression of MDGA1 in major depressive disorder. Brain Behav Immun Health. 2022;26:100534. doi:10.1016/j.bbih.2022.100534 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 673. Ye Q, Zhang Y, Zhang Y, Chen Z, Yu C, Zheng C, Yu H, Zhou D, Li X. Low VGF is associated with executive dysfunction in patients with major depressive disorder. J Psychiatr Res. 2022;152:182-186. doi:10.1016/j.jpsychires.2022.06.030 674. Han MH, Jiao S, Jia JM, Chen Y, Chen CY, Gucek M, Markey SP, Li Z. The novel caspase-3 substrate Gap43 is invol ved in AMPA receptor endocytosis and long-term depression. Mol Cell Proteomics. 2013;12(12):3719-3731. doi:10.1074/mcp.M113.030676 675. Webster MJ, Vawter MP, Freed WJ. Immunohistochemical localization of the cell adhesion molecules Thy-1 and L1 in the human prefrontal cortex patients with sc hizophrenia, bipolar disorder, and depression. Mol Psychiatry. 1999;4(1):46-52. doi:10.1038/sj.mp.4000450 676. Z e n g D , H e S , Y u S , L i G , M a C , W e n Y , S h e n Y , Y u Y , L i H . Analysis of the association of MI R124-1 and its target gene RGS4 polymorphisms with major depressive di sorder and antidepressant response. Neuropsychiatr Dis Treat. 2018;14:715-723. doi:10.2147/NDT.S155076 677. Barbiero I, Bianchi M, Kilstrup-Nielsen C. Therapeutic potential of pregnenolone and pregnenolone meth yl ether on depr essive and CDKL5 deficiency disorders: Focus on micr otubule targeting. J Neuroendocrinol. 2022;34(2):e13033. doi:10.1111/jne.13033 678. Wang X, Cheng W, Zhu J, Yin H, Chang S, Yue W, Yu H. Integrating genome-wide association study and expression quantit ative trait loci data identifies NEGR1 as a causal risk gene of major depression disorder. J Affect Disord. 2020;265:679-686. doi:10.1016/j.jad.2019.11.116 679. Yu S, Zhao Y, Luo Q, Gu B, Wang X, Cheng J, Wang Z, Liu D, Ho RCM, Ho CSH. Early life stress enhances the susceptibility to depression and interferes with neuroplasticity in the hippocampus of adolescent mice via regulating miR-34c-5p/SYT1 axis . J Psychiatr Res. 2024;170:262-276. doi:10.1016/j.jpsychires.2023.12.030 680. Wang Q, Wang Y, Ji W, Zhou G, He K, Li Z, Chen J, Li W, Wen Z, Shen J, et al. SNAP25 is associated with schizophrenia and major depressive disorder in the Han Chin ese population. J Clin Psychiatry. 2015;76(1):e76-e82. doi:10.4088/JCP.13m08962 681. Prats C, Arias B, Ortet G, Ibáñez MI, Moya J, Pomarol-Clotet E, Fañanás L, Fatjó-Vilas M. Neurotrophi ns role in depressive symptoms and (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint executive function performance: Association analysis of NRN1 gene and its interaction with BDNF gene in a no n-clinical sample. J Affect Disord. 2017;211:92-98. doi:10.1016/j.jad.2016.11.017 682. Shah MM. HCN1 channels: a new therapeutic target for depressive disorders?. Sci Signal. 2012;5(244):pe44. doi:10.1126/scisignal.2003593 683. Fuchsova B, Alvarez Juliá A, Rizavi HS, Frasch AC, Pandey GN. Expression of p21-activated kinases 1 and 3 is altered in the brain of subjects with depression. Neuros cience. 2016;333:331-344. doi:10.1016/j.neuroscience.2016.07.037 684. Yang W, Li S, Li XJ. AHI1: linking depression and impaired antiviral immune response. Cell Res. 2022;32(10):869-870. doi:10.1038/s41422-022- 00702-1 685. Ji W, Li T, Pan Y, Tao H, Ju K, Wen Z, Fu Y, An Z, Zhao Q, Wang T, et al. CNTNAP2 is significantly associated with schizophrenia and major depression in the Han Chinese population. Psychiatry Res. 2013;207(3):225- 228. doi:10.1016/j.psychres.2012.09.024 686. Auffenberg E, Hedrich UB, Barbieri R, Miely D, Groschup B, Wuttke TV, Vogel N, Lührs P, Zanardi I, Bertelli S, et al. Hyperexcitable interneurons trigger cortical spreadin g depression in an Scn1a migraine model. J Clin Invest. 2021;131(21):e142202. doi:10.1172/JCI142202 687. Huang G, Wang S, Yan J, Li C, Feng J, Chen Q, Zheng X, Li H, He Y, Young AJ, et al. Depression-/Anxiety-Like Behavior Alterations in Adult Slit2 Transgenic Mice. Front Behav Neurosci. 2021;14:622257. doi:10.3389/fnbeh.2020.622257 688. Fuchsova B, Alvarez Juliá A, Rizavi HS, Frasch AC, Pandey GN. Expression of p21-activated kinases 1 and 3 is altered in the brain of subjects with depression. Neuros cience. 2016;333:331-344. doi:10.1016/j.neuroscience.2016.07.037 689. Yang Y, Guan W, Sheng XM, Gu HJ. Role of Semaphorin 3A in common psychiatric illnesses such as schizophrenia, depression, and anxiety. Biochem Pharmacol. 2024;226:116358. doi:10.1016/j.bcp.2024.116358 690. Choi JE, Lee JJ, Kang W, Kim HJ, Cho JH, Han PL, Lee KJ. Proteomic Analysis of Hippocampus in a Mouse Model of Depression Reveals Neuroprotective Function of Ubiquitin C-terminal Hydrolase L1 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint (UCH-L1) via Stress-induced Cysteine Oxidative Mo difications. Mol Cell Proteomics. 2018;17(9):1803-1823. doi:10.1074/mcp.RA118.000835 691. Lee WH, Bondy C. Induction of EG R1/NGFI-A Gene Expression by Spreading Depression and Focal Cerebral Ischemia. Mol Cell Neurosci. 1993;4(3):225-230. doi:10.1006/mcne.1993.1028 692. Daftary S, Yon JM, Choi EK, Kim YB, Bice C, Kulikova A, Park J, Sherwood Brown E. Microtubule associat ed protein 2 in bipolar depression: Impact of pregnenolone. J Affect Disord. 2017;218:49-52. doi:10.1016/j.jad.2017.04.024 693. Kim YG, Chang HS, Won ES, Ham BJ, Lee MS. Serotonin-related polymorphisms in TPH1 and HTR5A genes are not associated with escitalopram treatment response in Ko rean patients with major depression. Neuropsychobiology. 2014;69(4):210-219. doi:10.1159/000362241 694. Filippone A, Cucinotta L, Bova V, Lanza M, Casili G, Paterniti I, Campolo M, Cuzzocrea S, Esposito E. Inhibition of LRRK2 Attenuates Depression-Related Symptoms in Mice with Moderate Traumatic Brain Injury. Cells. 2023;12(7):1040. doi:10.3390/cells12071040 695. Skiba A, Talarowska M, Szemraj J, Gałecki P. Is NRXN1 Gene Expression an Important Marker of Treatment of Depressive Disorders? A Pilot Study. J Pers Med. 2021;11(7):637. doi:10.3390/jpm11070637 696. Wang Z, Cheng X, Shuang R, Gao T, Zhao T, Hou D, Zhang Y, Yang J, Tao W. Dandouchi Polypeptide Alleviates Depressive-like Behavior and Promotes Hippocampal Neurogenesi s by Activating the TRIM67/NF- κ B Pathway in CUMS-Induced Mice. J Agric Food Chem. 2024;72(30):16726- 16738. doi:10.1021/acs.jafc.4c02183 697. Zhang H, Liu S, Qin Q, Xu Z, Qu Y, Wang Y, Wang J, Du Z, Yuan S, Hong S, et al. Genetic and Pharmacological Inhibition of Astrocytic Mysm1 Alleviates Depressive-Like Disorder s by Promoting ATP Production. Adv Sci (Weinh). 2022. doi:10.1002/advs.202204463 698. Figueroa KP, Gan SR, Perlman S, Wilmot G, Gomez CM, Schmahmann J, Paulson H, Shakkottai VG, Ying SH, Zesiewicz T, et al. C9orf72 repeat expansions as gene tic modifiers for depression in spinocerebellar ataxias. Mov Disord. 2018;33(3):497-498. doi:10.1002/mds.27258 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 699. Fee C, Banasr M, Sibille E. Somatostatin-Positive Gamma- Aminobutyric Acid Interneuron Deficits in Depression: Cortical Microcircuit and Therapeutic Perspectives. Biol Psychiatry. 2017;82(8):549- 559. doi:10.1016/j.biopsych.2017.05.024 700. Thaweethee-Sukjai B, Suttajit S, Thanoi S, Dalton CF, Reynolds GP, Nudmamud-Thanoi S. Parvalbumin Prom oter Methylation Altered in Major Depressive Disorder. Int J Med Sci. 2019;16(9):1207-1214. doi:10.7150/ijms.36131 701. Bilkei-Gorzo A, Racz I, Michel K, Zimmer A. Diminished anxiety- and depression-related behaviors in mice with selective deletion of the Tac1 gene. J Neurosci. 2002;22(22):10046-10052. doi: 10.1523/JNEUROSCI.22- 22-10046.2002 702. Sun L, Bai D, Lin M, Eerdenidalai, Zhang L, Wang F, Jin S. miR-96 Inhibits SV2C to Promote Depression-Like Behavior and Memory Disorders in Mice. Front Behav Neurosci. 2021;14:575345. doi:10.3389/fnbeh.2020.575345 703. Kirshenbaum GS, Saltzman K, Rose B, Petersen J, Vilsen B, Roder JC. Decreased neuronal Na+, K+ -ATP ase activity in Atp1a3 heterozygous mice increases susceptibility to depre ssion-like endophenotypes by chronic variable stress. Genes Br ain Behav. 2011;10(5):542-550. doi:10.1111/j.1601-183X.2011.00691.x 704. Li T, Tian Y, Li Q, Chen H, Lv H, Xie W, Han J. The Neurexin/N- Ethylmaleimide-sensitive Factor (NSF) Interaction Regulates Short Term Synaptic Depressi on. J Biol Chem. 2015;290(29):17656-17667. doi:10.1074/jbc.M115.644583 705. Amin M, Ott J, Gordon D, Wu R, Postolache TT, Vergare M, Gragnoli C. Comorbidity of Novel CRHR2 Gene Variants in Type 2 Diabetes and Depression. In t J Mol Sci. 2022;23(17):9819. doi:10.3390/ijms23179819 706. Tsetsenis T, Younts TJ, Chiu CQ, Kaeser PS, Castillo PE, Südhof TC. Rab3B protein is required for long -term depression of hippocampal inhibitory synapses and for normal reversal learning. Proc Natl Acad Sci U S A. 2011;108(34):14300-14305. doi:10.1073/pnas.1112237108 707. Gonda X, Eszlari N, Anderson IM, Deakin JF, Bagdy G, Juhasz G. Association of ATP6V1B2 rs1106634 with lifetime risk of depression and (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint hippocampal neurocognitive deficits: possible novel mechanisms in the etiopathology of depression. Tr ansl Psychiatry. 2016;6(11):e945. doi:10.1038/tp.2016.221 708. W a n g L , W a n g M , Z h a o C , J i a n J , Q i a o D . A s s o c i a t i o n o f H T R 3 B gene polymorphisms with depression and its executive dysfunction: a case- control study. BMC Psychiatry. 2023;23(1):128. doi: 10.1186/s12888-023- 04625-y 709. Costain G, Walker S, Argiropoulos B, Baribeau DA, Bassett AS, Boot E, Devriendt K, Kellam B, Marshall CR, Prasad A, et al. Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders. J Neurodev Disord. 2019;11(1):3. doi: 10.1186/s11689-019-9263- 3 710. Huang C, Yang X, Zeng B, Zeng L, Gong X, Zhou C, Xia J, Lian B, Qin Y, Yang L, et al. Proteomic analysis of olfactory bulb suggests CACNA1E as a promoter of CREB signaling in microbiota-induced depression. J Proteomics. 2019;194:132-147. doi:10.1016/j.jprot.2018.11.023 711. Lai J, Zhang P, Jiang J, Mou T, Li Y, Xi C, Wu L, Gao X, Zhang D, Chen Y, et al. New Evidence of Gut Microbiota Involvement in the Neuropathogenesis of Bi polar Depression by TRANK1 Modulation: Joint Clinical and Animal Data. Front Immunol. 2021;12:789647. doi:10.3389/fimmu.2021.789647 712. Lee JE, Park SY, Han PL. Aging- Dependent Downre gulation of SUV39H1 Histone Methyltransferase Increases Susceptibility to Stress- Induced Depressive Behavior. Mol Neurobiol. 2021;58(12):6427-6442. doi:10.1007/s12035-021-02529-0 713. Myrga JM, Juengst SB, Failla MD, Conley YP, Arenth PM, Grace AA, Wagner AK. OMT and ANKK1 Genetics Interact With Depression to Influence Behavior Following Severe TBI: An Initial Assessment. Neurorehabil Neural Repair. 2016;30(10):920-930. doi:10.1177/1545968316648409 714. Kim SJ. TRPC3 channel underlies cerebellar long-term depression. Cerebellum. 2013;12(3):334-337. doi:10.1007/s12311-013-0455-1 715. Lu X, Wang Y, Ma Y, Huang D, Lu Y, Liu X, Zhou R, Yu P, Zhang L, Chen J, et al. YAP1 induces marrow derived suppressor cell recruitment (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint in Chlamydia trachomatis infection. Immunol Lett. 2022;242:8-16. doi:10.1016/j.imlet.2021.12.003 716. Fuchs M, Trampuz A, Kirschbaum S, Winkler T, Sass FA. Soluble Pecam-1 as a Biomarker in Periprosthetic Joint Infection. J Clin Med. 2021;10(4):612. doi:10.3390/jcm10040612 717. Wu Y, Wu M, Ming S, Zhan X, Hu S, Li X, Yin H, Cao C, Liu J, Li J, et al. TREM-2 promotes Th1 responses by interacting with the CD3ζ -ZAP70 complex following Mycobacterium tuberculosis infection. J Clin Invest. 2021;131(17):e137407. doi:10.1172/JCI137407 718. Argentou N, Germanidis G, Hytiroglou P, Apostolou E, Vassiliadis T, Patsiaoura K, Sideras P, Germenis AE, Speletas M. TGF- β signaling is activated in patients with chronic HBV infection and repressed by SMAD7 overexpression after successful antiviral treatment. Inflamm Res. 2016;65(5):355-365. doi:10.1007/s00011-016-0921-6 719. Cao Y, Chen F, Zhu S, Zhu D, Qi H. Staphylococcus aureus infection initiates hypoxia-mediated STIP1 homology and U-box containing protein 1 upregulation to trigger osteomyelitis. Toxicon. 2024;248:108049. doi:10.1016/j.toxicon.2024.108049 720. Vincenzi M, Mercurio FA, Leone M. EPHA2 Receptor as a Possible Therapeutic Target in Viral Infections. Curr Med Chem. 2024;31(35):5670- 5701. doi:10.2174/0109298673256638231003111234 721. Nawandar DM, Wang A, Makielski K, Lee D, Ma S, Barlow E, Reusch J, Jiang R, Wille CK, Greenspan D, et al. Differentiation-Dependent KLF4 Expression Promotes Lytic Epstein-Barr Virus Infection in Epithelial Cells. PLoS Pathog. 2015;11(10):e1005195. doi:10.1371/journal.ppat.1005195 722. Aird A, Lagos M, Vargas-Hernández A, Posey JE, Coban-Akdemir Z, Jhangiani S, Mace EM, Reyes A, King A, Cavagnaro F, et al. Novel Heterozygous Mutation in NFKB2 Is Associated With Early Onset CVID and a Functional Defect in NK Cells Complicated by Disseminated CMV Infection and Severe Nephrotic Sy ndrome. Front Pediatr. 2019;7:303. doi:10.3389/fped.2019.00303 723. Chen YC, Hsiao CC, Chen TW, Wu CC, Chao TY, Leung SY, Eng HL, Lee CP, Wang TY, Lin MC. Whole Genome DNA Methylation Analysis of Active Pulmonary Tuberculosis Disease Identifies Novel (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Epigenotypes: PARP9/miR-505/RASG RP4/GNG12 Gene Methylation and Clinical Phenotypes. Int J Mol Sci. 2020;21(9):3180. doi:10.3390/ijms21093180 724. Suzuk i T, Tak ay a S, Kunimats u J, Ku tsuna S, H ay ak awa K, Shibata H, Yasumi T, Ohmagari N. GATA 2 mutation underlies hemophagocytic lymphohistiocytosis in an adult with primary cytomegalovirus infection. J Infect Chemother. 2020;26(2):252-256. doi:10.1016/j.jiac.2019.07.002 725. Wang T, Zhao D, Zhang Y, Yu D, Liu G, Zhang K. Annexin A2: A Double-Edged Sword in Pathogen Infection. Pathogens. 2024;13(7):564. doi:10.3390/pathogens13070564 726. Qiao RB, Dai WH, Li W, Yang X, He DM, Gao R, Cui YQ, Wang RX, Ma XY, Wang FJ, et al. The cytochrome P4501A1 (CYP1A1) inhibitor bergamottin enhances host tolerance to multidrug-resistant Vibrio vulnificus infection. Chin J Traumatol. 2024;27(5):295-304. doi:10.1016/j.cjtee.2024.07.003 727. Gonçalves AV, Margolis SR, Quirino GFS, Mascarenhas DPA, Rauch I, Nichols RD, Ansaldo E, Fontana MF, Vance RE, Zamboni DS. Gasdermin-D and Caspase-7 are the key Caspase-1/8 substrates downstream of the NAIP5/NLRC4 inflammasome requi red for restriction of Legionella pneumophila. PLoS Pathog. 2019;15(6):e1007886. doi:10.1371/journal.ppat.1007886 728. Siddiqui MA, Yamashita M. Toll-Like Receptor (TLR) Signaling Enables Cyclic GMP-AMP Synthase (cGAS) Sensing of HIV-1 Infection in Macrophages. mBio. 2021;12(6):e0281721. doi:10.1128/mBio.02817-21 729. Gutierrez FR, Lalu MM, Mariano FS, Milanezi CM, Cena J, Gerlach RF, Santos JE, Torres-Dueñas D, C unha FQ, Schulz R, et al. Increased activities of cardiac matrix metalloproteinases matrix metalloproteinase (MMP)-2 and MMP-9 are associated with mortality during the acute phase of experimental Trypanosoma cruzi infection. J Infect Dis. 2008;197(10):1468-1476. doi:10.1086/587487 730. Sultana H, Neelakanta G, Foellmer HG, Montgomery RR, Anderson JF, Koski RA, Medzhitov RM, Fikrig E. Semaphorin 7A contributes to West Nile virus pathogenesis through TGF- β 1/Smad6 signaling. J Immunol. 2012;189(6):3150-3158. doi:10.4049/jimmunol.1201140 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 731. He TS, Dang L, Zhang J, Zhang J, Wang G, Wang E, Xia H, Zhou W, Wu S, Liu X. The Hippo signaling component LATS2 enhances innate immunity to inhibit HIV-1 infection through PQBP1-cGAS pathway. Cell Death Differ. 2022;29(1):192-205. doi:10.1038/s41418-021-00849-1 732. Abbas M, Verma S, Verma S, Siddiqu i S, Khan FH, Raza ST, Siddiqi Z, Eba A, Mahdi F. Association of GSTM1 and GSTT1 gene polymorphisms with COVID-19 susceptibility and its outcome. J Med Virol. 2021;93(9):5446-5451. doi:10.1002/jmv.27076 733. Yin S, Yu J, Hu B, Lu C, Liu X, Gao X, Li W, Zhou L, Wang J, Wang D, et al. Runx3 Mediates Resistance to Intracellular Bacterial Infection by Promoting IL12 Signaling in Group 1 ILC and NCR+ILC3. Front Immunol. 2018;9:2101. doi:10.3389/fimmu.2018.02101 734. Ranjbar M, Rahimi A, Bagh ernejadan Z, Ghorbani A, Khorramdelazad H. Role of CCL2/CCR2 axis in the pathogenesis of COVID-19 and possible Treatments: All options on the Table. Int Immunopharmacol. 2022;113(Pt A):109325. doi:10.1016/j.intimp.2022.109325 735. Wakabayashi H, Oda H, Yamauchi K, Abe F. Lactoferrin for prevention of common viral infections. J Infect Chemother. 2014;20(11):666-671. doi:10.1016/j.jiac.2014.08.003 736. Ou G, Xu H, Yu H, Liu X, Yang L, Ji X, Wang J, Liu Z. The roles of HLA-DQB1 gene polymorphisms in hepa titis B virus infection. J Transl Med. 2018;16(1):362. doi:10.1186/s12967-018-1716-z 737. Feng J, Meng W, Chen L, Zhang X, Markazi A, Yuan W, Huang Y, Gao SJ. N6-Methyladeno sine and Reader Protein YTHDF2 Enhance the Innate Immune Response by Mediating DUSP1 mRNA Degradation and Activating Mitogen-Activated Protein Kinases during Bacterial and Viral Infections. mBio. 2023;14(1):e0334922. doi:10.1128/mbio.03349-22 738. Z h a n C , S u n Y , P a n J , C h e n L , Y u a n T . E f f e c t o f t h e N o t c h 4 / D l l 4 signaling pathway in early gestational intrauterine infection on lung development. Exp Ther Med. 2021;22(3):972. doi:10.3892/etm.2021.10404 739. Jiyarom B, Giannakopoulos S, Strange DP, Panova N, Gale M Jr, Verma S. RIG-I and MDA5 are modulated by bone morphogenetic protein (BMP6) and are essential for restrict ing Zika virus infection in human (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Sertoli cells. Front Microbiol. 2023;13:1062499. doi:10.3389/fmicb.2022.1062499 740. Kayama H, Koga R, Atarashi K, Okuyama M, Kimura T, Mak TW, Uematsu S, Akira S, Takayanagi H, Honda K, et al. NFATc1 mediates Toll- like receptor-independent innate immune responses during Trypanosoma cruzi infection. PLoS Pathog. 2009;5(7):e1000514. doi:10.1371/journal.ppat.1000514 741. Z h a n g J , J i a o Y , H o u S , T i a n T , Y u a n Q , H a o H , W u Z , B a o X . S100A4 contributes to colitis developm ent by increasing the adherence of Citrobacter rodentium in intestinal epithelial cells. Sci Rep. 2017;7(1):12099. doi:10.1038/s41598-017-12256-z 742. Nishijima T, Komatsu H, Higasa K, Takano M, Tsuchiya K, Hayashida T, Oka S, Gatanaga H. Single nucleotide polymorphisms in ABCC2 associate with tenofovir-induc ed kidney tubular dysfunction in Japanese patients with HIV-1 infec tion: a pharmacogenetic study. Clin Infect Dis. 2012;55(11):1558-1567. doi:10.1093/cid/cis772 743. An P, Penugonda S, Thorball CW, Ba rtha I, Goedert JJ, Donfield S, Buchbinder S, Binns-Roemer E, Kirk GD, Zhang W, et al. Role of APOBEC3F Gene Variation in HIV-1 Disease Progression and Pneumocystis Pneumonia. PL oS Genet. 2016;12(3):e1005921. doi:10.1371/journal.pgen.1005921 744. Lindo J, Nogueira C, Soares R, Cunha N, Almeida MR, Rodrigues L, Coelho P, Rodrigues F, Cunha RA, Gonçalves T. Genetic Polymorphisms of P2RX7 but Not of ADORA2A Are Associat ed with the Severity of SARS- CoV-2 Infection. Int J Mol Sci. 2024;25(11):6135. doi:10.3390/ijms25116135 745. Zacharioudaki M, Messaritakis I, Galanakis E. Vitamin D receptor, vitamin D binding protein and CYP27B 1 single nucleotide polymorphisms and susceptibility to viral infections in infants. Sci Rep. 2021;11(1):13835. doi:10.1038/s41598-021-93243-3 746. Scherrmann JM. Intracellular ABCB1 as a Possible Mechanism to Explain the Synergistic Effect of Hydroxychloroquine-Azithromycin Combination in COVID-19 Therapy. AAPS J. 2020;22(4):86. doi:10.1208/s12248-020-00465-w (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 747. Bauer R, Rauch I. The NAIP/NLRC4 inflammasome in infection and pathology. Mol Aspects Med. 2020;76:100863. doi:10.1016/j.mam.2020.100863 748. Hou Y, Cui Y, Zhou Z, Liu H, Zhang H, Ding Y, Nie H, Ji HL. Upregulation of the WNK4 Signaling Pathway Inhibits Epithelial Sodium Channels of Mouse Tracheal Epithelial Cells After Influenza A Infection. Front Pharmacol. 2019;10:12. doi:10.3389/fphar.2019.00012 749. Kutluay SB, Perez-Caballero D, Bieniasz PD. Fates of retroviral core components during unrestricted and TR IM5-restricted infection. PLoS Pathog. 2013;9(3):e1003214. doi:10.1371/journal.ppat.1003214 750. Wu J, Gao H, Rui H, Xu P, Ni L, Zhang J, Wang L.Exploring the role of YBX3 in PEDV infection through the utilization of YBX3 knockout and overexpression cell lines. Virus Genes. 2024. doi: 10.1007/s11262-024- 02109-z 751. Ma C, Li S, Yang F, Cao W, Liu H, Feng T, Zhang K, Zhu Z, Liu X, Hu Y, et al. FoxJ1 inhibits African swine fever virus replication and viral S273R protein decreases the expression of FoxJ1 to impair its antiviral effect. Virol Sin. 2022;37(3):445-454. doi:10.1016/j.virs.2022.04.008 752. Lee MT, Warren MK. CSF-1-induced resistance to viral infection in murine macrophages. J Immunol. 1987;138(9):3019-3022. 753. Cornet V, Khuyen TD, Mandiki SNM, Betoulle S, Bossier P, Reyes- López FE, Tort L, Kestemont P. GAS1: A New β -Glucan Immunostimulant Candidate to Increase Rainbow Trout (Oncorhynchus mykiss) Resistance to Bacterial Infections With Aeromonas salmonicida achromogenes. Front Immunol. 2021;12:693613. doi:10.3389/fimmu.2021.693613 754. Dong X, Hong Z, Chatterjee J, Kim S, Verma DP. Expression of callose synthase genes and its conne ction with Npr1 signaling pathway during pathogen infection. Planta. 2008;229(1):87-98. doi: 10.1007/s00425- 008-0812-3 755. Liu C, Zeng X, Yu S, Ren L, Sun X, Long Y, Wang X, Lu S, Song Y, et al. Up-regulated DNA-binding inhib itor Id3 promotes differentiation of regulatory T cell to influence antiviral immunity in chronic hepatitis B virus infection. Life Sci. 2021;285:119991. doi:10.1016/j.lfs.2021.119991 756. Mlambo ZP, Sebitloane M, Naicker T. Association of angiogenic factors (placental growth factor and soluble FMS-like tyrosine kinase-1) in (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint preeclamptic women of African ancestry comorbid with HIV infection. Arch Gynecol Obstet. 2024. doi:10.1007/s00404-024-07590-3 757. Wu B, Ramaiah A, Garcia G Jr, Hasiakos S, Arumugaswami V, Srikanth S. ORAI1 Limits SARS-CoV-2 Infection by Regulating Tonic Type I IFN Signaling. J Immunol. 2022;208(1):74-84. doi:10.4049/jimmunol.2100742 758. Cao W, Oldstone MB, De La Torre JC. Viral persistent infection affects both transcriptional and post transcriptional regulation of neuron- specific molecule GAP43. Virology. 1997;230(2):147-154. doi:10.1006/viro.1997.8458 759. Li Q, Wilkie AR, Weller M, Liu X, Cohen JI. THY-1 Cell Surface Antigen (CD90) Has an Important Role in the Initial Stage of Human Cytomegalovirus Infection. PLoS Pathog. 2015;11(7):e1004999. doi:10.1371/journal.ppat.1004999 760. Martins JSCC, Sousa TDC, Oliveira MLA, Gimba ERP, Siqueira MM, Matos ADR. Total Osteopontin and Its Isoform OPN4 Are Differently Expressed in Respiratory Sample s during Influenza A(H1N1)pdm09 Infection and Progression. Microorganisms. 2023;11(5):1349.doi:10.3390/microorganisms11051349 761. Kundu S, Ramshankar V, Verma AK, Thangaraj SV, Krishnamurthy A, Kumar R, Kannan R, Ghosh SK. Association of DFNA5, SYK, and NELL1 variants along with HPV infection in oral cancer among the prolonged tobacco-chewers. Tumour Biol. 2018;40(8):1010428318793023. doi:10.1177/1010428318793023 762. Hiller BE, Yin Y, Perng YC, de Ar aujo Castro Í, Fox LE, Locke MC, Monte KJ, López CB, Ornitz DM, et al. Fibroblast growth factor-9 expression in airway epithelial cells amplifies the type I interferon response and alters influenza A virus pathogenesis. PLoS Pathog. 2022;18(6):e1010228. doi:10.1371/journal.ppat.1010228 763. F a t e m i S H , S i d w e l l R , K i s t D , A k h t e r P , M e l t z e r H Y , B a i l e y K , Thuras P, Sedgwick J. Differential e xpression of synaptosome-associated protein 25 kDa [SNAP-25] in hippocampi of neonatal mice following exposure to human influenza virus in utero. Brain Res. 1998;800(1):1-9. doi:10.1016/s0006-8993(98)00450-8 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 764. de Antonellis P, Ferrucci V, Miceli M, Bibbo F, Asadzadeh F, Gorini F, Mattivi A, Boccia A, Russo R, Andolfo I, Lasorsa VA, et al. Targeting ATP2B1 impairs PI3K/Akt/FOXO signaling and reduces SARS-COV-2 infection and replication. EM BO Rep. 2024;25(7):2974-3007. doi:10.1038/s44319-024-00164-z 765. Heath RJ, Leong JM, Visegrády B, Machesky LM, Xavier RJ. Bacterial and host determinants of MAL activation upon EPEC infection: the roles of Tir, ABRA, and FLRT3. PLoS Pathog. 2011;7(4):e1001332. doi:10.1371/journal.ppat.1001332 766. Sun X, Wang T, Wang Y, Ai K, Pan G, Li Y, Zhou C, He S, Cong H. Downregulation of lncRNA-11496 in the Brain Contributes to Microglia Apoptosis via Regulation of Mef2c in Chronic T. gondii Infection Mice. Front Mol Neurosci. 2020;13:77. doi:10.3389/fnmol.2020.00077 767. Maruta H, He H. PAK1-blockers: Potential Therapeutics against COVID-19. Med Drug Discov. 2020;6:100039. doi:10.1016/j.medidd.2020.100039 768. Bhosle VK, Sun C, Patel S, Ho TWW, Westman J, Ammendolia DA, Langari FM, Fine N, Toepfner N, Li Z, et al. The chemorepellent, SLIT2, bolsters innate immunity against Staphylococcus aureus. Elife. 2023;12:e87392. doi:10.7554/eLife.87392 769. Zhu W, Zhu W, Wang S, Liu S, Zhang H. UCHL1 deficiency upon HCMV infection induces vascular endothelial inflammatory injury mediated by mitochondrial iron overload. Free Radic Biol Med. 2024;211:96-113. doi:10.1016/j.freeradbiomed.2023.12.002 770. Goto H, Kariya R, Kudo E, Katano H, Okada S. PAX5 functions as a tumor suppressor by RB-E2F-mediated ce ll cycle arrest in Kaposi sarcoma- associated herpesvirus-infected primary effusion lymphoma. Neoplasia. 2024;56:101035. doi:10.1016/j.neo.2024.101035 771. Weindel CG, Bell SL, Vail KJ, West KO, Patrick KL, Watson RO. LRRK2 maintains mitochondrial homeostasis and regulates innate immune responses to Mycobacterium tube rculosis. Elife. 2020;9:e51071. doi:10.7554/eLife.51071 772. Burberry A, Wells MF, Limone F, Couto A, Smith KS, Keaney J, Gillet G, van Gastel N, Wang JY, Pi etilainen O, et al. C9orf72 suppresses (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint systemic and neural inflammation induced by gut bacteria. Nature. 2020;582(7810):89-94. doi:10.1038/s41586-020-2288-7 773. Pisapia R, Capoluongo N, Palmiero G, Tascini C, Rescigno C. Relapsing Neurological Complications in a Child With ATP1A3 Gene Mutation and Influenza Infection: A Case Report. Front Neurol. 2021;12:774054. doi:10.3389/fneur.2021.774054 774. Xiong M, Liu X, Liang T, Ban Y, Liu Y, Zhang L, Xu Z, Song C. The Alpha-1 Subunit of the Na+/K+-ATPase (ATP1A1) Is a Host Factor Involved in the Attachment of Porcine Epidemic Diarrhea Virus. Int J Mol Sci. 2023;24(4):4000. doi:10.3390/ijms24044000 775. Beshara R, Sencio V, Soulard D, Ba rthélémy A, Fontaine J, Pinteau T, Deruyter L, Ismail MB, Paget C, Sirard JC, et al. Alteration of Flt3- Ligand-dependent de novo generation of conventional dendritic cells during influenza infection contributes to resp iratory bacterial superinfection. PLoS Pathog. 2018;14(10):e1007360. doi:10.1371/journal.ppat.1007360 776. Takeuchi Y, Tsuge M, Tsushima K, Suehiro Y, Fujino H, Ono A, Yamauchi M, Makokha GN, Nakahara T, Murakami E, et al. Signal Activation of Hepatitis B Virus-Related Hepatocarcinogenesis by Up- regulation of SUV39h1. J In fect Dis. 2020;222(12):2061-2070. doi:10.1093/infdis/jiaa317 777. Wu J, Ma S, Sandhoff R, Ming Y, Hotz-Wagenblatt A, Timmerman V, Bonello-Palot N, Schlotter-Weigel B, Auer-Grumbach M, Seeman P, et al. Loss of Neurological Disease HSAN-I-Associated Gene SPTLC2 Impairs CD8+ T Cell Responses to Infection by Inhibiting T Cell Metabolic Fitness. Immunity. 2019;50(5):1218-1231.e5. doi:10.1016/j.immuni.2019.03.005 778. Mendonça VR, Souza LC, Garcia GC, Magalhães BM, Lacerda MV, Andrade BB, Gonçalves MS, Barral-Netto M. DDX39B (BAT1), TNF and IL6 gene polymorphisms a nd association with clinical outcomes of patients with Plasmodium vivax malaria. Malar J. 2014;13:278. doi: 10.1186/1475- 2875-13-278 779. Wang M, Yang XY, Zhang NZ, Zhang DL, Zhu XQ. Evaluation of Protective Immune Responses Induced by Recombinant TrxLp and ENO2 Proteins against Toxoplasma gondii Infection in BALB/c Mice. Biomed Res Int. 2016;2016:3571962. doi:10.1155/2016/3571962 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 780. Zankharia U, Yi Y, Lu F, Vladimirova O, Karisetty BC, Wikramasinghe J, Kossenkov A, Collman RG, Lieberman PM. HIV-induced RSAD2/Viperin supports sustained infection of monocyte-derived macrophages. J Virol. 2024;98(10):e0086324. doi:10.1128/jvi.00863-24 781. Schütz M, Cordsmeier A, Wangen C, Horn AHC, Wyler E, Ensser A, Sticht H, Marschall M. The Interactive Complex between Cytomegalovirus Kinase vCDK/pUL 97 and Host Factors CDK7 -Cyclin H Determines Individual Patterns of Transcription in Infected Cells. Int J Mol Sci. 2023;24(24):17421. doi:10.3390/ijms242417421 782. Ferreira P, Dâmaso F, Anastácio M, Pinto F, Lynce A. Immune- Mediated Necrotizing Myopathy With Anti-3-Hydroxy-3-Methylglutaryl- CoA Reductase (HMGCR) Antibodies Following Viral Infection and Without Association With Statin Use: A Case Report. Cureus. 2024;16(9):e70281. doi:10.7759/cureus.70281 783. Leber A, Bassaganya-Riera J, Tubau-Juni N, Zoccoli-Rodriguez V, Lu P, Godfrey V, Kale S, Hontecillas R. Lanthionine Synthetase C-Like 2 Modulates Immune Responses to Influe nza Virus Infection. Front Immunol. 2017;8:178. doi:10.3389/fimmu.2017.00178 784. Mashayekhi F, Shabani S, Sasani ST, Salehi Z. The association of stem cell factor and soluble c-Kit (s-cKit) receptor serum concentrations with the severity and risk prediction of autism spectrum disorders. Metab Brain Dis. 2022;37(3):619-624. doi:10.1007/s11011-021-00883-5 785. Kameno Y, Iwata K, Matsuzaki H, Miyachi T, Tsuchiya KJ, Matsumoto K, Iwata Y, Suzuki K, Nakamura K, Maekawa M, et al. Serum levels of soluble platelet endothelial cell adhesion molecule-1 and vascular cell adhesion molecule-1 are decreas ed in subjects with autism spectrum disorder. Mol Autism. 2013;4(1):19. doi:10.1186/2040-2392-4-19 786. Rahbar MH, Samms-Vaughan M, Saroukhani S, Bressler J, Hessabi M, Grove ML, Shakspeare-Pellington S, Loveland KA, Beecher C, McLaughlin W. Associations of Metabolic Genes (GSTT1, GSTP1, GSTM1) and Blood Mercury Concentra tions Differ in Jamaican Children with and without Autism Spectrum Disorder. Int J Environ Res Public Health. 2021;18(4):1377. doi:10.3390/ijerph18041377 787. Akköprü H, Alnak A, Karado ğ an ZN, Ça ğ layan AO, Özçetin M, Coş kun M. Peripheral Expression of ADORA2A Is Increased and Is (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Correlated with Autism Spectrum Disorder Severity in a Sample of Turkish Children. Psychiatry Clin Psychopharmacol. 2023;33(1):14-19. doi:10.5152/pcp.2023.22509 788. Viggiano M, D'Andrea T, Cameli C, Posar A, Visconti P, Scaduto MC, Colucci R, Rochat MJ, Ceroni F, Milazzo G, et al. Contribution of CACNA1H Variants in Autism Spectrum Disorder Susceptibility. Front Psychiatry. 2022;13:858238. doi:10.3389/fpsyt.2022.858238 789. Kim YJ, Park JK, Kang WS, Kim SK, Park HJ, Nam M, Kim JW. LAMB1 polymorphism is associated with autism symptom severity in Korean autism spectrum disorder patients. Nord J Psychiatry. 2015;69(8):594-598. doi:10.3109/08039488.2015.102259 790. Szczurkowska J, Pischedda F, Pinto B, Managò F, Haas CA, Summa M, Bertorelli R, Papaleo F, Schäfer MK, Piccoli G, et al. NEGR1 and FGFR2 cooperatively regulate cortical development and core behaviours related to autism disorders in mice. Brain. 2018;141(9):2772-2794. doi:10.1093/brain/awy190 791. Bolognesi E, Guerini FR, Carta A, Chiappedi M, Sotgiu S, Mensi MM, Agliardi C, Zanzottera M, Clerici M. The Role of SNAP-25 in Autism Spectrum Disorders Onset Patterns. Int J Mol Sci. 2023;24(18):14042. doi:10.3390/ijms241814042 792. Li H, Yamagata T, Mori M, Momoi MY. Association of autism in two patients with hereditary multiple exostoses caused by novel deletion mutations of EXT1. J Hum Genet. 2002;47(5):262-265. doi:10.1007/s100380200036 793. Seiffert S, Pendziwiat M, Bierhals T, Goel H, Schwarz N, van der Ven A, Boßelmann CM, Lemke J, Syrbe S, Willemsen MH, et al. Modulating effects of FGF12 varian ts on NaV1.2 and NaV1.6 being associated with developmental and epileptic encephalopathy and Autism spectrum disorder: A case seri es. EBioMedicine. 2022;83:104234. doi:10.1016/j.ebiom.2022.104234 794. Basu S, Ro EJ, Liu Z, Kim H, Benne tt A, Kang S, Suh H. The Mef2c Gene Dose-Dependently Controls Hippocampal Neurogenesis and the Expression of Autism-Like Behaviors. J Neurosci. 2024;44(5):e1058232023. doi:10.1523/JNEUROSCI.1058-23.2023 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 795. Floris C, Rassu S, Boccone L, Gasp erini D, Cao A, Crisponi L. Two patients with balanced translocations and autistic disorder: CSMD3 as a candidate gene for autism found in their common 8q23 breakpoint area. Eur J Hum Genet. 2008;16(6):696-704. doi:10.1038/ejhg.2008.7 796. Alvarez Retuerto AI, Cantor RM, Gleeson JG, Ustaszewska A, Schackwitz WS, Pennacchio LA, Geschwind DH. Association of common variants in the Joubert syndrome gene (AHI1) with autism. Hum Mol Genet. 2008;17(24):3887-3896. doi:10.1093/hmg/ddn291 797. Kruth KA, Grisolano TM, Ahern CA, Williams AJ. SCN2A channelopathies in the autism spectrum of neuropsychiatric disorders: a role for pluripotent stem cells?. Mol Autism. 2020;11(1):23. doi:10.1186/s13229-020-00330-9 798. Jang WE, Park JH, Park G, Bang G, Na CH, Kim JY, Kim KY, Kim KP, Shin CY, An JY, et al. Cntnap2-dependent molecular networks in autism spectrum disorder revealed through an integrative multi-omics analysis. Mol Psychiatry. 2023;28(2):810-821. doi: 10.1038/s41380-022- 01822-1 799. Coskunpinar EM, Tur S, Cevher Binici N, Yazan Songür C. Association of GABRG3, GABRB3, HT R2A gene variants with autism spectrum disorder. Gene. 2023;870:147399. doi:10.1016/j.gene.2023.147399 800. Papp-Hertelendi R, Tényi T, Hadzsiev K, Hau L, Benyus Z, Csábi G. First report on the association of SCN1A mutation, childhood schizophrenia and autism spectrum disorder without epilepsy. Psychiatry Res. 2018;270:1175-1176. doi:10.1016/j.psychres.2018.07.028 801. Matrone C, Ferretti G. Semaphorin 3A influences neuronal processes that are altered in patients with autism spectrum disorder: Potential diagnostic and therapeutic implications. Neurosci Biobehav Rev. 2023;153:105338. doi:10.1016/j.neubiorev.2023.105338 802. Çetin İ , Tezdi ğ İ , Tarakçioğ lu MC, Kadak MT, Demirel ÖF, Özer ÖF, Erdoğ an F, Do ğ angün B. Do Low Serum UCH-L1 and TDP-43 Levels Indicate Disturbed Ubiquitin-Proteosome System in Autism Spectrum Disorder?. Noro Psikiyatr Ars. 2017;54(3):267-271. doi:10.5152/npa.2017.14873 803. Moreno-Ramos OA, Olivares AM, Haider NB, de Autismo LC, Lattig MC. Whole-Exome Sequencing in a South American Cohort Links (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint ALDH1A3, FOXN1 and Retinoic Acid Regulation Pathways to Autism Spectrum Disorders. PLoS One. 2015;10(9):e0135927. doi:10.1371/journal.pone.0135927 804. Kaiser FMP, Gruenbacher S, Oyaga MR, Nio E, Jaritz M, Sun Q, van der Zwaag W, Kreidl E, Zopf LM, Dalm VASH, et al. Biallelic PAX5 mutations cause hypogammaglobulinemia, sensorimotor deficits, and autism spectrum disorder. J Exp Med. 2022;219(9):e20220498. doi:10.1084/jem.20220498 805. Pescucci C, Meloni I, Bruttini M, Ariani F, Longo I, Mari F, Canitano R, Hayek G, Zappella M, Renieri A. Chromosome 2 deletion encompassing the MAP2 gene in a patient with autism and Rett-like features. Clin Genet. 2003;64(6):497-501. doi:10.1046/j.1399-0004.2003.00176.x 806. F a n g X , F e e T , D a v i s J , S t o l e r m a n E S , C a y l o r R C . C l i n i c a l c a s e report: mosaic ANK3 pathogenic variant in a patient with autism spectrum disorder and neurodevelopmental delay. Co ld Spring Harb Mol Case Stud . 2023;9(3):a006233.. doi:10.1101/mcs.a006233 807. Labonne JDJ, Driessen TM, Harris ME, Kong IK, Brakta S, Theisen J, Sangare M, Layman LC, Kim CH, Lim J, et al. Comparative Genomic Mapping Implicates LRRK2 for Intellectual Disability and Autism at 12q12, and HDHD1, as Well as PNPLA4, for X-Linked Intellectual Disability at Xp22.31. J Clin Med. 2020;9(1):274. doi:10.3390/jcm9010274 808. Cooper JN, Mittal J, Sangadi A, Klassen DL, King AM, Zalta M, Mittal R, Eshraghi AA. Landscape of NRXN1 Gene Variants in Phenotypic Manifestations of Autism Spectrum Disorder: A Systematic Review. J Clin Med. 2024;13(7):2067. doi:10.3390/jcm13072067 809. Yang W, Liu J, Zheng F, Jia M, Zhao L, Lu T, Ruan Y, Zhang J, Yue W, Zhang D, et al. The evidence for association of ATP2B2 polymorphisms with autism in Chinese Han population. PLoS One. 2013;8(4):e61021. doi:10.1371/journal.pone.0061021 810. Soueid J, Kourtian S, Makhoul NJ, Makoukji J, Haddad S, Ghanem SS, Kobeissy F, Boustany RM. RY R2, PTDSS1 and AREG genes are implicated in a Lebanese population-ba sed study of copy number variation in autism. Sci Rep. 2016;6:19088. doi:10.1038/srep19088 811. Shin S, Santi A, Huang S. Conditional Pten knockout in parvalbumin- or somatostatin-positive neurons sufficiently leads to autism-related (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint behavioral phenotypes. Mol Brain. 2021;14(1):24. doi: 10.1186/s13041-021- 00731-8 812. Janickova L, Rechberger KF, Wey L, Schwaller B. Absence of parvalbumin increases mitochondria vol ume and branching of dendrites in inhibitory Pvalb neurons in vivo: a point of convergence of autism spectrum disorder (ASD) risk gene phenoty pes. Mol Autism. 2020;11(1):47. doi:10.1186/s13229-020-00323-8 813. Bitar T, Hleihel W, Marouillat S, Vonwill S, Vuillaume ML, Soufia M, Vourc'h P, Laumonnier F, Andres CR. Identification of rare copy number variations reveals PJA2, APCS, SY NPO, and TAC1 as novel candidate genes in Autism Spectrum Disorders. Mol Genet Genomic Med. 2019;7(8):e786. doi:10.1002/mgg3.786 814. Taketomi T, Tsuruta F. Mutations in Hevin/Sparcl1 and risk of autism spectrum disorder. Neural Re gen Res. 2023;18(7):1499-1500. doi:10.4103/1673-5374.361543 815. Chien WH, Gau SS, Liao HM, Chiu YN, Wu YY, Huang YS, Tsai WC, Tsai HM, Chen CH. Deep exon resequencing of DLGAP2 as a candidate gene of autism spectrum di sorders. Mol Autism. 2013;4(1):26. doi:10.1186/2040-2392-4-26 816. Torres A, Brownstein CA, Tembulkar SK, Graber K, Genetti C, Kleiman RJ, Sweadner KJ, Mavros C, Liu KX, Smedemark-Margulies N, et al. De novo ATP1A3 and compound heterozygous NLRP3 mutations in a child with autism spectrum disorder, episodic fatigue and somnolence, and muckle-wells syndrome. Mol Ge net Metab Rep. 2018;16:23-29. doi:10.1016/j.ymgmr.2018.06.001 817. Sriwimol W, Limprasert P. Significant Changes in Plasma Alpha- Synuclein and Beta-Synuclein Levels in Male Children with Autism Spectrum Disorder. Biomed Res Int. 2018;2018:4503871. doi:10.1155/2018/4503871 818. Iwata K, Matsuzaki H, Tachibana T, Ohno K, Yoshimura S, Takamura H, Yamada K, Matsuzaki S, Nakamura K, Tsuchiya KJ, et al. N- ethylmaleimide-sensitive factor interacts with the serotonin transporter and modulates its trafficking: implications for pathophysiology in autism. Mol Autism. 2014;5:33. doi:10.1186/2040-2392-5-33 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 819. Zhubi A, Chen Y, Guidotti A, Grayson DR. Epigenetic regulation of RELN and GAD1 in the frontal cortex (FC) of autism spectrum disorder (ASD) subjects. Int J Dev Neurosci. 2017;62:63-72. doi:10.1016/j.ijdevneu.2017.02.003 820. Wang X, Sun Z, Yang T, Lin F, Ye S, Yan J, Li T, Chen J. Sodium butyrate facilitates CRHR2 expression to alleviate HPA axis hyperactivity in autism-like rats induced by prenatal lipopolysaccharides through histone deacetylase inhibition. mSystems. 2023;8(4):e0041523. doi:10.1128/msystems.00415-23 821. Orabona GM, Griesi-Oliveira K, Vadasz E, Bulcão VL, Takahashi VN, Moreira ES, Furia-Silva M, Ros-Melo AM, Dourado F, Matioli SR, et al. HTR1B and HTR2C in autism spectrum disorders in Brazilian families. Brain Res. 2009;1250:14-19. doi:10.1016/j.brainres.2008.11.007 822. Baris RO, Sahin N, Bilgic AD, Oz demir C, Edgunlu TG. Molecular and in silico analyses of SYN III gene variants in autism spectrum disorder. Ir J Med Sci. 2023;192(6):2887-2895. doi:10.1007/s11845-023-03402-w 823. Dohrn MF, Bademci G, Rebelo AP, Jeanne M, Borja NA, Beijer D, Danzi MC, Bivona SA, Gueguen P, Zafeer MF; et al. Recurrent ATP1A1 variant Gly903Arg causes developmental delay, intellectual disability, and autism. Ann Clin Transl Neurol. 2024;11(4):1075-1079. doi:10.1002/acn3.51963 824. Ali G, Shin KC, Habbab W, Alkhadairi G, AbdelAleem A, AlShaban FA, Park Y, Stanton LW. Characterization of a loss-of-function NSF attachment protein beta mutation in monozygotic triplets affected with epilepsy and autism using cortical neurons from proband-derived and CRISPR-corrected induced pluripotent stem cell lines. Front Neurosci. 2024;17:1302470. doi:10.3389/fnins.2023.1302470 825. Pavinato L, Stanic J, Barzasi M, Gu rgone A, Chiantia G, Cipriani V, Eberini I, Palazzolo L, Di Luca M, Costa A, et al. Missense variants in RPH3A cause defects in excitatory synaptic function and are associated with a clinically variable neurodevelopmental disorder. Genet Med. 2023;25(11):100922. doi:10.1016/j.gim.2023.100922 826. Soueid J, Hamze Z, Bedran J, Chahrour M, Boustany RM. A novel autism-associated UBLCP1 mutation impacts proteasome (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint regulation/activity. Transl Psychiatry. 2023;13(1):404. doi: 10.1038/s41398- 023-02702-0 827. Wang M, Yang XY, Zhang NZ, Zhang DL, Zhu XQ. Evaluation of Protective Immune Responses Induced by Recombinant TrxLp and ENO2 Proteins against Toxoplasma gondii Infection in BALB/c Mice. Biomed Res Int. 2016;2016:3571962. doi:10.1155/2016/3571962 828. Aoki Y, Cortese S. Mitochondrial Aspartate/Glutamate Carrier SLC25A12 and Autism Spectrum Disorder: a Meta-Analysis. Mol Neurobiol. 2016;53(3):1579-1588. doi:10.1007/s12035-015-9116-3 829. Kantojärvi K, Kotala I, Rehnström K, Ylisaukko-Oja T, Vanhala R, von Wendt TN, von Wendt L, Järvelä I. Fine mapping of Xq11.1-q21.33 and mutation screening of RPS6KA6, ZNF711, ACSL4, DLG3, and IL1RAPL2 for autism spectrum disorders (ASD). Autism Res. 2011;4(3):228-233. doi:10.1002/aur.187 830. Kwon SJ, Hong KW, Choi S, Hong JS, Kim JW, Kim JW, Lee HJ, Jang HB, Yum KS. Association of 3-hydroxy-3-methylglutaryl-coenzyme A reductase gene polymorphism with ob esity and lipid metabolism in children and adolescents with autism spectrum disorder. Metab Brain Dis. 2022;37(2):319-328. doi:10.1007/s11011-021-00877-3 831. Shimamoto C, Ohnishi T, Maekawa M, Watanabe A, Ohba H, Arai R, Iwayama Y, Hisano Y, Toyota T, Toyoshima M, et al. Functional characterization of FABP3, 5 and 7 gene variants identified in schizophrenia and autism spectrum disorder and mouse behavioral studies. Hum Mol Genet. 2014;23(24):6495-6511. doi:10.1093/hmg/ddu369 832. Corti S, Nizzardo M, Nardini M, Do nadoni C, Salani S, Simone C, Falcone M, Riboldi G, Govoni A, Bresolin N, et al. Systemic transplantation of c-kit+ cells exerts a therapeutic ef fect in a model of amyotrophic lateral sclerosis. Hum Mol Ge net. 2010;19(19):3782-3796. doi:10.1093/hmg/ddq293 833. Yamada S, Hashizume A, Hijikata Y, Ito D, Kishimoto Y, Iida M, Koike H, Hirakawa A, Katsuno M. Ratio of urinary N-terminal titin fragment to urinary creatinine is a novel biomarker for amyotrophic lateral sclerosis. J Neurol Neurosur g Psychiatry. 2021;92(10):1072-1079. doi:10.1136/jnnp-2020-324615 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 834. Capponi S, Geuens T, Geroldi A, Origone P, Verdiani S, Cichero E, A d r i a e n s s e n s E , D e W i n t e r V , B a n d e t t i n i d i P o g g io M , B a r b e r i s M , e t a l . Molecular Chaperones in the Pathogenesis of Amyotrophic Lateral Sclerosis: The Role of HSPB1. Hum Mutat. 2016;37(11):1202-1208. doi:10.1002/humu.23062 835. Ajroud-Driss S, Saeed M, Khan H, Siddique N, Hung WY, Sufit R, Heller S, Armstrong J, Casey P, Siddique T, et al. Riluzole metabolism and CYP1A1/2 polymorphisms in patients with ALS. Amyotroph Lateral Scler. 2007;8(5):305-309. doi:10.1080/17482960701500650 836. Fang L, Teuchert M, Huber-Abel F, Schattauer D, Hendrich C, Dorst J, Zettlmeissel H, Wlaschek M, Scharffetter-Kochanek K, Kapfer T, et al. MMP-2 and MMP-9 are elevated in spinal cord and skin in a mouse model of ALS. J Neurol Sci. 2010;294(1-2):51-56. doi:10.1016/j.jns.2010.04.005 837. Li X, Guan Y, Chen Y, Zhang C, Shi C, Zhou F, Yu L, Juan J, Wang X. Expression of Wnt5a and its receptor Fzd2 is changed in the spinal cord of adult amyotrophic lateral sclerosis transgenic mice. Int J Clin Exp Pathol. 2013;6(7):1245-1260. 838. Gupta PK, Prabhakar S, Abburi C, Sharma NK, Anand A. Vascular endothelial growth factor-A and chemokine ligand (CCL2) genes are upregulated in peripheral blood mononuclear cells in Indian amyotrophic lateral sclerosis patients. J Neuroinflammation. 2011;8:114. doi:10.1186/1742-2094-8-114 839. Milani M, Mammarella E, Rossi S, Miele C, Lattante S, Sabatelli M, Cozzolino M, D'Ambrosi N, Apolloni S. Targeting S100A4 with niclosamide attenuates inflammatory and profibrotic pathways in models of amyotrophic lateral sclerosis. J Neuroinflammation. 2021;18(1):132. doi:10.1186/s12974-021-02184-1 840. Si Y, Kazamel M, Kwon Y, Lee I, Anderson T, Zhou S, Bamman M, Wiggins D, Kwan T, King PH. The vitamin D activator CYP27B1 is upregulated in muscle fibers in denervating disease and can track progression in amyotrophic lateral sclerosis. J Steroid Biochem Mol Biol. 2020;200:105650. doi:10.1016/j.jsbmb.2020.105650 841. Qosa H, Lichter J, Sarlo M, Markandaiah SS, McAvoy K, Richard JP, Jablonski MR, Maragakis NJ, Pasinelli P, Trotti D. Astrocytes drive upregulation of the multidrug resistance transporter ABCB1 (P- (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Glycoprotein) in endothelial cells of the blood-brain barrier in mutant superoxide dismutase 1-linked amyo trophic lateral sclerosis. Glia. 2016;64(8):1298-1313. doi:10.1002/glia.23003 842. Rzhepetskyy Y, Lazniewska J, Bles neac I, Pamphlett R, Weiss N. CACNA1H missense mutations associ ated with amyotrophic lateral sclerosis alter Cav3.2 T-type calcium channel activity and reticular thalamic neuron firing. Channels (Austin). 2016;10(6):466-477. doi:10.1080/19336950.2016.1204497 843. Trias E, Kovacs M, King PH, Si Y, Kwon Y, Varela V, Ibarburu S, Moura IC, Hermine O, Beckman JS, et al. Schwann cells orchestrate peripheral nerve inflammation through the expression of CSF1, IL-34, and SCF in amyotrophic lateral scle rosis. Glia. 2020;68(6):1165-1181. doi:10.1002/glia.23768 844. Iłzecka J. Decreased serum endoglin level in patients with amyotrophic lateral sclerosis: a preli minary report. Scand J Clin Lab Invest. 2008;68(4):348-351. doi:10.1080/00365510701604628 845. Noda Y, Tanaka M, Nakamura S, Ito J, Kakita A, Hara H, Shimazawa M. Identification of VGF nerve growth factor inducible-producing cells in human spinal cords and expression ch ange in patients with amyotrophic lateral sclerosis. Int J Med Sci. 2020;17(4):480-489. doi:10.7150/ijms.39101 846. Ikemoto A, Hirano A, Akiguchi I. Increased expression of growth- associated protein 43 on the surface of the anterior horn cells in amyotrophic lateral sclerosis. Acta Ne uropathol. 1999;98(4):367-373. doi:10.1007/s004010051096 847. Liu Y, Yan D, Yang L, Chen X, Hu C, Chen M. Stathmin 2 is a potential treatment target for TDP-43 proteinopathy in amyotrophic lateral sclerosis. Transl Neurodegener. 2024;13(1):20. doi: 10.1186/s40035-024- 00413-0 848. Arosio A, Sala G, Rodriguez-Menendez V, Grana D, Gerardi F, Lunetta C, Ferrarese C, Tremolizzo L. MEF2D and MEF2C pathways disruption in sporadic and familial ALS patients. Mol Cell Neurosci. 2016;74:10-17. doi:10.1016/j.mcn.2016.02.002 849. Birger A, Ottolenghi M, Perez L, Reubinoff B, Beha r O. ALS-related human cortical and motor neurons survival is differentially affected by Sema3A. Cell Death Dis. 2018;9(3):256. doi:10.1038/s41419-018-0294-6 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 850. Li R, Wang J, Xie W, Liu J, Wang C. UCHL1 from serum and CSF is a candidate biomarker for amyotrophic lateral sclerosis. Ann Clin Transl Neurol. 2020;7(8):1420-1428. doi:10.1002/acn3.51141 851. Silvestri B, Mochi M, Mawrie D, de Turris V, Colantoni A, Borhy B, Medici M, Anderson EN, Garone MG, Zammerilla CP, et al. HuD (ELAVL4) gain-of-function impairs ne uromuscular junctions and induces apoptosis in in vitro and in vivo models of amyotrophic lateral sclerosis. Preprint. bioRxiv. 2024;2023.08.22.554258. doi:10.1101/2023.08.22.554258 852. Whittle AJ, Ross OA, Naini A, Gordon P, Mistumoto H, Dächsel JC, Stone JT, Wszolek ZK, Farrer MJ, Przedborski S. Pathogenic Lrrk2 substitutions and Amyotrophic lateral sclerosis. J Neural Transm (Vienna). 2007;114(3):327-329. doi:10.1007/s00702-006-0525-3 853. van Doormaal PT, Ticozzi N, Gellera C, Ratti A, Taroni F, Chiò A, Calvo A, Mora G, Restagno G, Traynor BJ, et al. Analysis of the KIFAP3 gene in amyotrophic lateral sclerosis: a multicenter survival study. Neurobiol Aging. 2014;35(10):2420.e13-2420.e14. doi:10.1016/j.neurobiolaging.2014.04.014 854. Syeda SB, Lone MA, Mohassel P, Do nkervoort S, Munot P, França MC Jr, Galarza-Brito JE, Eckenweiler M, Asamoah A, Gable K, et al. Recurrent de novo SPTLC2 variant causes childhood-onset amyotrophic lateral sclerosis (ALS) by excess sphingolipid synthesis. J Neurol Neurosurg Psychiatry. 2024;95(2):103-113. doi:10.1136/jnnp-2023-332132 855. Ruban A, Malina KC, Cooper I, Gr aubardt N, Babakin L, Jona G, Teichberg VI. Combined Treatment of an Amyotrophic Lateral Sclerosis Rat Model with Recombinant GOT1 and Oxaloacetic Acid: A Novel Neuroprotective Treatment. Neur odegener Dis. 2015;15(4):233-242. doi:10.1159/000382034 856. Jiang Y, Liang M, Chen L, Wang J, Huang Y, Huo H, Xiao D, Hu Y, Wang Z, Ji Q, et al. Myeloid SENP3 deficiency protects mice from diet and age-induced obesity via regulation of YAP1 SUMOylation. Cell Mol Life Sci. 2023;81(1):4. doi:10.1007/s00018-023-05050-w 857. Maehle BO, Tretli S, Thorsen T. The associations of obesity, lymph node status and prognosis in breast cancer patients: dependence on estrogen and progesterone receptor status. APMIS. 2004;112(6):349-357. doi:10.1111/j.1600-0463.2004.apm1120605.x (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 858. Deng Y, Qiu T, Zhang M, Wu J, Zhang X, Wang J, Chen K, Feng J, Ha X, Xie J, et al. High Level of Palmitic Acid Induc ed Over-Expressed Methyltransferase Inhibits Anti-Inflammation Factor KLF4 Expression in Obese Status. Inflammation. 2020;43(3):821-832. doi: 10.1007/s10753-019- 01168-x 859. Pan X, Chen X, Ren Q, Yue L, Niu S, Li Z, Zhu R, Chen X, Jia Z, Zhen R, et al. Single-cell transcriptom ics identifies Col1a1 and Col1a2 as hub genes in obesity-induced cardiac fibrosis. Biochem Biophys Res Commun. 2022;618:30-37. doi:10.1016/j.bbrc.2022.06.018 860. Zhang W, Shi B, Li S, Liu Z, Li S, Dong S, Cheng Y, Zhu J, Zhang G, Zhong M. Sleeve gastrectomy improves lipid dysmetabolism by downregulating the USP20-HSPA2 axis in diet-induced obese mice. Front Endocrinol (Lausanne). 2022;13:1041027. doi:10.3389/fendo.2022.1041027 861. Pilch W, Wyrostek J, Major P, Zuziak R, Piotrowska A, Czerwi ń ska- Ledwig O, Grzybkowska A, Zasada M, Ziemann E, Ż ychowska M. The effect of whole-body cryostimulation on body composition and leukocyte expression of HSPA1A, HSPB1, and CRP in obese men. Cryobiology. 2020;94:100-106. doi:10.1016/j.cryobiol.2020.04.002 862. Makey KL, Patterson SG, Robinson J, Loftin M, Waddell DE, Miele L, Chinchar E, Huang M, Smith AD, Weber M, et al. ncreased plasma levels of soluble vascular endothelial growth factor receptor 1 (sFlt-1) in women by moderate exercise and increased plasma levels of vascular endothelial growth factor in overweight/ob ese women. Eur J Cancer Prev. 2013;22(1):83-89. doi:10.1097/CEJ.0b013e328353ed81 863. Ye B, Chen X, Chen Y, Lin W, Xu D, Fang Z, Chattipakorn N, Huang W, Wang X, Wu G, et al. Inhibition of TAK1/TAB2 complex formation by costunolide attenuates obesity cardiomyopathy via the NF- κ B signaling pathway. Phytomedicine. 2023;108:154523. doi:10.1016/j.phymed.2022.154523 864. Patel SJ, Liu N, Piaker S, Gulko A, Andrade ML, Heyward FD, Sermersheim T, Edinger N, Srinivasan H, Emont MP, et al. Hepatic IRF3 fuels dysglycemia in obesity through direct regulation of Ppp2r1b. Sci Transl Med. 2022;14(637):eabh3831. doi:10.1126/scitranslmed.abh3831 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 865. Hao J, Liu Z, Ju W, He F, Liu K, Wu J. Role and mechanism of FLT4 in high-fat diet-induced obesity in mice. Biochem Biophys Res Commun. 2023;675:61-70. doi:10.1016/j.bbrc.2023.06.025 866. Menghini R, Marchetti V, Cardelli ni M, Hribal ML, Mauriello A, Lauro D, Sbraccia P, Lauro R, Federici M. Phosphorylation of GATA2 by Akt increases adipose tissue differentiation and reduces adipose tissue- related inflammation: a novel pathway linking obesity to atherosclerosis. Circulation. 2005;111(15):1946-1953. doi:10.1161/01.CIR.0000161814.02942.B2 867. Wang Y, Cheng YS, Yin XQ, Yu G, Jia BL. Anxa2 gene silencing attenuates obesity-induced insulin resistance by suppressing the NF- κ B signaling pathway. Am J Physiol Cell Physiol. 2019;316(2):C223-C234. doi:10.1152/ajpcell.00242.2018 868. DuBois BN, O'Tierney-Ginn P, Pearson J, Friedman JE, Thornburg K, Cherala G. Maternal obesity alters feto-placental cytochrome P4501A1 activity. Placenta. 2012;33(12):1045-1051. doi:10.1016/j.placenta.2012.09.008 869. Bai J, Cervantes C, Liu J, He S, Zhou H, Zhang B, Cai H, Yin D, Hu D, Li Z, et al. DsbA-L prevents obesity-induced inflammation and insulin resistance by suppressing the mt DNA release-activated cGAS-cGAMP- STING pathway. Proc Natl Acad Sci U S A. 2017;114(46):12196-12201. doi:10.1073/pnas.1708744114 870. Morgan AR, Han DY, Thompson JM, Mitchell EA, Ferguson LR. Analysis of MMP2 promoter polymorphisms in childhood obesity. BMC Res Notes. 2011;4:253. doi:10.1186/1756-0500-4-253 871. Cui Z, Liu Y, Wan W, Xu Y, Hu Y, Ding M, Dou X, Wang R, Li H, Meng Y, et al. Ethacrynic acid targets GSTM1 to ameliorate obesity by promoting browning of white adipocytes. Protein Cell. 2021;12(6):493-501. doi:10.1007/s13238-020-00717-7 872. Van de Pette M, Tunster SJ, John RM. Loss of Imprinting of Cdkn1c Protects against Age and Diet-I nduced Obesity. Int J Mol Sci. 2018;19(9):2734.. Int J Mol Sci. 2018;19(9):2734. doi:10.3390/ijms19092734 873. Wu Y, Ma Y. CCL2-CCR2 signaling axis in obesity and metabolic diseases. J Cell Physiol. 2024;239(4):e31192. doi:10.1002/jcp.31192 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 874. Jamka M, Kaczmarek N, M ą dry E, Krzy ż anowska-Jankowska P, Bajerska J, Kr ę gielska-Naroż na M, Bogda ń ski P, Walkowiak J. Metabolic Health in Obese Subjects-Is There a Link to Lactoferrin and Lactoferrin Receptor-Related Gene Polymorphisms?. Nutrients. 2020;12(9):2843. doi:10.3390/nu12092843 875. Gómez-Úriz AM, Milagro FI, Mansego ML, Cordero P, Abete I, De Arce A, Goyenechea E, Blázquez V, Martínez-Zabaleta M, Martínez JA, et al. Obesity and ischemic stroke modulate the methylation levels of KCNQ1 in white blood cells. Hum Mol Genet. 2015;24(5):1432-1440. doi:10.1093/hmg/ddu559 876. Khadir A, Tiss A, Abubaker J, Abu-Farha M, Al-Khairi I, Cherian P, John J, Kavalakatt S, Warsame S, Al-Madhoun A, et al. MAP kinase phosphatase DUSP1 is ove rexpressed in obese humans and modulated by physical exercise. Am J Physiol E ndocrinol Metab. 2015;308(1):E71-E83. doi:10.1152/ajpendo.00577.2013 877. Anguita-Ruiz A, Mendez-Gutierrez A, Ruperez AI, Leis R, Bueno G, Gil-Campos M, Tofe I, Gomez-Llorente C, Moreno LA, Gil Á, Aguilera CM. The protein S100A4 as a novel marker of insulin resistance in prepubertal and pubertal children with obesity. Metabolism. 2020;105:154187. doi:10.1016/j.metabol.2020.154187 878. AlSedairy SA, Al-Harbi LN, Binobead MA, At hinarayanan J, Arzoo S, Al-Tamimi DS, Shamlan G, Alshatwi AA, Periasamy VS. Association of CYP2R1 and CYP27B1 genes with th e risk of obesity and vitamin D metabolism in Saudi women. J Genet Eng Biotechnol. 2023;21(1):59. doi:10.1186/s43141-023-00508-7 879. Justesen S, Bilde K, Olesen RH, Pedersen LH, Ernst E, Larsen A. ABCB1 expression is increased in human first trimester placenta from pregnant women classified as overweight or obese. Sci Rep. 2023;13(1):5175. doi:10.1038/s41598-023-31598-5 880. Sachan A, Aggarwal S, Pol MM, Singh A, Yadav R. Expression analysis of MMP14: Key enzyme action in modulating visceral adipose tissue plasticity in patients with obesity. Clin Obes. 2023;13(5):e12607. doi:10.1111/cob.12607 881. Takahashi D, Mori T, Sohara E, Tanaka M, Chiga M, Inoue Y, N o m u r a N , Z e n i y a M , O c h i H , T a k e d a S , e t a l . W N K 4 i s a n A d i p o g e n i c (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Factor and Its Deletion Reduces Diet-Induced Obesity in Mice. EBioMedicine. 2017;18:118-127. doi:10.1016/j.ebiom.2017.03.011 882. Rivera-Gonzalez O, Mills MF, Konadu BD, Wilson NA, Murphy HA, Newberry MK, Hyndman KA, Garrett MR, Webb DJ, Speed JS. Adipocyte endothelin B receptor activation inhibits adiponectin production and causes insulin resistance in obese mice. Acta Physiol (Oxf). 2024;240(10):e14214. doi:10.1111/apha.14214 883. Pervanidou P, Chouliaras G, Akalestos A, Bastaki D, Apostolakou F, Papassotiriou I, Chrousos GP. Increased placental growth factor (PlGF) concentrations in children and adoles cents with obesity and the metabolic syndrome. Hormones (Athens). 2014;13(3):369-374. doi:10.14310/horm.2002.1491 884. Pereira MJ, Vranic M, Kamble PG, Jernow H, Kristófi R, Holbikova E, Skrtic S, Kullberg J, Svensson MK, Hetty S, et al. CDKN2C expression in adipose tissue is reduced in type II diabetes and central obesity: impact on adipocyte differentiation and lipid storage?. Transl Res. 2022;242:105-121. doi:10.1016/j.trsl.2021.12.003 885. Folon L, Baron M, Toussaint B, Vaillant E, Boissel M, Scherrer V, Loiselle H, Leloire A, Badreddine A, Balkau B, et al. Contribution of heterozygous PCSK1 variants to obesity and implications for precision medicine: a case-control study. Lancet Diabetes Endocrinol. 2023;11(3):182-190. doi:10.1016/S2213-8587(22)00392-8 886. Hahm S, Fekete C, Mizuno TM, Windsor J, Yan H, Boozer CN, Lee C, Elmquist JK, Lechan RM, Mobbs CV, et al. VGF is required for obesity induced by diet, gold thioglucose treatment, and agouti and is differentially regulated in pro-opiomelanocortin- and neuropeptide Y-containing arcuate neurons in response to fastin g. J Neurosci. 2002;22(16):6929-6938. doi:10.1523/JNEUROSCI.22-16-06929.2002 887. Bekar E, Altunkaynak BZ, Balcı K, Aslan G, Ayyıldız M, Kaplan S. Effects of high fat diet induced obesity on peripheral nerve regeneration and levels of GAP 43 and TGF- β in rats. Biotech Histochem. 2014;89(6):446- 456. doi:10.3109/10520295.2014.894575 888. Al-Ameri HW, Shetty S, Rahman B, Gopalakrishnan ARK, Ismail AA, Acharya AB. Evaluation of salivary Thy-1 in health, periodontitis, and obesity. Oral Dis. 2024;30(4):2670-2677. doi:10.1111/odi.14652 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 889. Michaelides M, Miller ML, Egervari G, Primeaux SD, Gomez JL, Ellis RJ, Landry JA, Szutorisz H, Hoffman AF, Lupica CR, et al. Striatal Rgs4 regulates feeding and susceptibility to diet-induced obesity. Mol Psychiatry. 2020;25(9):2058-2069. doi:10.1038/s41380-018-0120-7 890. Sun Y, Wang R, Zhao S, Li W, Liu W, Tang L, Wang Z, Wang W, Liu R, Ning G, et al. FGF9 inhibits browning program of white adipocytes and associates with human obesity. J Mol Endocrinol. 2019;62(2):79-90. doi:10.1530/JME-18-0151 891. Huang T, Zhang X, Li Q, Li X, Yao J, Song J, Chen Y, Ye L, Li C, Xiran P, et al. The Association between Obesity Susceptibility and Polymorphisms of MC4R, SH2B1, and NEGR1 in Tibetans. Genet Test Mol Biomarkers. 2024;28(7):267-274. doi:10.1089/gtmb.2023.0546 892. Ceddia RP, Zurawski Z, Thompson Gray A, Adegboye F, McDonald- B o y e r A , S h i F , L i u D , M a l d o n a d o J , F e n g J , L i Y , e t a l . Gβγ -SNAP25 exocytotic brake removal enhances insulin action, promotes adipocyte browning, and protects against diet-induced obesity. J Clin Invest. 2023;133(19):e160617. doi:10.1172/JCI160617 893. Wang M, Li B, Qin F, Ye J, Jin L. Obesity induced Ext1 reduction mediates the occurrence of NAFLD. Biochem Biophys Res Commun. 2022;589:123-130. doi:10.1016/j.bbrc.2021.12.017 894. Huang L, Teng D, Wang H, Sheng G, Liu T. Association of copy number variation in the AHI1 gene with risk of obesity in the Chinese population. Eur J Endocrinol. 2012;166(4):727-734. doi: 10.1530/EJE-11- 0999 895. Yi H, Liu C, Shi J, Wang S, Zhang H, He Y, Tao J, Li S, Zhang R. GCG Alleviates Obesity-Induced Myocardial Fibrosis in Rats by Enhancing Expression of SCN5A. Front Cardiovasc Med. 2022;9:869279. doi:10.3389/fcvm.2022.869279 896. Naudhani S, Ahmad A, Khan Bazai F, Pervez MT, Zafar A, Shah SA, Raheem N, Baloch AH, Mushtaq M, Daud S. Missense Pathogenic Variant in a Conserved Region of CNTNAP2 Is Associated with Obesity, Seizures, and Language Impairment in a Pakistani Family. Mol Syndromol. 2023;14(4):293-302. doi:10.1159/000529427 897. Wang H, Wang Y, Zhang H, Liang Z, Hu W, Qiu S, Li K, Zhang L, Dai H, Yang M, et al. Hedgehog interacting protein as a circulating (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint biomarker in women with obesity: a cross-sectional study and intervention studies. Ann Med. 2023;55(1):2206162. doi:10.1080/07853890.2023.2206162 898. Li Z, Shi B, Li N, Sun J, Zeng X, Huang R, Bok S, Chen X, Han J, Yallowitz AR, et al. Bone controls browning of white adipose tissue and protects from diet-induced obesity through Schnurri-3-regulated SLIT2 secretion. Nat Commun. 2024;15(1):6697. doi:10.1038/s41467-024-51155-6 899. Chen X, Ruiz-Velasco A, Zou Z, Hille SS, Ross C, Fonseka O, Gare SR, Alatawi NHO, Raja R, Zhang J, et al. PAK3 Exacerbates Cardiac Lipotoxicity via SREBP1c in Obesity Cardiomyopathy. Diabetes. 2024;73(11):1805-1820. doi:10.2337/db24-0240 900. Zhang J, Zhang Y, Sun T, Guo F, Huang S, Chandalia M, Abate N, Fan D, Xin HB, Chen YE, et al. Dietary obesity-induced Egr-1 in adipocytes facilitates energy storage via suppression of FOXC2. Sci Rep. 2013;3:1476. doi:10.1038/srep01476 901. Zafar A, Ng HP, Chan ER, Dunwoodie SL, Mahabeleshwar GH. Myeloid-CITED2 Deficiency Exacer bates Diet-Induced Obesity and Pro- Inflammatory Macrophage Re sponse. Cells. 2023;12(17):2136. doi:10.3390/cells12172136 902. Shintani T, Suzuki R, Takeuchi Y, Shirasawa T, Noda M. Deletion or inhibition of PTPRO prevents ectopic fat accumulation and induces healthy obesity with markedly reduced systemic inflammation. Life Sci. 2023;313:121292. doi:10.1016/j.lfs.2022.121292 903. Zhang T, Linghu KG, Tan J, Wang M, Chen D, Shen Y, Wu J, Shi M, Zhou Y, Tang L, Liu L, et al. TIGAR exacerbates obesity by triggering LRRK2-mediated defects in macroautophagy and chaperone-mediated autophagy in adipocytes. Autophagy. 2024;20(8):1741-1761. doi:10.1080/15548627.2024.2338576 904. Bai N, Lu X, Jin L, Alimujiang M, Ma J, Hu F, Xu Y, Sun J, Xu J, Zhang R, et al. CLSTN3 gene variant associates with obesity risk and contributes to dysfunction in white adipose tissue. Mol Metab. 2022;63:101531. doi:10.1016/j.molmet.2022.101531 905. Kumar U, Singh S. Role of Somatostatin in the Regulation of Central and Peripheral Factors of Satiety and Obesity. Int J Mol Sci. 2020;21(7):2568. doi:10.3390/ijms21072568 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 906. Prakash J, Mittal B, Awasthi S, Srivastava N. Association of the - 243A>G, +61450C>A Polymorphisms of the Glutamate Decarboxylase 2 (GAD2) Gene with Obesity and Insulin Level in North Indian Population. Iran J Public Health. 2016;45(4):460-468. 907. Mazzarella L, Botteri E, Matthews A, Gatti E, Di Salvatore D, Bagnardi V, Breccia M, Montesinos P, Bernal T, Gil C, et al. Obesity is a risk factor for acute promyelocytic leukemia: evidence from population and cross-sectional studies and correlation with FLT3 mutations and polyunsaturated fatty acid metabolism. Haematologica. 2020;105(6):1559- 1566. doi:10.3324/haematol.2019.223925 908. Costantino S, Paneni F, Virdis A, Hussain S, Mohammed SA, Capretti G, Akhmedov A, Dalgaard K, Chiandotto S, Pospisilik JA, et al. Interplay among H3K9-editing enzymes SUV39H1, JMJD2C and SRC-1 drives p66Shc transcription and vascular oxidat ive stress in obesity. Eur Heart J. 2019;40(4):383-391. doi:10.1093/eurheartj/ehx615 909. Nawrocki AR, Rodriguez CG, Toolan DM, Price O, Henry M, Forrest G, Szeto D, Keohane CA, Pan Y, Smith KM, et al. Genetic deletion and pharmacological inhibition of phosp hodiesterase 10A protects mice from diet-induced obesity and insulin resi stance. Diabetes. 2014;63(1):300-311. doi:10.2337/db13-0247 910. Aliasghari F, Nazm SA, Yasari S, Mahdavi R, Bonyadi M. Associations of the ANKK1 and DRD2 gene polymorphisms with overweight, obesity and hedonic hung er among women from the Northwest of Iran. Eat Weight Disord. 2021;26(1):305-312. doi: 10.1007/s40519-020- 00851-5 911. Ma WW, Ding BJ, Yuan LH, Zhao L, Yu HL, Xi YD, Xiao R. Neurocalcin-delta: a potential memory-related factor in hippocampus of obese rats induced by high-fat diet . Afr Health Sci. 2017;17(4):1211-1221. doi:10.4314/ahs.v17i4.32 912. Moreno-Navarrete JM, Moreno M, Ortega F, Sabater M, Xifra G, Ricart W, Fernández-Real JM. CISD1 in association with obesity-associated dysfunctional adipogenesis in human visceral adipose tissue. Obesity (Silver Spring). 2016;24(1):139-147. doi:10.1002/oby.21334 913. Shimada Y, Kuninaga S, Ariyoshi M, Zhang B, Shiina Y, Takahashi Y, Umemoto N, Nishimura Y, Enari H, Tanaka T. E2F8 promotes hepatic (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint steatosis through FABP3 expression in diet-induced obesity in zebrafish. Nutr Metab (Lond). 2015;12:17. doi:10.1186/s12986-015-0012-7 914. Khalilian S, Hojati Z, Dehghanian F, Shaygannejad V, Imani SZH, Kheirollahi M, Khorrami M, Mirmosayyeb O. Gene expression profiles of YAP1, TAZ, CRB3, and VDR in familial and sporadic multiple sclerosis among an Iranian population. Sci Rep. 2021;11(1):7713. doi:10.1038/s41598-021-87131-z 915. Zarobkiewicz MK, Morawska I, Kowalska W, Halczuk P, Roli ń ski J, Bojarska-Junak AA. PECAM-1 Is Down-Regulated in γδ T Cells during Remission, but Up-Regulated in Relapse of Multiple Sclerosis. J Clin Med. 2022;11(11):3210. doi:10.3390/jcm11113210 916. Haupeltshofer S, Leichsenring T, Berg S, Pedreiturria X, Joachim SC, Tischoff I, Otte JM, Bopp T, Fantini MC, Esser C, et al. Smad7 in intestinal CD4+ T cells determines autoimmunity in a spontaneous model of multiple sclerosis. Proc Natl Acad Sci U S A. 2019;116(51):25860-25869. doi:10.1073/pnas.1905955116 917. Zare-Chahoki A, Ahmadi-Zeidabadi M, Azadarmaki S, Ghorbani S, Noorbakhsh F. Inflammation in an Animal Model of Multiple Sclerosis Leads to MicroRNA-25-3p Dysregulation Associated with Inhibition of Pten and Klf4. Iran J Allergy Asthma Immunol. 2021;20(3):314-325 doi:10.18502/ijaai.v20i3.6337 918. Azimi G, Ranjbaran F, Arsang-Jang S, Ghafouri-Fard S, Mazdeh M, Sayad A, Taheri M. Upregulation of VEGF-A and correlation between VEGF-A and FLT-1 expre ssions in Iranian multiple sclerosis patients. Neurol Sci. 2020;41(6):1459-1465. doi:10.1007/s10072-019-04234-2 919. T e z u k a K , S u z u k i M , S a t o R , K a w a r a d a S , T e r a s a k i T , U c h i d a Y . Activation of Annexin A2 signaling at the blood-brain barrier in a mouse model of multiple sclerosis. J Neurochem. 2022;160(6):662-674. doi:10.1111/jnc.15578 920. Luo F, Tran AP, Xin L, Sanapala C, Lang BT, Silver J, Yang Y. Modulation of proteoglycan receptor PTP σ enhances MMP-2 activity to promote recovery from multiple sc lerosis. Nat Commun. 2018;9(1):4126. doi:10.1038/s41467-018-06505-6 921. Shaker OG, Golam RM, Ayoub S, Daker LI, Elguaad MKA, Said ES, Khalil MAF. Correlation between LincR-Gng2-5'and LincR-Epas1-3'as with (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint the severity of multiple sclerosis in Egyptian patients. Int J Neurosci. 2020;130(5):515-521. doi:10.1080/00207454.2019.1695610 922. Goris A, Williams-Gray CH, Foltynie T, Brown J, Maranian M, Walton A, Compston DA, Barker RA, Sawcer SJ. Investigation of TGFB2 as a candidate gene in multiple sclero sis and Parkinson's disease. J Neurol. 2007;254(7):846-848. doi:10.1007/s00415-006-0414-6 923. Aliomrani M, Sahraian MA, Shirkhanloo H, Sharifzadeh M, Khoshayand MR, Ghahremani MH. Correlation between heavy metal exposure and GSTM1 polymorphism in Iranian multiple sclerosis patients. Neurol Sci. 2017;38(7):1271-1278. doi:10.1007/s10072-017-2934-5 924. Jaime-Pérez JC, Turrubiates-Hernández GA, López-Silva LJ, Salazar- Riojas R, Gómez-Almaguer D. Early changes in IL-21, IL-22, CCL2, and CCL4 serum cytokines after outpatient autologous transplantation for multiple sclerosis: A proof of concept study. Clin Transplant. 2020;34(12):e14114. doi:10.1111/ctr.14114 925. Abdelalim LR, Elnaggar YSR, Abda llah OY. Lactoferrin, chitosan double-coated oleosomes loaded with clobetasol propionate for remyelination in multiple sclerosis: Physicochemical characterization and in- vivo assessment in a cuprizone-indu ced demyelination model. Int J Biol Macromol. 2024;277(Pt 1):134144. doi:10.1016/j.ijbiomac.2024.134144 926. Č ierny D, Lehotský J, Kantorová E, Sivák Š, Javor J, Kur č a E, Dobrota D, Michalik J. The HLA-DRB1 and HLA-DQB1 alleles are associated with multiple sclerosis disability progression in Slovak population. Neurol Res. 2018;40(7):607-614. doi:10.1080/01616412.2018.1456711 927. Luo H, Broux B, Wang X, Hu Y, Ghannam S, Jin W, Larochelle C, Prat A, Wu J. EphrinB1 and EphrinB2 regulate T cell chemotaxis and migration in experimental autoimmune encephalomyelitis and multiple sclerosis. Neurobiol Dis. 2016;91:292-306. doi:10.1016/j.nbd.2016.03.013 928. Moll NM, Hong E, Fauveau M, Naruse M, Kerninon C, Tepavcevic V, Klopstein A, Seilhean D, Chew LJ, Gallo V, et al. SOX17 is expressed in regenerating oligodendrocytes in experimental models of demyelination and in multiple sclerosis. Glia. 2013;61(10):1659-1672. doi:10.1002/glia.22547 929. L u M , S h i H , T a y l o r B V , K ö r n e r H . A l t e r a t i o n s o f s u b s e t a n d cytokine profile of peripheral T helper cells in PBMCs from Multiple (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Sclerosis patients or from individuals with MS risk SNPs near genes CYP27B1 and CYP24A1. Cytokine. 2022;153:155866. doi:10.1016/j.cyto.2022.155866 930. Avasarala JR, Jones JR, Rogers CR. Forkhead box C1 gene variant causing glaucoma and small vessel angiopathy can mimic multiple sclerosis. Mult Scler Relat Disord. 2018;22:157-160. doi:10.1016/j.msard.2018.04.004 931. Thöne J, Kleiter I, Stahl A, Ellr ichmann G, Gold R, Hellwig K. Relevance of endoglin, IL-1 α , IL-1 β and anti-ovarian antibodies in females with multiple sclerosis. J Neurol Sci. 2016;362:240-243. doi:10.1016/j.jns.2016.01.057 932. Granström AL, Markljung E, Fink K, Nordenskjöld E, Nilsson D, Wester T, Nordenskjöld A. A novel stop mutation in the EDNRB gene in a family with Hirschsprung's disease associated with multiple sclerosis. J Pediatr Surg. 2014;49(4):622-625. doi:10.1016/j.jpedsurg.2013.10.027 933. Rot U, Sandelius Å, Emerši č A, Zetterberg H, Blennow K. Cerebrospinal fluid GAP-43 in early multiple sclerosis. Mult Scler J Exp Transl Clin. 2018;4(3):2055217318792931. doi:10.1177/2055217318792931 934. Cunningham S, O'Doherty C, Patter son C, McDonnell G, Hawkins S, Marrosu MG, Vandenbroeck K. The neuropeptide genes TAC1, TAC3, TAC4, VIP and PACAP(ADCYAP1), and susceptibility to multiple sclerosis. J Neuroimmuno l. 2007;183(1-2):208-213. doi:10.1016/j.jneuroim.2006.11.002 935. Thümmler K, Wrzos C, Franz J, McElroy D, Cole JJ, Hayden L, Arseni D, Schwarz F, Junker A, Edgar JM, et al. Fibroblast growth factor 9 (FGF9)-mediated neurodegeneration: Implications for progressive multiple sclerosis?. Neuropathol Appl Neurobiol. 2023;49(5):e12935. doi:10.1111/nan.12935 936. Brugger SW, Gardner MC, Beales JT, Briggs F, Davis MF. Depression in multiple sclerosis patients associated with risk variant near NEGR1. Mult Scler Rela t Disord. 2020;46:102537. doi:10.1016/j.msard.2020.102537 937. Graves JS, Barcellos LF, Simpson S, Belman A, Lin R, Taylor BV, Ponsonby AL, Dwyer T, Krupp L, Waubant E, et al. The multiple sclerosis risk allele within the AHI1 gene is associated with relapses in children and (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint adults. Mult Scler Relat Disord. 2018;19:161-165. doi:10.1016/j.msard.2017.10.008 938. Şİ mŞ ek F, ÖztÜrk N. DCLK-1 level in multiple sclerosis patients and its correlation with clinic. Mult Scler Relat Disord. 2020;43:102179. doi:10.1016/j.msard.2020.102179 939. E i z a N , G a r t y M , S t a u n - R a m E , M i l l e r A , V a d a s z Z . T h e p o s s i b l e involvement of sema3A and sema4A in the pathogenesis of multiple sclerosis. Clin Immunol. 2022;238:109017. doi:10.1016/j.clim.2022.109017 940. Duan J, Lv A, Guo Z, Liu Q, Tian C, Yang Y, Bi J, Yu X, Peng G, Luo B, et al. CX3CR1+/UCHL1+ microglial extracellular vesicles in blood: a potential biomarker for multiple sclerosis. J Neuroinflammation. 2024;21(1):254. doi:10.1186/s12974-024-03243-z 941. Shafit-Zagardo B, Kress Y, Zhao ML, Lee SC. A novel microtubule- associated protein-2 expressed in oligodendrocytes in multiple sclerosis lesions. J Neurochem. 1999;73(6):2531-2537. doi: 10.1046/j.1471- 4159.1999.0732531.x 942. Benítez-Fernández R, Josa-Prado F, Sánchez E, Lao Y, García-Rubia A , C u m e l l a J , M a r t í n e z A , P a l o m o V , d e C a s t r o F . E f f i c a c y o f a benzothiazole-based LRRK2 inhibitor in oligodendrocyte precursor cells and in a murine model of multiple sclerosis. CNS Neurosci Ther. 2024;30(1):e14552. doi:10.1111/cns.14552 943. König T, Leutmezer F, Berger T, Zimprich A, Schmied C, Stögmann E, Zrzavy T. No Association of Multiple Sclerosis with C9orf72 Hexanucleotide Repeat Size in an Austrian Cohort. Int J Mol Sci. 2023;24(14):11254. doi:10.3390/ijms241411254 944. Basivireddy J, Somvanshi RK, Romero IA, Weksler BB, Couraud PO, Oger J, Kumar U. Somatostatin preserved blood brain barrier against cytokine induced alterations: possible role in multiple sclerosis. Biochem Pharmacol. 2013;86(4):497-507. doi:10.1016/j.bcp.2013.06.001 945. Ziccardi S, Tamanti A, Ruggieri C, Guandalini M, Marastoni D, Camera V, Montibeller L, Mazziotti V, Rossi S, Calderone M, Pizzini FB, et al. CSF Parvalbumin Levels at Multiple Sclerosis Diagnosis Predict Future Worse Cognition, Physical Disability, Fatigue, and Gray Matter Damage. Neurol Neuroimmunol Neuroinflamm. 2024;11(6):e200301. doi:10.1212/NXI.0000000000200301 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 946. Cunningham S, O'Doherty C, Patter son C, McDonnell G, Hawkins S, Marrosu MG, Vandenbroeck K. The neuropeptide genes TAC1, TAC3, TAC4, VIP and PACAP(ADCYAP1), and susceptibility to multiple sclerosis. J Neuroimmuno l. 2007;183(1-2):208-213. doi:10.1016/j.jneuroim.2006.11.002 947. Bridel C, Koel-Simmelink MJA, Pe feroen L, Derada Troletti C, Durieux S, Gorter R, Nutma E, Gami P, Iacobaeus E, Brundin L, et al. Brain endothelial cell expression of SPARCL-1 is specific to chronic multiple sclerosis lesions and is regulated by inflammatory mediators in vitro. Neuropathol Appl Neurobiol. 2018;44(4):404-416. doi:10.1111/nan.12412 948. Davies JL, Thompson S, Kaur-Sandhu H, Sawcer S, Coles A, Ban M, Jones J. Increased THEMIS First Exon Usage in CD4+ T-Cells Is Associated with a Genotype that Is Protective against Multiple Sclerosis. PLoS One. 2016;11(7):e0158327. doi:10.1371/journal.pone.0158327 949. Jazireian P, Sasani ST, Assarzadegan F, Azimian M. TRAILR1 (rs20576) and GRIA3 (rs12557782) are not associated with interferon- β response in multiple sclerosis pati ents. Mol Biol Rep. 2020;47(12):9659- 9665. doi:10.1007/s11033-020-06026-w 950. Otaegui D, Zuriarrain O, Castillo-Triviño T, Aransay A, Ruíz- Martinez J, Olaskoaga J, Marti-Masso J, Lopez de Munain A. Association between synapsin III gene promoter SN Ps and multiple sclerosis in Basque patients. Mult Scler. 2009;15(1):124-128. doi:10.1177/1352458508096682 951. Hughes AJ, Dunn KM, Chaffee T, Bhattarai JJ, Beier M. Diagnostic and Clinical Utility of the GAD-2 for Screening Anxiety Symptoms in Individuals With Multiple Sclerosis. Arch Phys Med Rehabil. 2018;99(10):2045-2049. doi:10.1016/j.apmr.2018.05.029 952. Wu Q, Du X, Cheng J, Qi X, Liu H, Lv X, Gong X, Shao C, Wang M, Yue L, et al. PECAM-1 drives β -catenin-mediated EndMT via internalization in colon cancer with diabetes mellitus. Cell Commun Signal. 2023;21(1):203. doi:10.1186/s12964-023-01193-2 953. Ferjeni Z, Bouzid D, Fourati H, Stayoussef M, Abida O, Kammoun T, Hachicha M, Penha-Gonçalves C, Masm oudi H. Association of TCR/CD3, PTPN22, CD28 and ZAP70 gene polymorphisms with type 1 diabetes risk in Tunisian population: family based association study. Immunol Lett. 2015;163(1):1-7. doi:10.1016/j.imlet.2014.11.005 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 954. Wang Y, Zhang R, Shen H, Kong J, Lv X. Pioglitazone protects blood vessels through inhibition of the apelin signaling pathway by promoting KLF4 expression in rat models of T2DM. Biosci Rep. 2019;39(12):BSR20190317. doi:10.1042/BSR20190317 955. Tokuda H, Kuroyanagi G, Tsujimoto M, Enomoto Y, Matsushima- Nishiwaki R, Onuma T, Kojima A, Doi T, Tanabe K, Akamatsu S, et al. Release of Phosphorylated HSP27 (HSPB1) from Platelets Is Accompanied with the Acceleration of Aggregation in Diabetic Patients. PLoS One. 2015;10(6):e0128977. doi:10.1371/journal.pone.0128977 956. Bayat M, Chien S, Chehelcheraghi F. Co- localization of Flt1 and tryptase of mast cells in skin wound of rats with type I diabetes: Initial studies. Acta Histochem. 2021;123(2):151680. doi:10.1016/j.acthis.2021.151680 957. Kosoy R, Concannon P. Functional variants in SUMO4, TAB2, and NFkappaB and the risk of type 1 diabetes. Genes Immun. 2005;6(3):231- 235. doi:10.1038/sj.gene.6364174 958. Chuang PY, Dai Y, Liu R, He H, Kretzler M, Jim B, Cohen CD, He JC.Alteration of forkhead box O (foxo4) acetylation mediates apoptosis of podocytes in diabetes mellitus. PLoS One. 2011;6(8):e23566. doi:10.1371/journal.pone.0023566 959. Liu J, Cheng Q, Wu X, Zhu H, Deng X, Wang M, Yang S, Xu J, Chen Q, Li M, et al. Icariin Treatment Rescues Diabetes Induced Bone Loss via Scavenging ROS and Activating Primary Cilia/Gli2/Osteocalcin Signaling Pathway. Cells. 2022;11(24):4091. doi:10.3390/cells11244091 960. Wang XL, Greco M, Sim AS, Duarte N, Wang J, Wilcken DE. Effect of CYP1A1 MspI polymorphism on ci garette smoking related coronary artery disease and diabetes. Athe rosclerosis. 2002;162(2):391-397. doi:10.1016/s0021-9150(01)00723-7 961. Gajewska B, Ś liwiń ska-Mossoń M. Association of MMP-2 and MMP- 9 Polymorphisms with Diabetes and Pathogenesis of Diabetic Complications. Int J Mol Sci. 2022;23(18):10571. doi:10.3390/ijms231810571 962. Li M, Huang S, Zhang Y, Song Z, Fu H, Lin Z, Huang X. Regulation of the unfolded protein response transducer IRE1 α by SERPINH1 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint aggravates periodontitis with diabetes mellitus via prolonged ER stress. Cell Signal. 2022;91:110241. doi:10.1016/j.cellsig.2022.110241 963. Gao C, Lin X, Fan F, Liu X, Wan H, Yuan T, Zhao X, Luo Y. Status of higher TGF-β 1 and TGF-β 2 levels in the aqueous humour of patients with diabetes and cataracts. BM C Ophthalmol. 2022;22(1):156. doi:10.1186/s12886-022-02317-x 964. Yuan T, Annamalai K, Naik S, Lupse B, Geravandi S, Pal A, Dobrowolski A, Ghawali J, Ruhlandt M, Gorrepati KDD, et al. The Hippo kinase LATS2 impairs pancreatic β -cell survival in diabetes through the mTORC1-autophagy axis. Nat Commun. 2021;12(1):4928. doi:10.1038/s41467-021-25145-x 965. Stoian A, B ă nescu C, B ă laş a RI, Mo ţăţă ianu A, Stoian M, Moldovan VG, Void ă zan S, Dobreanu M. Influence of GSTM1, GSTT1, and GSTP1 Polymorphisms on Type 2 Diabetes Mellitus and Diabetic Sensorimotor Peripheral Neuropathy Risk . Dis Markers. 2015;2015:638693. doi:10.1155/2015/638693 966. Jin Q, Lin L, Zhao T, Yao X, Teng Y, Zhang D, Jin Y, Yang M. Overexpression of E3 ubiquitin ligase Cbl attenuates endothelial dysfunction in diabetes mellitus by inhibiting the JAK2/STAT4 signaling and Runx3- mediated H3K4me3. J Transl Med. 2021;19(1):469. doi: 10.1186/s12967- 021-03069-w 967. Kerns SL, Guevara-Aguirre J, Andrew S, Geng J, Guevara C, Guevara-Aguirre M, Guo M, Oddoux C, Shen Y, Zurita A, et al. A novel variant in CDKN1C is associated with intrauterine growth restriction, short stature, and early-adulthood-onset diabetes. J Clin Endocrinol Metab. 2014;99(10):E2117-E2122. doi:10.1210/jc.2014-1949 968. Mir MM, Alfaifi J, Sohail SK, Rizvi SF, Akhtar MT, Alghamdi MAA, Mir R, Wani JI, Sabah ZU, Alhum aydhi FA, et al. The Role of Pro- Inflammatory Chemokines CCL-1, 2, 4, and 5 in the Etiopathogenesis of Type 2 Diabetes Mellitus in Subjects from the Asir Region of Saudi Arabia: Correlation with Different Degrees of Obesity. J Pers Med. 2024;14(7):743. doi:10.3390/jpm14070743 969. Mohamed WA, Schaalan MF. Antidiabet ic efficacy of lactoferrin in type 2 diabetic pediatrics; controlling impact on PPAR-γ , SIRT-1, and TLR4 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint downstream signaling pathway. Di abetol Metab Syndr. 2018;10:89. doi:10.1186/s13098-018-0390-x 970. Wang X, Zhu L, Liu J, Ma Y, Qiu C, Liu C, Gong Y, Yuwen Y, Guan G, Zhang Y, et al. Palmitic acid in type 2 diabetes mellitus promotes atherosclerotic plaque vulnerability via macrophage Dll4 signaling. Nat Commun. 2024;15(1):1281. doi:10.1038/s41467-024-45582-8 971. Guo Q, Wang W, Abboud R, Guo Z. Impairment of maturation of BMP-6 (35 kDa) correlates with delaye d fracture healing in experimental diabetes. J Orthop Surg Res. 2020;15(1):186. doi: 10.1186/s13018-020- 01705-7 972. Preeti K, Fernandes V, Sood A, Khan I, Khatri DK, Singh SB. Necrostatin-1S mitigates type-2 diabetes-associated cognitive decrement and lipotoxicity-induced neuro-microglia changes through p-RIPK-RIPK3-p- MLKL axis. Metab Brain Dis. 2023;38(5):1581-1612. doi: 10.1007/s11011- 023-01185-8 973. Arner P, Petrus P, Esteve D, Boulomié A, Näslund E, Thorell A, Gao H, Dahlman I, Rydén M. Screening of potential adipokines identifies S100A4 as a marker of pernicious adipose tissue and insulin resistance. Int J Obes (Lond). 2018;42(12):2047-2056. doi:10.1038/s41366-018-0018-0 974. Hertle E, Arts IC, van der Kallen CJ, Feskens EJ, Schalkwijk CG, Hoffmann-Petersen IT, Thiel S, Stehouwer CD, van Greevenbroek MM. Distinct Longitudinal Associations of MBL, MASP-1, MASP-2, MASP-3, and MAp44 With Endothelial Dysfunc tion and Intima-Media Thickness: The Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) Study. Arterioscler Thromb Vasc Biol. 2016;36(6):1278-1285. doi:10.1161/ATVBAHA.115.306552 975. Charles BA, Conley YP, Chen G, Miller RG, Dorman JS, Gorin MB, Ferrell RE, Sereika SM, Rotimi CN, Orchard TJ. Variants of the adenosine A(2A) receptor gene are protective against proliferative diabetic retinopathy in patients with type 1 diabetes. Ophthalmic Res. 2011;46(1):1-8. doi:10.1159/000317057 976. Hussein AG, Mohamed RH, Alghobashy AA. Synergism of CYP2R1 and CYP27B1 polymorphisms and suscep tibility to type 1 diabetes in Egyptian children. Cell Immunol. 2012;279(1):42-45. doi:10.1016/j.cellimm.2012.08.006 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 977. Wu J, Wang X, Chen H, Yang R, Yu H, Wu Y, Hu Y. Type 2 Diabetes Risk and Lipid Metabolism Related to the Pleiotropic Effects of an ABCB1 Variant: A Chinese Family-Bas ed Cohort Study. Metabolites. 2022;12(9):875. doi:10.3390/metabo12090875 978. Ghodsian N, Ismail P, Ahmadloo S, Heidari F, Haghvirdizadeh P, Ataollahi Eshkoor S, Etemad A. Novel Association of WNK4 Gene, Ala589Ser Polymorphism in Essential Hypertension, and Type 2 Diabetes Mellitus in Malaysia. J Di abetes Res. 2016;2016:8219543. doi:10.1155/2016/8219543 979. C h e n K , W u Q , H u K , Y a n g C , W u X , C h e u n g P , W i l l i a m s K J . Suppression of Hepatic FLOT1 (Flotillin -1) by Type 2 Diabetes Mellitus Impairs the Disposal of Remnant Lipoproteins via Syndecan-1. Arterioscler Thromb Vasc Biol. 2018;38(1):102-113. doi:10.1161/ATVBAHA.117.310358 980. Dikilitaş A, Karaaslan F, Evirgen Ş , Ertu ğ rul AS. Gingival crevicular fluid CSF-1 and IL-34 levels in patients with stage III grade C periodontitis and uncontrolled type 2 diabetes me llitus. J Periodontal Implant Sci. 2022;52(6):455-465. doi:10.5051/jpis.2106260313 981. Blázquez-Medela AM, García-Ortiz L, Gómez-Marcos MA, Recio- Rodríguez JI, Sánchez-Rodríguez A, López-Novoa JM, Martínez-Salgado C. Increased plasma soluble endoglin levels as an indicator of cardiovascular alterations in hypertensive and di abetic patients. BMC Med. 2010;8:86. doi:10.1186/1741-7015-8-86 982. Yin Y, Li L, Yu S, Xin Y, Zhu L, Hu X, Chen K, Gu W, Mu Y, Zang L, et al. The first compound heterozygous mutations in SLC12A3 and PDX1 genes: a unique presentation of Gite lman syndrome with distinct insulin resistance and familial diabetes insights. Front Endocrinol (Lausanne). 2024;14:1327729. doi:10.3389/fendo.2023.1327729 983. Gautheron J, Morisseau C, Chung WK, Zammouri J, Auclair M, Baujat G, Capel E, Moulin C, Wang Y, Yang J, et al. EPHX1 mutations cause a lipoatrophic diabetes syndrome due to impaired epoxide hydrolysis and increased cellular sene scence. Elife. 2021;10:e68445. doi:10.7554/eLife.68445 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 984. Zhang S, Zang W. The Role and Mechanism of STIM1/Orai1- Regulated Ca2+ Influx in Myocardial Hypertrophy in Type 2 Diabetes Mellitus. Ann Clin Lab Sci. 2024;54(1):17-25. 985. Li Y, Ma WG, Li XC. Identification of Blood miR-216a, miR-377 and Their Target Genes ANGPTL4, GAP-43 and Serum of PPARG as Biomarkers for Diabetic Peripheral Neuropathy of Type 2 Diabetes. Clin Lab. 2021;67(4):10.7754/Clin.Lab.2020.191220. doi:10.7754/Clin.Lab.2020.191220 986. Zhang XL, Zhao X, Wu Y, Huang WQ, Chen JJ, Hu P, Liu W, Chen YW, Hao J, Xie RR, et al. Angiot ensin(1-7) activates MAS-1 and upregulates CFTR to promote in sulin secretion in pancreatic β -cells: the association with type 2 diabetes. Endocr Connect. 2022;11(1):e210357.doi:10.1530/EC-21-0357 987. Aparicio JM, Wakisaka A, Takada A, Matsuura N, Yoshiki T. Non- HLA genetic factors and insulin dependent diabetes mellitus in the Japanese: TCRA, TCRB and TCRG, INS, THY1, CD3D and ETS1. Dis Markers. 1990;8(5):283-294. 988. Demir I, Yilmaz I, Horoz E, Bozkaya G, Bilgir O. The relationship between stathmin-2 level and metabolic parameters in newly diagnosed type 2 diabetes mellitus patients. Am J Med Sci. 2024;368(1):25-32. doi:10.1016/j.amjms.2024.03.023 989. Zhang X, Lv H, Mei J, Ji B, Huang S, Li X. The Potential Role of R4 Regulators of G Protein Signaling (RGS) Proteins in Type 2 Diabetes Mellitus. Cells. 2022;11(23):3897. doi:10.3390/cells11233897 990. Gu HF. Genetic variation screening and association studies of the adenylate cyclase activating polypeptide 1 (ADCYAP1) gene in patients with type 2 diabetes. Hum Mutat. 2002;19(5):572-573. doi:10.1002/humu.9034 991. W a l l n e r C , S c h i r a J , W a g n e r J M , S c h u l t e M , F i s c h e r S , H i r s c h T , Richter W, Abraham S, Kneser U, Lehnhardt M, et al. Application of VEGFA and FGF-9 enhances angiog enesis, osteogen esis and bone remodeling in type 2 diabetic long bone regeneration. PLoS One. 2015;10(3):e0118823. doi:10.1371/journal.pone.0118823 992. Ng MC, Tam CH, So WY, Ho JS, Chan AW, Lee HM, Wang Y, Lam VK, Chan JC, Ma RC. Implication of genetic variants near NEGR1, (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint SEC16B, TMEM18, ETV5/DGKG, GNPDA2, LIN7C/BDNF, MTCH2, BCDIN3D/FAIM2, SH2B1, FTO, MC4R, and KCTD15 with obesity and type 2 diabetes in 7705 Chinese. J Clin Endocrinol Metab. 2010;95(5):2418- 2425. doi:10.1210/jc.2009-2077 993. Al-Daghri NM, Costa AS, Alokail MS, Zanzottera M, Alenad AM, Mohammed AK, Clerici M, Guerini FR. Synaptosomal Protein of 25 kDa (Snap25) Polymorphisms Associated with Glycemic Parameters in Type 2 Diabetes Patients. J Diabetes Res. 2016;2016:8943092. doi:10.1155/2016/8943092 994. Alessi MC, Nicaud V, Scroyen I, Lange C, Saut N, Fumeron F, Marre M, Lantieri O, Fontaine -Bisson B, Juhan-Vague I, et al. Association of vitronectin and plasminogen activator inhibitor-1 levels with the risk of metabolic syndrome and type 2 diabetes mellitus. Results from the D.E.S.I.R. prospective cohort. Thromb Haemost. 2011;106(3):416-422. doi:10.1160/TH11-03-0179 995. Razeghi P, Young ME, Cockrill TC, Frazier OH, Taegtmeyer H. Downregulation of myocardial myocyte enhancer factor 2C and myocyte enhancer factor 2C-regulated gene expression in diabetic patients with nonischemic heart failure. Circulation. 2002;106(4):407-411. doi:10.1161/01.cir.0000026392.80723.dc 996. Veluthakal R, Chepurny OG, Leech CA, Schwede F, Holz GG, Thurmond DC. Restoration of Glucose-Stimulated Cdc42-Pak1 Activation and Insulin Secretion by a Selective Epac Activator in Type 2 Diabetic Human Islets. Diabetes. 2018;67(10):1999-2011. doi:10.2337/db17-1174 997. Holmkvist J, Anthonsen S, Wegner L, Andersen G, Jørgensen T, Borch-Johnsen K, Sandbaek A, Lauritzen T, Pedersen O, Hansen T. Polymorphisms in AHI1 are not associated with type 2 diabetes or related phenotypes in Danes: non-replication of a genome-wide association result. Diabetologia. 2008;51(4):609-614. doi:10.1007/s00125-008-0925-z 998. Ji L, Yang X, Jin Y, Li L, Yang B, Zhu W, Xu M, Wang Y, Wu G, Luo W, et al. Blockage of DCLK1 in cardiomyocytes suppresses myocardial inflammation and alleviates diabetic cardiomyopathy in streptozotocin- induced diabetic mice. Biochim Biophys Acta Mo l Basis Dis. 2024;1870(1):166900. doi:10.1016/j.bbadis.2023.166900 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 999. Lin AC, Hung HC, Chen YW, Cheng KP, Li CH, Lin CH, Chang CJ, Wu HT, Ou HY. Elevated Hedgehog-Interacting Protein Levels in Subjects with Prediabetes and Type 2 Diabetes. J Clin Med. 2019;8(10):1635. doi:10.3390/jcm8101635 1000. Li P, Qin D, Chen T, Hou W, Song X, Yin S, Song M, Fernando WCHA, Chen X, Sun Y, et al. Dysregulated Rbfox2 produces aberrant splicing of CaV1.2 calcium channel in diabetes-induced cardiac hypertrophy. Cardiovasc Di abetol. 2023;22(1):168. doi:10.1186/s12933- 023-01894-5 1001. Kang YE, Choung S, Lee JH, Kim HJ, Ku BJ. The Role of Circulating Slit2, the One of the Newly Batokines, in Human Diabetes Mellitus. Endocrinol Metab (Seoul). 2017;32(3):383-388. doi:10.3803/EnM.2017.32.3.383 1002. Qiao Q, Xu X, Song Y, Song S, Zhu W, Li F. Semaphorin 3A promotes osteogenic differentiation of BMSC from type 2 diabetes mellitus rats. J Mol Histol. 2018;49(4):369-376. doi:10.1007/s10735-018-9776-1 1003. Costes S, Huang CJ, Gurlo T, Daval M, Matveyenko AV, Rizza RA, Butler AE, Butler PC. β -cell dysfunctional ERAD /ubiquitin/proteasome system in type 2 diabetes mediated by islet amyloid polypeptide-induced UCH-L1 deficiency. Diabetes. 2011;60(1):227-238. doi:10.2337/db10-0522 1004. Ke RQ, Wang Y, Hong SH, Xiao LX. Anti-diabetic effect of quercetin in type 2 diabetes mell itus by regulating the microRNA-92b- 3p/EGR1 axis. J Physiol Pharmacol. 2023;74(2):10.26402/jpp.2023.2.03. doi:10.26402/jpp.2023.2.03 1005. Jia G, Sowers JR. Targeting CITED2 for Angiogenesis in Obesity and Insulin Resistance. Diabetes. 2016;65(12):3535-3536. doi: 10.2337/dbi16- 0052 1006. Chang TJ, Chiu YF, Sheu WH, Shih KC, Hwu CM, Quertermous T, Jou YS, Kuo SS, Chang YC, Chuang LM. Genetic polymorphisms of PCSK2 are associated with glucose homeostasis and progression to type 2 diabetes in a Chinese population. Sci Rep. 2015;5:14380. doi:10.1038/srep14380 1007. Huang MH, Liu YF, Nfor ON, Hsu SY, Lin WY, Chang YS, Liaw YP. nteractive Association Between Intronic Polymorphism (rs10506151) of (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint the LRRK2 Gene and Type 2 Diabetes on Neurodegenerative Diseases. Pharmgenomics Pers Med. 2021;14:839-847. doi:10.2147/PGPM.S316158 1008. Bansal V, Winkelmann BR, Dietrich JW, Boehm BO. Whole-exome sequencing in familial type 2 diabetes identifies an atypical missense variant in the RyR2 gene. Front Endocrinol (Lausanne). 2024;15:1258982. doi:10.3389/fendo.2024.1258982 1009. Bonner SM, Pietropaolo SL, Fan Y, Chang Y, Sethupathy P, Morran MP, Beems M, Giannoukakis N, Trucco G, Palumbo MO, et al. Sequence variation in promoter of Ica1 gene, which encodes protein implicated in type 1 diabetes, causes transcription factor autoimmune regulator (AIRE) to increase its binding and down-regulate expression. J Biol Chem. 2012;287(21):17882-17893. doi:10.1074/jbc.M111.319020 1010. Kwon YJ, Hong KW, Park BJ, Jung DH. Serotonin receptor 3B polymorphisms are associated with ty pe 2 diabetes: The Korean Genome and Epidemiology Study. Diabetes Res Clin Pract. 2019;153:76-85. doi:10.1016/j.diabres.2019.05.032 1011. Li Q, Qiao ZR, Liu DB, Zeng JT, Zhang J, Bo Y, Zu HY, Hu Q, Wu X, Dong SS. Relationship between serum GAD-Ab and the genetic polymorphisms of GAD2 and type 2 diabetes mellitus. Genet Mol Res. 2015;14(2):3002-3009. doi:10.4238/2015.April.10.10 1012. Abosheasha MA, Zahran F, Bessa SS, El-Magd MA, Mohamed TM. Association between a n ovel G94A single nucleotide polymorphism in ATP1A1 gene and type 2 diabetes mell itus among Egyptian patients. J Res Med Sci. 2019;24:62. doi:10.4103/jrms.JRMS_975_18 1013. Díaz-García JD, Leyva-Leyva M, Sánchez-Aguillón F, de León- Bautista MP, Fuentes-Venegas A, To rres-Viloria A, Tenorio-Aguirre EK, Morales-Lázaro SL, Olivo-Díaz A, González-Ramírez R. Association Study of CACNA1D, KCNJ11, KCNQ1, and CACNA1E Single-Nucleotide Polymorphisms with Type 2 Diabetes Mellitus. Int J Mol Sci. 2024;25(17):9196. doi:10.3390/ijms25179196 1014. Goru SK, Kadakol A, Pandey A, Malek V, Sharma N, Gaikwad AB. Histone H2AK119 and H2BK120 mono-ubiquitination modulate SET7/9 and SUV39H1 in type 1 diabetes-induced renal fibrosis. Biochem J. 2016;473(21):3937-3949. doi:10.1042/BCJ20160595 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 1015. Wysocka-Mincewicz M, Groszek A, Ambrozkiewicz F, Paziewska A, Dą browska M, Rybak A, Konopka E, Ochoci ń ska A, Ż eber-Lubecka N, Karczmarski J, et al. Combination of HLA-DQ2/-DQ8 Haplotypes and a Single MSH5 Gene Variant in a Polish Population of Patients with Type 1 Diabetes as a First Line Screening for Celiac Disease?. J Clin Med. 2022;11(8):2223. doi:10.3390/jcm11082223 1016. Ramos-Lopez O, Mejia-Godoy R, Frías-Delgadillo KJ, Torres- Valadez R, Flores-García A, Sánchez-Enríquez S, Aguiar-García P, Martínez-López E, Zepeda-Carrillo EA. Interactions between DRD2/ANKK1 TaqIA Polymorphism and Dietary Factors Influence Plasma Triglyceride Concentrations in Diabetic Patients from Western Mexico: A Cross-sectional Study. Nu trients. 2019;11(12):2863. doi:10.3390/nu11122863 1017. Takei S, Nagashima S, Takei A, Yamamuro D, Wakabayashi T, Murakami A, Isoda M, Yamazaki H, Ebihara C, Takahashi M, et al. β -Cell- Specific Deletion of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) Reductase Causes Overt Diab etes due to Reduction of β -Cell Mass and Impaired Insulin Secretion. Diabetes. 2020;69(11):2352-2363. doi:10.2337/db19-0996 1018. Liu F, Dong Y, Zhong F, Guo H, Dong P. CISD1 Is a Breast Cancer Prognostic Biomarker Associated with Diabetes Mellitus. Biomolecules. 2022;13(1):37. doi:10.3390/biom13010037 1019. Lu P, Bevan DR, Lewis SN, Hontecillas R, Bassaganya-Riera J. Molecular modeling of lanthionine synthetase component C-like protein 2: a potential target for the discovery of no vel type 2 diabetes prophylactics and therapeutics. J Mol Model. 2011;17(3):543-553. doi: 10.1007/s00894-010- 0748-y 1020. Zbidi H, López JJ, Amor NB, Bartegi A, Salido GM, Rosado JA. Enhanced expression of STIM1/Orai1 and TRPC3 in platelets from patients with type 2 diabetes mellitus. Blood Cells Mol Dis. 2009;43(2):211-213. doi:10.1016/j.bcmd.2009.04.005. 1021. Rodríguez-Calvo R, Granado-Casas M, Pérez-Montes de Oca A, Julian MT, Domingo M, Codina P, Santiago-Vacas E, Cediel G, Julve J, Rossell J, et al. Fatty Acid Binding Proteins 3 and 4 Predict Both All-Cause and Cardiovascular Mortality in Subj ects with Chronic Heart Failure and (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Type 2 Diabetes Mellitus. Antio xidants (Basel). 2023;12(3):645. doi:10.3390/antiox12030645 1022. Adeyemo AA, Zaghloul NA, Chen G, Doumatey AP, Leitch CC, Hostelley TL, Nesmith JE, Zhou J, Be ntley AR, Shriner D, et al. ZRANB3 is an African-specific type 2 diabetes locus associated with beta-cell mass and insulin response. Nat Commun. 2019;10(1):3195. doi: 10.1038/s41467- 019-10967-7 1023. Z h a o J , A n K , M a o Z , Q u Y , W a n g D , L i J , M i n Z , X u e Z . C C L 5 promotes LFA-1 expression in T h17 cells and induces LCK and ZAP70 activation in a mouse model of Parkinson's disease. Front Aging Neurosci. 2023;15:1250685. doi:10.3389/fnagi.2023.1250685 1024. Tan JSY, Lee B, Lim J, Ma DR, Goh JX, Goh SY, Gulam MY, Koh SM, Lee WW, Feng L, et al. Parkinson's Disease-Specific Autoantibodies against the Neuroprotective Co-Chaperone STIP1. Cells. 2022;11(10):1649. doi:10.3390/cells11101649 1025. Zamanian MY, Golmohammadi M, Amin RS, Bustani GS, Romero- Parra RM, Zabibah RS, Oz T, Jalil AT, Soltani A, Kujawska M. Therapeutic Targeting of Krüppel-Like Factor 4 and Its Pharmacological Potential in Parkinson's Disease: a Comprehensive Review. Mol Neurobiol. 2024;61(6):3596-3606. doi:10.1007/s12035-023-03800-2 1026. M e n g J , F a n g J , B a o Y , C h e n H , H u X , W a n g Z , L i M , C h e n g Q , Dong Y, Yang X, et al. The biphasic role of Hspb1 on ferroptotic cell death in Parkinson's disease. Theranostics. 2024;14(12):4643-4666. doi:10.7150/thno.98457 1027. Zhang B, Hu YB, Li G, Yu HX, Cui C, Han YY, Li HX, Li G. Itga5- PTEN signaling regulates striatal synaptic strength and motor coordination in Parkinson's disease. Int J Biol Sci. 2024;20(9):3302-3316. doi:10.7150/ijbs.96116 1028. Kurzawski M, Białecka M, Sławek J, Kłodowska-Duda G, Dro ź dzik M. Association study of GATA-2 transcription factor gene (GATA2) polymorphism and Parkinson's dis ease. Parkinsonism Relat Disord. 2010;16(4):284-287. doi:10.1016/j.parkreldis.2009.10.006 1029. Chan DK, Mellick GD, Buchanan DD, Hung WT, Ng PW, Woo J, Kay R. Lack of association between CYP1A1 polymorphism and (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Parkinson's disease in a Chinese popul ation. J Neural Transm (Vienna). 2002;109(1):35-39. doi:10.1007/s702-002-8234-8 1030. M a C , L i u Y , L i S , M a C , H u a n g J , W e n S , Y a n g S , W a n g B . Microglial cGAS drives neuroinflammation in the MPTP mouse models of Parkinson's disease. CNS Neurosci Ther. 2023;29(7):2018-2035. doi:10.1111/cns.14157 1031. Booth HDE, Wessely F, Connor-Robson N, Rinaldi F, Vowles J, Browne C, Evetts SG, Hu MT, Co wley SA, Webber C, et al. RNA sequencing reveals MMP2 and TGFB1 downregulation in LRRK2 G2019S Parkinson's iPSC-derived astrocytes. Neurobiol Dis. 2019;129:56-66. doi:10.1016/j.nbd.2019.05.006 1032. Wang T, Wang B. Association between Glutathione S-transferase M1/Glutathione S-transferase T1 polymorphisms and Parkinson's disease: a meta-analysis. J Neurol Sci. 2014;338(1-2):65-70. doi:10.1016/j.jns.2013.12.018 1033. Huang P, Wan Z, Qu S. Targeting the RUNX3-miR-186-3p-DAT- IGF1R axis as a therapeutic strategy in a Parkinson's disease model. J Transl Med. 2024;22(1):719. doi:10.1186/s12967-024-05535-7 1034. Xiromerisiou G, Mar ogianni C, Lampropoulos IC, Dardiotis E, Speletas M, Ntavaroukas P, Androutsopoulou A, Kalala F, Grigoriadis N, Papoutsopoulou S. Peripheral Inflammatory Markers TNF- α and CCL2 Revisited: Association with Parkinson's Disease Severity. Int J Mol Sci. 2022;24(1):264. doi:10.3390/ijms24010264 1035. Tang S, Wang A, Yan X, Chu L, Yang X, Song Y, Sun K, Yu X, Liu R, Wu Z, et al. rain-targeted intranasal delivery of dopamine with borneol and lactoferrin co-modified nanopartic les for treating Parkinson's disease. Drug Deliv. 2019;26(1):700-707. doi:10.1080/10717544.2019.1636420 1036. Pandi S, Chinniah R, Sevak V, Ravi PM, Raju M, Vellaiappan NA, Karuppiah B. Association of HLA- DRB1, DQA1 and DQB1 alleles and haplotype in Parkinson's disease from South India. Neurosci Lett. 2021;765:136296. doi:10.1016/j.neulet.2021.136296 1037. Deng H, Zhu SH, Le WD, Yang HR, Lv HW, Xu HB, Xie WJ, Jankovic J. Examination of the MSX1 gene in patients with Parkinson's disease. Acta Neurol Sc and. 2009;120(6):442-444. doi: 10.1111/j.1600- 0404.2009.01271.x (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 1038. Müller T. ABCB1: is there a role in the drug treatment of Parkinson's disease?. Expert Opin Drug Me tab Toxicol. 2018;14(2):127-129. doi:10.1080/17425255.2018.1416096 1039. Chang KH, Wu YR, Chen YC, Wu HC, Chen CM. Association between CSF1 and CSF1R Polymorphi sms and Parkinson's Disease in Taiwan. J Clin Med. 2019;8(10):1529. doi:10.3390/jcm8101529 1040. Ellioff KJ, Osting SMK, Lentine A, Welper AD, Burger C, Greenspan DS. Ablation of Mitochondrial RCC1-L Induces Nigral Dopaminergic Neurodegeneration and Parkinsonian -like Motor Symptoms. Preprint. bioRxiv. 2024;2023.12.01.567409. doi:10.1101/2023.12.01.567409 1041. Cocco C, Corda G, Lisci C, Noli B, Carta M, Brancia C, Manca E, Masala C, Marrosu F, Solla P, et al. VGF peptides as novel biomarkers in Parkinson's disease. Cell Ti ssue Res. 2020;379(1):93-107. doi:10.1007/s00441-019-03128-1 1042. Saal KA, Galter D, Roeber S, Bähr M, Tönges L, Lingor P. Altered Expression of Growth Associated Protein-43 and Rho Kinase in Human Patients with Parkinson's Diseas e. Brain Pathol. 2017;27(1):13-25. doi:10.1111/bpa.12346 1043. Torres ERS, Stanojlovic M, Zelikowsky M, Bonsberger J, Hean S, Mulligan C, Baldauf L, Fleming S, Masliah E, Chesselet MF, et al. Alpha- synuclein pathology, microgliosis, and parvalbumin neuron loss in the amygdala associated with enhanced fear in the Thy1-aSyn model of Parkinson's disease. Neurobiol Dis. 2021;158:105478. doi:10.1016/j.nbd.2021.105478 1044. Kochmanski J, Kuhn NC, Bernstein AI. Parkinson's disease- associated, sex-specific changes in DNA methylation at PARK7 (DJ-1), SLC17A6 (VGLUT2), PTPRN2 (IA-2 β ), and NR4A2 (NURR1) in cortical neurons. NPJ Parkinsons Dis. 2022;8(1):120. doi: 10.1038/s41531-022- 00355-2 1045. Shen Y, Cui X, Hu Y, Zhang Z, Zhang Z. LncRNA-MIAT regulates the growth of SHSY5Y cells by re gulating the miR-34-5p-SYT1 axis and exerts a neuroprotective effect in a mouse model of Parkinson's disease. Am J Transl Res. 2021;13(9):9993-10013. (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 1046. Patel S, Howard D, French L. A pH-eQTL Interaction at the RIT2- SYT4 Parkinson's Disease Risk Locus in the Substantia Nigra. Front Aging Neurosci. 2021;13:690632. doi:10.3389/fnagi.2021.690632 1047. Shulskaya MV, Semenova EI, Rudenok MM, Partevian SA, Lukashevich MV, Karabanov AV, Fedotova EY, Illarioshkin SN, Slominsky PA, Shadrina MI, et al. Analysis of LRRN3, MEF2C, SLC22A, and P2RY12 Gene Expression in the Periph eral Blood of Patients in the Early Stages of Parkinson's Disease. Biomedicines. 2024;12(7):1391. doi:10.3390/biomedicines12071391 1048. Yu J, Meng J, Qin Z, Yu Y, Liang Y, Wang Y, Min D. Dysbiosis of gut microbiota inhibits NMNAT2 to promote neurobehavioral deficits and oxidative stress response in the 6-OHDA-lesioned rat model of Parkinson's disease. J Neuroinflammation. 2023;20(1):117. doi:10.1186/s12974-023- 02782-1 1049. Bai X, Jin J, Li S, Wang H, Xie A. CUB and Sushi Multiple Domains (CSMD1) Gene Polymor phisms and Susceptibilities to Idiopathic Parkinson's Disease in Northern Chin ese Han Population: A Case-Control Study. Parkinsons Dis. 2021;2021:6661162. doi:10.1155/2021/6661162 1050. Wang J, Si YM, Liu ZL, Yu L. Cholecystokinin, cholecystokinin-A receptor and cholecystokinin-B receptor gene polymorphisms in Parkinson's disease. Pharmacogenetics. 2003;13(6):365-369. doi: 10.1097/00008571- 200306000-00008 1051. Qi L, Tang YG, Wang L, He W, Pan HH, Nie RR, Can Y. ole of Rho- mediated ROCK-Semaphorin3A signaling pathway in the pathogenesis of Parkinson's disease in a mouse model. J Neurol Sci. 2016;370:21-26. doi:10.1016/j.jns.2016.08.061 1052. Ham SJ, Lee D, Xu WJ, Cho E, Choi S, Min S, Park S, Chung J. Loss of UCHL1 rescues the defe cts related to Parkinson's disease by suppressing glycolysis. Sci Adv. 2021;7(28):eabg4574. doi:10.1126/sciadv.abg4574 1053. DeStefano AL, Latourelle J, Lew MF, Suchowersky O, Klein C, Golbe LI, Mark MH, Growdon JH, Wooten GF, Watts R, et al. eplication of association between ELAVL4 and Park inson disease: the GenePD study. Hum Genet. 2008;124(1):95-99. doi:10.1007/s00439-008-0526-4 1054. Guo S, Gao Y, Zhao Y. Neuroprotective microRNA-381 Binds to Repressed Early Growth Response 1 (EGR1) and Alleviates Oxidative (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Stress Injury in Parkinson's Disease. ACS Chem Neurosci. 2023;14(11):1981-1991. doi:10.1021/acschemneuro.2c00724 1055. Sabbir MG, Speth RC, Albensi BC. Loss of Cholinergic Receptor Muscarinic 1 (CHRM1) Protein in the Hippocampus and Temporal Cortex of a Subset of Individuals with Alzheimer's Disease, Parkinson's Disease, or Frontotemporal Dementia: Implications for Patient Survival. J Alzheimers Dis. 2022;90(2):727-747. doi:10.3233/JAD-220766 1056. D'Andrea MR, Ilyin S, Plata-Salaman CR. Abnormal patterns of microtubule-associated protein-2 (MAP -2) immunolabeling in neuronal nuclei and Lewy bodies in Parkinson's disease substantia nigra brain tissues. Neurosci Lett. 2001;306(3):137-140. doi:10.1016/s0304-3940(01)01811-0 1057. Tan S, Chi H, Wang P, Zhao R, Zhang Q, Gao Z, Xue H, Tang Q, Li G. Protein tyrosine phosphatase receptor type O serves as a key regulator of insulin resistance-induced α -synuclein aggregation in Parkinson's disease. Cell Mol Life Sci. 2024;81(1):403. doi:10.1007/s00018-024-05436-4 1058. Chang KH, Chen CM, Chen YC, Fung HC, Wu YR. Polymorphisms of ACMSD-TMEM163, MCCC1, and BCKDK-STX1B Are Not Associated with Parkinson's Disease in Taiw an. Parkinsons Dis. 2019;2019:3489638. doi:10.1155/2019/3489638 1059. Lázaro-Figueroa A, Hernández-Medrano AJ, Ramírez-Pineda DB, Navarro Cadavid A, Makarious M, Foo JN, Alvarado CX, Bandres-Ciga S, Periñan MT; Global Parkinson's Ge netics Program (GP2). s SH3GL2 p.G276V the Causal Functional Varian t Underlying Parkinson's Disease Risk at this Locus?. M ov Disord. 2024;39(11):2117-2119. doi:10.1002/mds.29719 1060. Fong CS, Shyu HY, Shieh JC, Fu YP, Chin TY, Wang HW, Cheng CW. Association of MTHFR, MTR, and MTRR polymorphisms with Parkinson's disease among ethnic Chinese in Taiwan. Clin Chim Acta. 2011;412(3-4):332-338. doi:10.1016/j.cca.2010.11.004 1061. G u o C , Z h u J , W a n g J , D u a n J , M a S , Y i n Y , Q u a n W , Z h a n g W , Guan Y, Ding Y, et al. Neuroprotective effects of protocatechuic aldehyde through PLK2/p-GSK3 β /Nrf2 signaling pathway in both in vivo and in vitro models of Parkinson's disease. Aging (Albany NY). 2019;11(21):9424-9441. doi:10.18632/aging.102394 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 1062. Theuns J, Verstraeten A, Sleegers K, Wauters E, Gijselinck I, Smolders S, Crosiers D, Corsmit E, Elinck E, Sharma M, et al. Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease. Neurology. 2014;83(21):1906-1913. doi:10.1212/WNL.0000000000001012 1063. Strittmatter M, Hamann GF, Strubel D, Cramer H, Schimrigk K. Somatostatin-like immunoreactivity, its molecular forms and monoaminergic metabolites in aged and demented patients with Parkinson's disease--effect of L-Dopa. J Neural Transm (Vienna). 1996;103(5):591-602. doi:10.1007/BF01273156 1064. Lanoue AC, Blatt GJ, Soghomon ian JJ. Decreased parvalbumin mRNA expression in dorsolateral prefrontal cortex in Parkinson's disease. Brain Res. 2013;1531:37-47. doi:10.1016/j.brainres.2013.07.025 1065. Chang CH, Lim KL, Foo JN. Synap tic Vesicle Glycoprotein 2C: a role in Parkinson's disease. Fr ont Cell Neurosci. 2024;18:1437144. doi:10.3389/fncel.2024.1437144 1066. Beyer K, Ispierto L, Latorre P, Tolosa E, Ariza A. Alpha- and beta- synuclein expression in Parkinson di sease with and without dementia. J Neurol Sci. 2011;310(1-2):112-117. doi:10.1016/j.jns.2011.05.049 1067. Tanji K, Kamitani T, Mori F, Kakita A, Takahashi H, Wakabayashi K. TRIM9, a novel brain-specific E3 ubiquitin ligase, is repressed in the brain of Parkinson's disease and dementia with Lewy bodies. Neurobiol Dis. 2010;38(2):210-218. doi:10.1016/j.nbd.2010.01.007 1068. Nedic Erjavec G, Grubor M, Zi vkovic M, Bozina N, Sagud M, Nikolac Perkovic M, Mihaljevic-Peles A, Pivac N, Svob Strac D. SLC6A3, HTR2C and HTR6 Gene Polymorphism s and the Risk of Haloperidol- Induced Parkinsonism. Biomedicines. 2022;10(12):3237.doi:10.3390/biomedicines10123237 1069. Faustini G, Longhena F, Masato A, Bassareo V, Frau R, Klingstedt T, Shirani H, Brembati V, Parrella E, Vezzoli M, et al. Synapsin III gene silencing redeems alpha-synuclein transgenic mice from Parkinson's disease- like phenotype. Mol Ther. 2022;30(4):1465-1483. doi:10.1016/j.ymthe.2022.01.021 1070. Sukhanov I, Dorotenko A, Fesenko Z, Savchenko A, Efimova EV, Mor MS, Belozertseva IV, Sotnikova TD, Gainetdinov RR. Inhibition of (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint PDE10A in a New Rat Model of Severe Dopamine Depletion Suggests New Approach to Non-Dopamine Parkinson's Disease Therapy. Biomolecules. 2022;13(1):9. doi:10.3390/biom13010009 1071. Pérez-Santamarina E, García-Ruiz P, Martínez-Rubio D, Ezquerra M, Pla-Navarro I, Puente J, Martí MJ, Palau F, Hoenicka J. Author Correction: Regulatory rare variants of the dopaminergic gene ANKK1 as potential risk factors for Parkinson's disease. Sci Rep. 2022;12(1):12719. doi:10.1038/s41598-022-17301-0 1072. Turcotte MA, Garant JM, Cossette-Roberge H, Perreault JP. Guanine Nucleotide-Binding Protein-Like 1 (GNL1) binds RNA G-quadruplex structures in genes associated with Parkinson's disease. RNA Biol. 2021;18(9):1339-1353. doi:10.1080/15476286.2020.1847866 1073. Verbovaya ER, Kadnikov IA, Logvinov IO, Antipova TA, Voronin MV, Seredenin SB. In vitro modelling of Parkinson's disease using 6-OHDA is associated with increased NQO2 activity. Toxicol In Vitro. 2024;101:105940. doi:10.1016/j.tiv.2024.105940 1074. Geldenhuys WJ, Benkovic SA, Lin L, Yonutas HM, Crish SD, Sullivan PG, Darvesh AS, Brown CM, Richardson JR. MitoNEET (CISD1) Knockout Mice Show Signs of Striat al Mitochondrial Dysfunction and a Parkinson's Disease Phenotype. ACS Chem Neurosci. 2017;8(12):2759- 2765. doi:10.1021/acschemneuro.7b00287 1075. Fu Y, Pickford R, Galper J, Phan K, Wu P, Li H, Kim YB, Dzamko N, Halliday GM, Kim WS. A protective role of ABCA5 in response to elevated sphingomyelin levels in Parkinson's disease. NPJ Parkinsons Dis. 2024;10(1):20. doi:10.1038/s41531-024-00632-2 1076. Haga H, Yamada R, Izumi H, Shinoda Y, Kawahata I, Miyachi H, Fukunaga K. Novel fatty acid-binding protein 3 ligand inhibits dopaminergic neuronal death and improves moto r and cognitive impairments in Parkinson's disease model mice. Pharmacol Biochem Behav. 2020;191:172891. doi:10.1016/j.pbb.2020.172891 1077. Liu W, Shi R, Yang W, Zhao N, Du Y, Zou Y, Yu W. Sy nchronous alteration pattern between serine-threonine kinase receptor-associated protein and Smad7 in pilocarpine-induced rats of epilepsy. Synapse. 2014;68(6):275-282. doi:10.1002/syn.21739 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 1078. Chen Y, Chen J, Chen Y, Li Y. miR-146a/KLF4 axis in epileptic mice: A novel regulator of synaptic plasticity involving STAT3 signaling. Brain Res. 2022;1790:147988. doi:10.1016/j.brainres.2022.147988 1079. Jin X, Liao X, Wu L, Huang J, Li Z, Li Y, Guo F. FOXO4 alleviates hippocampal neuronal damage in epileptic mice via the miR-138-5p/ROCK2 axis. Am J Med Genet B Neuropsy chiatr Genet. 2022;189(7-8):271-284. doi:10.1002/ajmg.b.32904 1080. M a L , W u Q , Y u a n J , W a n g Y , Z h a n g P , L i u Q , T a n D , L i a n g M , Chen Y. Inhibition of ANXA2 activity attenuates epileptic susceptibility and GluA1 phosphorylation. CNS Ne urosci Ther. 2023;29(11):3644-3656. doi:10.1111/cns.14295 1081. Talwar P, Kanojia N, Mahendru S, Baghel R, Grover S, Arora G, Grewal GK, Parween S, Srivastava A, Singh M, et al. Genetic contribution of CYP1A1 variant on treatment outcom e in epilepsy patients: a functional and interethnic perspective. Pharmacogenomics J. 2017;17(3):242-251. doi:10.1038/tpj.2016.1 1082. Z h ai J, W an g C , Jin L , L iu F , X iao Y , G u H , L iu M , C h en Y. G u t Microbiota Metabolites Mediate Bax to Reduce Neuronal Apoptosis via cGAS/STING Axis in Epilepsy. Mol Neurobiol. 2023. doi: 10.1007/s12035- 023-03545-y 1083. Wang R, Zeng GQ, Tong RZ, Zhou D, Hong Z. Serum matrix metalloproteinase-2: A potential biomarker for diagnosis of epilepsy. Epilepsy Res. 2016;122:114-119. doi:10.1016/j.eplepsyres.2016.02.009 1084. Ercegovac M, Jovic N, Sokic D, Savic-Radojevic A, Coric V, Radic T, Nikolic D, Kecmanovic M, Matic M, Simic T, et al. GSTA1, GSTM1, GSTP1 and GSTT1 polymorphisms in progressive myoclonus epilepsy: A Serbian case-control study. Seizure. 2015;32:30-36. doi:10.1016/j.seizure.2015.08.010 1085. Č eská K, Papež J, Ošlejšková H, Slabý O, Radová L, Loja T, Libá Z, Svě ráková A, Brázdil M, Aulická Š. et al. CCL2/MCP-1, interleukin-8, and fractalkine/CXC3CL1: Potential biomarkers of epileptogenesis and pharmacoresistance in childhood ep ilepsy. Eur J Paediatr Neurol. 2023;46:48-54. doi:10.1016/j.ejpn.2023.06.001 1086. Tiron C, Campuzano O, Pérez-Serra A, Mademont I, Coll M, Allegue C, Iglesias A, Partemi S, Striano P, Oliva A, et al. Further evidence of the (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint association between LQT syndrome and epilepsy in a family with KCNQ1 pathogenic variant. Seizure. 2015;25:65-67. doi:10.1016/j.seizure.2015.01.003 1087. Horta WG, Paradela E, Figueiredo A, Meira ID, Pereira VC, Rego CC, Oliveira R, Andraus ME, de Lacerda GC, Moura P, et al. Genetic association study of the HLA class II alleles DRB1, DQA1, and DQB1 in patients with pharmacoresistant temporal lobe epilepsy associated with mesial hippocampal sclerosi s. Seizure. 2015;31:7-11. doi:10.1016/j.seizure.2015.06.005 1088. Shao LL, Gao MM, Gong JX, Yang LY. DUSP1 regulates hippocampal damage in epilepsy rats via ERK1/2 pathway. J Chem Neuroanat. 2021;118:102032. doi:10.1016/j.jchemneu.2021.102032 1089. Zan X, Yue G, Hao Y, Sima X. A systematic review and meta- analysis of the association of ABCC2/ABCG2 polymorphisms with antiepileptic drug responses in epileptic patients. Epilepsy Res. 2021;175:106678. doi:10.1016/j.eplepsyres.2021.106678 1090. Shi NR, Wang Q, Liu J, Zhang JZ, Deng BL, Hu XM, Yang J, Wang X, Chen X, Zuo YQ, et al. Association of the ADORA2A receptor and CD73 polymorphisms with epilepsy. Front Pharmacol. 2023;14:1152667. doi:10.3389/fphar.2023.1152667 1091. Heinrich A, Zhong XB, Rasmussen TP. Variability in expression of the human MDR1 drug efflux transporter and genetic variation of the ABCB1 gene: implications for drug-resi stant epilepsy. Curr Opin Toxicol. 2018;11-12:35-42. doi:10.1016/j.cotox.2018.12.004 1092. Algahtani HA, Shirah BH, Samman A, Alhazmi A. Epilepsy and Hearing Loss in a Patient with a Rare Heterozygous Variant in the CACNA1H Gene. J Epilepsy Res. 2022;12(1):33-35. doi:10.14581/jer.22006 1093. Chen Z, Luo S, Liu ZG, Deng YC, He SL, Liu XR, Yi YH, Wang J, Gao LD, Li BM, et al. CELSR1 variants are associated with partial epilepsy of childhood. Am J Med Genet B Neuropsychiatr Genet. 2022;189(7-8):247- 256. doi:10.1002/ajmg.b.32916 1094. Hu T, Zeng X, Tian T, Liu J. Association of EPHX1 polymorphisms with plasma concentration of car bamazepine in epileptic patients: (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Systematic review and meta-analysi s. J Clin Neurosci. 2021;91:159-171. doi:10.1016/j.jocn.2021.07.009 1095. Majewski L, Wojtas B, Maci ą g F, Kuznicki J. Changes in Calcium Homeostasis and Gene Expression Implicated in Epilepsy in Hippocampi of Mice Overexpressing ORAI1. Int J Mol Sci. 2019;20(22):5539. doi:10.3390/ijms20225539 1096. Blümcke I, Schewe JC, Normann S, Brüstle O, Schramm J, Elger CE, Wiestler OD. Increase of nestin-immunoreactive neural precursor cells in the dentate gyrus of pediatric patients with early-onset temporal lobe epilepsy. Hippocampus. 2001;11(3):311-321. doi:10.1002/hipo.1045 1097. Nemes AD, Ayasoufi K, Ying Z, Zhou QG, Suh H, Najm IM. Growth Associated Protein 43 (GAP-43) as a Novel Target for the Diagnosis, Treatment and Prevention of Epilept ogenesis. Sci Rep. 2017;7(1):17702. doi:10.1038/s41598-017-17377-z 1098. Hong W, Haviland I, Pestana-Knight E, Weisenberg JL, Demarest S, Marsh ED, Olson HE. CD KL5 Deficiency Disorde r-Related Epilepsy: A Review of Current and Emerging Treatment. CNS Drugs. 2022;36(6):591- 604. doi:10.1007/s40263-022-00921-5 1099. Liu Y, Cai N, Xu F, Shi Y, Wang Z, Wang N, Chen W, Yang K. Deep brain stimulation in progressive my oclonus epilepsy with SERPINI1 mutation. Parkinsonism Relat Disord. 2024;127:107085. doi:10.1016/j.parkreldis.2024.107085 1100. Guo M, Cui C, Song X, Jia L, Li D, Wang X, Dong H, Ma Y, Liu Y, Cui Z, et al. Deletion of FGF9 in GABAergic neurons causes epilepsy. Cell Death Dis. 2021;12(2):196. doi:10.1038/s41419-021-03478-1 1101. Wang P, Zhang Y, Wang Z, Yang A, Li Y, Zhang Q. miR-128 regulates epilepsy sensitivity in mice by suppressing SNAP-25 and SYT1 expression in the hippocampus. Biochem Biophys Res Commun. 2021;545:195-202. doi:10.1016/j.bbrc.2021.01.079 1102. Klöckner C, Sticht H, Zacher P, Popp B, Babcock HE, Bakker DP, Barwick K, Bonfert MV, Bönnemann CG, Brilstra EH; et al. De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy. Genet Med. 2021;23(4):653-660. doi: 10.1038/s41436-020- 01020-w (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 1103. Zhang Q, Forster-Gibson C, Bercovici E, Bernardo A, Ding F, Shen W, Langer K, Rex T, Kang JQ. Epilep sy plus blindness in microdeletion of GABRA1 and GABRG2 in mouse and human. Exp Neurol. 2023;369:114537. doi:10.1016/j.expneurol.2023.114537 1104. Ohori S, Miyauchi A, Osaka H, Lourenco CM, Arakaki N, Sengoku T, Ogata K, Honjo RS, Kim CA, Mitsuhashi S, et al. Biallelic structural variations within FGF12 detected by long-read sequencing in epilepsy. Life Sci Alliance. 2023;6(8):e202302025. doi:10.26508/lsa.202302025 1105. Zheng D, Li M, Li G, Hu J, Jiang X, Wang Y, Sun Y. Circular RNA circ_DROSHA alleviates the neural damage in a cell model of temporal lobe epilepsy through regulating miR-106b-5p/MEF2C axis. Cell Signal. 2021;80:109901. doi:10.1016/j.cellsig.2020.109901 1106. Bleakley LE, Reid CA. HCN1 epilepsy: From genetics and mechanisms to precision therapies. J Neurochem. 2023. doi:10.1111/jnc.15928 1107. Shimizu A, Asakawa S, Sasaki T, Yamazaki S, Yamagata H, Kudoh J, Minoshima S, Kondo I, Shimizu N. A novel giant gene CSMD3 encoding a protein with CUB and sushi multiple domains: a candidate gene for benign adult familial myoclonic epilepsy on human chromosome 8q23.3-q24.1. Biochem Biophys Res Comm un. 2003;309(1):143-154. doi: 10.1016/s0006- 291x(03)01555-9 1108. Panneerselvam S, Wang J, Zhu W, Dai H, Pappas JG, Rabin R, Low KJ, Rosenfeld JA, Emrick L, Xiao R, et al. PPP3CA truncating variants clustered in the regulatory domain cause early-onset refractory epilepsy. Clin Genet. 2021;100(2):227-233. doi:10.1111/cge.13979 1109. Zeng Q, Yang Y, Duan J, Niu X, Chen Y, Wang D, Zhang J, Chen J, Yang X, Li J, et al. CN2A-Related Epilepsy: The Phenotypic Spectrum, Treatment and Prognosis. Front Mol Neurosci. 2022;15:809951. doi:10.3389/fnmol.2022.809951 1110. Remme CA. SCN5A channelopathy: arrhythmia, cardiomyopathy, epilepsy and beyond. Philos Trans R Soc Lond B Biol Sci. 2023;378(1879):20220164. doi:10.1098/rstb.2022.0164 1111. Ul Mudassir B, Agha Z. Novel and known minor alleles of CNTNAP2 gene variants are associated with comorbidity of intellectual disability and epilepsy phenotypes: a case-control association study reveals (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint potential biomarkers. Mol Biol Rep. 2024;51(1):276. doi: 10.1007/s11033- 023-09176-9 1112. Yang Y, Zeng Q, Cheng M, Niu X, Xiangwei W, Gong P, Li W, Ma J, Zhang X, Yang X, et al. GABRB3-related epilepsy: novel variants, clinical features and therapeutic im plications. J Neurol. 2022;269(5):2649- 2665. doi:10.1007/s00415-021-10834-w 1113. Brunklaus A, Brünger T, Feng T, Fons C, Lehikoinen A, Panagiotakaki E, Vintan MA, Symonds J, Andrew J, Arzimanoglou A, et al. The gain of function SCN1A disorder spectrum: novel epilepsy phenotypes and therapeutic implications. Brain. 2022;145(11):3816-3831. doi:10.1093/brain/awac210 1114. Fang M, Liu GW, Pan YM, Shen L, Li CS, Xi ZQ, Xiao F, Wang L, Chen D, Wang XF. Abnormal expression and spatiotemporal change of Slit2 in neurons and astrocytes in temporal lobe epileptic foci: A study of epileptic patients and experimental animals. Brain Res. 2010;1324:14-23. doi:10.1016/j.brainres.2010.02.007 1115. Baglietto MG, Caridi G, Gimelli G, Mancardi M, Prato G, Ronchetto P, Cuoco C, Tassano E. RORB gene and 9q21.13 microdeletion: report on a patient with epilepsy and mild inte llectual disability. Eur J Med Genet. 2014;57(1):44-46. doi:10.1016/j.ejmg.2013.12.001 1116. Vega-García A, Orozco-Suárez S, Villa A, Rocha L, Feria-Romero I, Alonso Vanegas MA, Guevara-Guzmán R. Cortical expression of IL1- β , Bcl-2, Caspase-3 and 9, SEMA-3a, NT-3 and P-glycoprotein as biological markers of intrinsic severity in drug-re sistant temporal lobe epilepsy. Brain Res. 2021;1758:147303. doi:10.1016/j.brainres.2021.147303 1117. Aksoy HU, Yılmaz C, Orak SA, Ayça S, Polat M. Evaluation of GFAP, S100B, and UCHL-1 Levels in Children With Refractory Epilepsy. J Child Neurol. 2024;39(9-10):317-323. doi:10.1177/08830738241273339 1118. Gurnett CA, Veile R, Zempel J, Bl ackburn L, Lovett M, Bowcock A. Disruption of sodium bicarbonate transporter SLC4A10 in a patient with complex partial epilepsy and mental retardation. Arch Neurol. 2008;65(4):550-553. doi:10.1001/archneur.65.4.550 1119. Koskinen LL, Seppälä EH, Weissl J, Jokinen TS, Viitmaa R, Hänninen RL, Quignon P, Fischer A, André C, Lohi H. ADAM23 is a (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint common risk gene for canine idiopathic epilepsy. BMC Genet. 2017;18(1):8. doi:10.1186/s12863-017-0478-6 1120. Dong Z, Min F, Zhang S, Zhang H, Zeng T. EGR1-Driven METTL3 Activation Curtails VIM-Mediated Neuron Injury in Epilepsy. Neurochem Res. 2023;48(11):3349-3362. doi:10.1007/s11064-023-03950-8 1121. Srivastava S, Cohen J, Pevsner J, Aradhya S, McKnight D, Butler E, Johnston M, Fatemi A. A novel variant in GABRB2 associated with intellectual disability and epilepsy. Am J Med Genet A. 2014;164A(11):2914-2921. doi:10.1002/ajmg.a.36714 1122. Marcé-Grau A, Elorza-Vidal X, Pére z-Rius C, Ruiz-Nel Lo A, Sala- Coromina J, Gabau E, Estévez R, Macaya A. Muscarinic acetylcholine receptor M1 mutations causing neurod evelopmental disorder and epilepsy. Hum Mutat. 2021;42(10):1215-1220. doi:10.1002/humu.24252 1123. Xue J, Song Z, Ma S, Yi Z, Yang C, Li F, Liu K, Zhang Y. A Novel De Novo TUBB3 Variant Causing Developmental Delay, Epilepsy and Mild Ophthalmological Symptoms in a Chinese Child. J Mol Neurosci. 2022;72(1):37-44. doi:10.1007/s12031-021-01909-4 1124. Westphal DS, Andres S, Makowski C, Meitinger T, Hoefele J. MAP2 - A Candidate Gene for Epilepsy, De velopmental Delay and Behavioral Abnormalities in a Patient With Microdeletion 2q34. Front Genet. 2018;9:99. doi:10.3389/fgene.2018.00099 1125. Villacres JE, Riveira N, Kim S, Colgin LL, Noebels JL, Lopez AY. Abnormal patterns of sleep and waking behaviors are accompanied by neocortical oscillation disturbances in an Ank3 mouse model of epilepsy- bipolar disorder comorbidity. Tr ansl Psychiatry. 2023;13(1):403. doi:10.1038/s41398-023-02700-2 1126. Ke P, Gu J, Liu J, Liu Y, Tian X, Ma Y, Meng Y, Xiao F. Syntabulin regulates neuronal excitation/inhibition balance and epileptic seizures by transporting syntaxin 1B. Cell Death Discov. 2023;9(1):187. doi:10.1038/s41420-023-01461-7 1127. Desprairies C, Valence S, Maurey H, Helal SI, Weckhuysen S, Soliman H, Mefford HC, Spentchian M, Héron D, Leguern E, et al. Three novel patients with epileptic encephalopathy due to biallelic mutations in the PLCB1 gene. Clin Genet. 2020;97(3):477-482. doi:10.1111/cge.13696 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 1128. Rochtus AM, Trowbridge S, Goldstein RD, Sheidley BR, Prabhu SP, Haynes R, Kinney HC, Poduri AH. Mutations in NRXN1 and NRXN2 in a patient with early-onset epileptic encephalopathy and respiratory depression. Cold Spring Harb Mol Ca se Stud. 2019;5(1):a003442. doi:10.1101/mcs.a003442 1129. Xing Y, Cui T, Sun F. A novel RyR2 mutation associated with co- morbid catecholaminergic polymorphic ventricular tachycardia (CPVT) and benign epilepsy with centrotemporal spikes (BECTS). J Electrocardiol. 2024;84:75-80. doi:10.1016/j.jelectrocard.2024.03.013 1130. Luo FM, Deng MX, Yu R, Liu L, Fan LL. Case Report: Chorea- Acanthocytosis Presents as Epilepsy in a Consanguineous Family With a Nonsense Mutation of in VPS 13A. Front Neurosci. 2021;15:604715. doi:10.3389/fnins.2021.604715 1131. Komulainen-Ebrahim J, Saastamoinen E, Rahikkala E, Helander H, Hinttala R, Risteli L, Rantala H, Uusimaa J. Intractable Epilepsy due to MTR Deficiency: Importance of Homocysteine Analysis. Neuropediatrics. 2017;48(6):467-472. doi:10.1055/s-0037-1603976 1132. C a i S , L i J , W u Y , J i a n g Y . D e n o v o m u t a t i o n s o f T U B B 2 A c a u s e infantile-onset epilepsy and deve lopmental delay. J Hum Genet. 2020;65(7):601-608. doi:10.1038/s10038-020-0739-5 1133. Muroni A, Floris G, Polizzi L, Fadda L, Piga G, Primicerio G, Rocchi L, Defazio G. Does epilepsy contribute to the clinical phenotype of C9orf72 mutation in fronto-temporal dementia?. Epilepsy Behav. 2022;133:108783. doi:10.1016/j.yebeh.2022.108783 1134. Wengert ER, Miralles RM, Wedgwood KCA, Wagley PK, Strohm SM, Panchal PS, Idrissi AM, Wenker IC, Thompson JA, Gaykema RP, et al. Somatostatin-Positive Interneurons Contribute to Seizures in SCN8A Epileptic Encephalopathy. J Neurosci. 2021;41(44):9257-9273. doi:10.1523/JNEUROSCI.0718-21.2021 1135. Wang Y, Liang J, Chen L, Shen Y, Zhao J, Xu C, Wu X, Cheng H, Ying X, Guo Y, et al. Pharmaco-genetic therapeutics targeting parvalbumin neurons attenuate temporal lobe epilepsy. Neurobiol Dis. 2018;117:149-160. doi:10.1016/j.nbd.2018.06.006 1136. Ranta S, Zhang Y, Ross B, Takk unen E, Hirvasniemi A, de la Chapelle A, Gilliam TC, Lehesjoki AE. Positional cloning and (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint characterisation of the human DLGAP2 gene and its exclusion in progressive epilepsy with mental retardation. Eur J Hum Genet. 2000;8(5):381-384. doi:10.1038/sj.ejhg.5200440 1137. Tian MQ, Li RK, Yang F, Shu XM, Li J, Chen J, Peng LY, Yu XH, Yang CJ. Phenotypic expansion of KC NH1-associated disorders to include isolated epilepsy and its associations with genotypes and molecular sub- regional locations. CNS Neurosci Ther. 2023;29(1):270-281. doi:10.1111/cns.14001 1138. Hayashi T, Yano N, Kora K, Yokoyama A, Maizuru K, Kayaki T, Nishikawa K, Osawa M, Niwa A, Takenouchi T, et al. Involvement of mTOR pathway in neurodegeneration in NSF-related developmental and epileptic encephalopathy. Hum Mol Genet. 2023;32(10):1683-1697. doi:10.1093/hmg/ddad008 1139. Mertens A, Papadopoulou MT, Papathanasiou Terzi MA, Lesca G, Biela M, Smigiel R, Panagiotakaki E. Epilepsy with eyelid myoclonia in a patient with ATP1A3-related neurologic disorder. Epileptic Disord. 2024. doi:10.1002/epd2.20272 1140. Okano S, Makita Y, Miyamoto A, Taketazu G, Kimura K, Fukuda I, Tanaka H, Yanagi K, Kaname T. GR IA3 p.Met661Thr variant in a female with developmental epileptic encephalopathy. Hum Genome Var. 2023;10(1):4. doi:10.1038/s41439-023-00232-1 1141. Neuray C, Maroofian R, Scala M, Sultan T, Pai GS, Mojarrad M, Khashab HE, deHoll L, Yue W, Alsaif HS, et al. Early-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants. Brain. 2020;143(8):2388-2397. doi:10.1093/brain/awaa178 1142. Pazarlar BA, Aripaka SS, Petukhov V, Pinborg L, Khodosevich K, Mikkelsen JD. Expression profile of sy naptic vesicle glycoprotein 2A, B, and C paralogues in temporal neocortex tissue from patients with temporal lobe epilepsy (TLE). Mol Brain. 2022;15(1):45. doi: 10.1186/s13041-022- 00931-w 1143. Massey CA, Thompson SJ, Ostrom RW, Drabek J, Sveinsson OA, Tomson T, Haas EA, Mena OJ, Goldman AM, Noebels JL. X-linked serotonin 2C receptor is associated with a non-canonical pathway for sudden unexpected death in epilepsy. Brain Commun. 2021;3(3):fcab149. doi:10.1093/braincomms/fcab149 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 1144. Sheng W, Wang P, Cai Y, Zhai C, Wang H, Zhou F, Liu X, Wang L, Li D, Shu J, et al. Epilepsy due to potential loss of ATP6V1B2 function with mechanistic insight by a Drosophila Vha55 model. Clin Genet. 2024;106(6):702-712. doi:10.1111/cge.14600 1145. Carvill GL. Calcium Channel Dysfunction in Epilepsy: Gain of CACNA1E. Epilepsy Curr. 2019;19(3):199-201. doi:10.1177/1535759719845324 1146. Alsemari A, Al-Younes B, Goljan E, Jaroudi D, BinHumaid F, Meyer BF, Arold ST, Monies D. Recessive VARS2 mutation underlies a novel syndrome with epilepsy, mental retardation, short stature, growth hormone deficiency, and hypogonadism . Hum Genomics. 2017;11(1):28. doi:10.1186/s40246-017-0124-4 1147. Polani S, Dean M, Lichter-Peled A, Hendrickson S, Tsang S, Fang X, F e n g Y , Q i a o W , A v n i G , K a h i l a B a r - G a l G . S e q u e n c e V a r i a n t i n t h e TRIM39-RPP21 Gene Readthrough is Shared Across a Cohort of Arabian Foals Diagnosed with Juvenile Idiopa thic Epilepsy. J Genet Mutat Disord. 2022;1(1):103. 1148. Jiang J, Feng Y, Tang Q, Zhao C, Guo M, Wu J, Guo R, Lu H, Sun X, Gao J, et al. Novel IARS1 variants cause syndromic developmental disorder with epilepsy in a Chinese patient and the literature review. Mol Genet Genomic Med. 2024;12(1):e2326. doi:10.1002/mgg3.2326 1149. Li H, Wang X, Zhou Y, Ni G, Su Q, Chen Z, Chen Z, Li J, Chen X, Hou X, et al. Association of LEPR and ANKK1 Gene Polymorphisms with Weight Gain in Epilepsy Patients Receiving Valproic Acid. Int J Neuropsychopharmacol. 2015;18(7):pyv021.doi:10.1093/ijnp/pyv021 1150. Z en g C , Z ho u P, J ian g T , Y u a n C , M a Y , F en g L , L iu R , T an g W, Long X, Xiao B, et al. Upregulation and Diverse Roles of TRPC3 and TRPC6 in Synaptic Reorganization of the Mossy Fiber Pathway in Temporal Lobe Epilepsy. Mol Neurobiol. 2015;52(1):562-572. doi: 10.1007/s12035- 014-8871-x 1151. Miller JP, Yates BE, Al-Ramahi I, Berman AE, Sanhueza M, Kim E, de Haro M, DeGiacomo F, Torcassi C, Holcomb J, et al. A genome-scale RNA-interference screen identifies RRA S signaling as a pathologic feature of Huntington's di sease. PLoS Genet. 2012;8(11):e1003042. doi:10.1371/journal.pgen.1003042 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 1152. Sharma M, Rajendrarao S, Shahani N, Ramírez-Jarquín UN, Subramaniam S. Cyclic GMP-AMP synt hase promotes the inflammatory and autophagy responses in Huntington disease. Proc Natl Acad Sci U S A. 2020;117(27):15989-15999. doi:10.1073/pnas.2002144117 1153. Taylor DM, Moser R, Régulier E, Breuillaud L, Dixon M, Beesen AA, Elliston L, Silva Santos Mde F, Kim J, Jones L, et al. MAP kinase phosphatase 1 (MKP-1/DUSP1 ) is neuroprotective in Huntington's disease via additive effects of JNK and p38 inhibition. J Neurosci. 2013;33(6):2313- 2325. doi:10.1523/JNEUROSCI.4965-11.2013 1154. Taherzadeh-Fard E, Saft C, Wieczorek S, Epplen JT, Arning L. Age at onset in Huntington's disease: replication study on the associations of ADORA2A, HAP1 and OGG1. Neurogenetics. 2010;11(4):435-439. doi:10.1007/s10048-010-0248-3 1155. Elbaz EM, Helmy HS, El-Sahar AE, Saad MA, Sayed RH. Lercanidipine boosts the efficacy of mesenchymal stem cell therapy in 3- NP-induced Huntington's disease mo del rats via modulation of the calcium/calcineurin/NFATc4 and Wnt/ β -catenin signalling pathways. Neurochem Int. 2019;131:104548. doi:10.1016/j.neuint.2019.104548 1156. Noda Y, Shimazawa M, Tanaka H, Tamura S, Inoue T, Tsuruma K, Hara H. VGF and striatal cell damage in in vitro and in vivo models of Huntington's disease. Pharmacol Res Perspect. 2015;3(3):e00140. doi:10.1002/prp2.140 1157. Yusuf IO, Chen HM, Cheng PH, Chang CY, Tsai SJ, Chuang JI, Wu CC, Huang BM, Sun HS, Chen CM, et al. FGF9 induces neurite outgrowth upon ERK signaling in knock-in striatal Huntington's disease cells. Life Sci. 2021;267:118952. doi:10.1016/j.lfs.2020.118952 1158. Smith R, Klein P, Koc-Schmitz Y, Waldvogel HJ, Faull RL, Brundin P, Plomann M, Li JY. Loss of SNAP-25 and rabphilin 3a in sensory-motor cortex in Huntington's disease. J Neurochem. 2007;103(1):115-123. doi:10.1111/j.1471-4159.2007.04703.x 1159. Xu EH, Tang Y, Li D, Jia JP. Polymorphism of HD and UCHL-1 genes in Huntington's disease. J Clin Neurosci. 2009;16(11):1473-1477. doi:10.1016/j.jocn.2009.03.027 1160. Lee J, Hwang YJ, Shin JY, Lee WC, Wie J, Kim KY, Lee MY, Hwang D, Ratan RR, Pae AN, et al. Epigenetic regulation of cholinergic (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint receptor M1 (CHRM1) by histone H3K9me3 impairs Ca(2+) signaling in Huntington's diseas e. Acta Neuropathol. 2013;125(5):727-739. doi:10.1007/s00401-013-1103-z 1161. Cabrera JR, Lucas JJ. MAP2 Splicing is Altered in Huntington's Disease. Brain Pathol. 2017;27(2):181-189. doi:10.1111/bpa.12387 1162. Cho K, Kim GW. Neurexin1 level in Huntington's Disease and decreased Neurexin1 in disease progression. Neurosci Res. 2024. doi:10.1016/j.neures.2024.10.006 1163. García-García E, Carreras-Caballé M, Coll-Manzano A, Ramón- Lainez A, Besa-Selva G, Pérez-Navarro E, Malagelada C, Alberch J, Masana M, Rodríguez MJ. reserved VP S13A distribution and expression in Huntington's disease: divergent mechanisms of action for similar movement disorders?. Front Ne urosci. 2024;18:1394478. doi:10.3389/fnins.2024.1394478 1164. Alva-Diaz C, Alarcon-Ruiz CA, Pacheco-Barrios K, Mori N, Pacheco-Mendoza J, Traynor BJ, Rivera-Valdivia A, Lertwilaiwittaya P, Bird TD, Cornejo-Olivas M. C9orf72 Hexanucleotide Repeat in Huntington- Like Patients: Systematic Review and Meta-Analysis. Front Genet. 2020;11:551780. doi:10.3389/fgene.2020.551780 1165. Aronin N, Cooper PE, Lorenz LJ, Bird ED, Sagar SM, Leeman SE, Martin JB. omatostatin is increased in the basal ganglia in Huntington disease. Ann Neurol. 1983;13(5):519-526. doi:10.1002/ana.410130508 1166. Beaumont V, Zhong S, Lin H, Xu W, Bradaia A, Steidl E, Gleyzes M, Wadel K, Buisson B, Padovan-Neto FE, et al. Phosphodiesterase 10A Inhibition Improves Cortico-Basal Ganglia Function in Huntington's Disease Models. Neuron. 2016;92(6):1220-1237. doi:10.1016/j.neuron.2016.10.064 1167. Santos R, Linker SB, Stern S, Mendes APD, Shokhirev MN, Erikson G, Randolph-Moore L, Racha V, Kim Y, Kelsoe JR, et al. Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bi polar disorder patients. Mol Psychiatry. 2021;26(6):2440-2456. doi:10.1038/s41380-020-00981-3 1168. Mohammadynejad P, Saadat I, Ghanizadeh A, Saadat M. Bipolar disorder and polymorphisms of glutathione S-transferases M1 (GSTM1) and T1 (GSTT1). Psychiatry Res. 2011;186(1):144-146. doi:10.1016/j.psychres.2010.06.017 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 1169. Ghoryani M, Faridhosseini F, Tala ei A, Faridhosseini R, Tavakkol- Afshari J, Dadgar Moghaddam M, Azim P, Salimi Z, Marzouni HZ, Mohammadi M. Gene expression pattern of CCL2, CCL3, and CXCL8 in patients with bipolar disord er. J Res Med Sci. 2019;24:45. doi:10.4103/jrms.JRMS_763_18 1170. Le Clerc S, Lombardi L, Baune BT, Amare AT, Schubert KO, Hou L, Clark SR, Papiol S, Cearns M, Heilbronner U, et al. HLA-DRB1 and HLA- DQB1 genetic diversity modulates response to lithium in bipolar affective disorders. Sci Rep. 2021;11(1):17823. doi:10.1038/s41598-021-97140-7 1171. Zhang T, Rao Q, Lin K, He Y, Cai J, Yang M, Xu Y, Hou L, Lin Y, Liu H. CYP2C19-rs4986893 confers risk to major depressive disorder and bipolar disorder in the Han Chinese population whereas ABCB1-rs1045642 acts as a protective factor. BMC Psychiatry. 2023;23(1):69. doi:10.1186/s12888-022-04514-w 1172. Li J, Liu J, Feng G, Li T, Zhao Q, Li Y, Hu Z, Zheng L, Zeng Z, He L, et al. The MDGA1 gene confers risk to schizophrenia and bipolar disorder. Schizophr Res. 2011;125(2-3):194-200. doi:10.1016/j.schres.2010.11.002 1173. Chen S, Jiang H, Hou Z, Yue Y, Zhang Y, Zhao F, Xu Z, Li Y, Mou X, Li L, et al. Higher serum VGF protein levels discriminate bipolar depression from major depressive disorder. J Neurosci Res. 2019;97(5):597- 606. doi:10.1002/jnr.2437 1174. Wang Y, Zhang J, Li X, Ji J, Yang F, Wan C, Feng G, Wan P, He L, He G. SCN8A as a novel candidate gene associated with bipolar disorder in the Han Chinese population. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(8):1902-1904. doi:10.1016/j.pnpbp.2008.09.003 1175. L i Y , Z h a o Q , Z h a n g Z , W a n g P , C h e R , T a n g W , F e n g G , Lindpaintner K, He L, Shi Y. Associ ation study between RGS4 and bipolar disorder in the Chinese Han popula tion. Psychiatr Genet. 2010;20(3):130- 132. doi:10.1097/YPG.0b013e32833a2009 1176. Lucash J, Hong W, Swanson L, Maski K, Urion D, Kim J, Leonard H, Olson H. Bipolar Disorder in a female with CDKL5 Deficiency Disorder: A Case Report. Preprint. Re s Sq. 2024;rs.3.rs-4851179. doi: 10.21203/rs.3.rs- 4851179/v1 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 1177. Lohoff FW, Bloch PJ, Weller AE, Ferraro TN, Berrettini WH. Association analysis of the pituitary adenylate cyclase-activating polypeptide (PACAP/ADCYAP1) gene in bipolar disorder. Psychiatr Genet. 2008;18(2):53-58. doi:10.1097/YPG.0b013e3282f60320 1178. Houenou J, Boisgontier J, Henrion A, d'Albis MA, Dumaine A, Linke J, Wessa M, Daban C, Hamdani N, Delavest M, et al. A Multilevel Functional Study of a SNAP25 At-Risk Variant for Bipolar Disorder and Schizophrenia. J Neurosci. 2017;37(43):10389-10397. doi:10.1523/JNEUROSCI.1040-17.2017 1179. Fatjó-Vilas M, Prats C, Pomarol-Clotet E, Lázaro L, Moreno C, González-Ortega I, Lera-Miguel S, Miret S, Muñoz MJ, Ibáñez I, et al. Involvement of NRN1 gene in schizophrenia-spectrum and bipolar disorders and its impact on age at onset and cognitive functioning. World J Biol Psychiatry. 2016;17(2):129-139. doi:10.3109/15622975.2015.1093658 1180. Slonimsky A, Levy I, Kohn Y, Ri gbi A, Ben-Asher E, Lancet D, Agam G, Lerer B. Lymphoblast and brain expression of AHI1 and the novel primate-specific gene, C6orf217, in schizophrenia and bipolar disorder. Schizophr Res. 2010;120(1-3):159-166. doi:10.1016/j.schres.2010.03.041 1181. Xu W, Cohen-Woods S, Chen Q, Noor A, Knight J, Hosang G, Parikh SV, De Luca V, Tozzi F, Muglia P, et al. Genome-wide association study of bipolar disorder in Canadian and UK populations corroborates disease loci including SYNE1 and CSMD1. BMC Med Genet. 2014;15:2. doi:10.1186/1471-2350-15-2 1182. McGrath CL, Glatt SJ, Sklar P, Le-Niculescu H, Kuczenski R, Doyle AE, Biederman J, Mick E, Faraone SV, Niculescu AB, et al. Evidence for genetic association of RORB with bipolar disorder. BMC Psychiatry. 2009;9:70. doi:10.1186/1471-244X-9-70 1183. Chen J, Tsang SY, Zhao CY, Pun FW, Yu Z, Mei L, Lo WS, Fang S, Liu H, Stöber G, et al. GABRB2 in schizophrenia and bipolar disorder: disease association, gene expression and clinical correlations. Biochem Soc Trans. 2009;37(Pt 6):1415-1418. doi:10.1042/BST0371415 1184. Maheshwari H, Garg P, Srivastava P. In silico analysis predicts mutational consequences of CITED2, NU DT4, and Ar18B in patients with bipolar disorder. Beha v Brain Res. 2025;476:115257. doi:10.1016/j.bbr.2024.115257 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 1185. Yosifova A, Mushiroda T, Stoianov D, Vazharova R, Dimova I, Karachanak S, Zaharieva I, Milanova V, Madjirova N, Gerdjikov I, et al. Case-control association study of 65 candidate genes revealed a possible association of a SNP of HTR5A to be a factor susceptible to bipolar disease in Bulgarian population. J Affe ct Disord. 2009;117(1-2):87-97. doi:10.1016/j.jad.2008.12.021 1186. Gaynor LS, Yadollahikhales G, Tsoy E, Hall M, Boxer AL, Miller BL, Grinberg LT. C9orf72 Repeat Expansion Initially Presenting as Late- Onset Bipolar Disorder With Psyc hosis. Neurologist. 2024;29(2):109-112. doi:10.1097/NRL.0000000000000527 1187. Pantazopoulos H, Wiseman JT, Markota M, Ehrenfeld L, Berretta S. Decreased Numbers of Somatostatin-E xpressing Neurons in the Amygdala of Subjects With Bipolar Disorder or Schizophrenia: Relationship to Circadian Rhythms. Biol Ps ychiatry. 2017;81(6):536-547. doi:10.1016/j.biopsych.2016.04.006 1188. Philibert RA, Cheung D, Welsh N, Damschroder-Williams P, Thiel B, Ginns EI, Gershenfeld HK. Absence of a significant linkage between Na(+),K(+)-ATPase subunit (ATP1A3 and ATP1B3) genotypes and bipolar affective disorder in the old-order Amish. Am J Med Genet. 2001;105(3):291-294. doi:10.1002/ajmg.1322 1189. Gray L, Scarr E, Dean B. N-Ethylmaleimide sensitive factor in the cortex of subjects with schizophrenia and bipolar I disorder. Neurosci Lett. 2006;391(3):112-115. doi:10.1016/j.neulet.2005.08.051 1190. Gécz J, Barnett S, Liu J, Hollway G, Donnelly A, Eyre H, Eshkevari HS, Baltazar R, Grunn A, Nagaraja R, et al. Characterization of the human glutamate receptor subunit 3 gene (GRIA3), a candidate for bipolar disorder and nonspecific X-linked mental retardation. Genomics. 1999;62(3):356- 368. doi:10.1006/geno.1999.6032 1191. Anjanappa RM, Nayak S, Moil y NS, Manduva V, Nadella RK, Viswanath B, Reddy YCJ, Jain S, Anand A. A linkage and exome study implicates rare variants of KANK4 and CAP2 in bipolar disorder in a multiplex family. Bipolar Disord. 2020;22(1):70-78. doi:10.1111/bdi.12815 1192. Sitbon J, Nestvogel D, Kappeler C, Nicolas A, Maciuba S, Henrion A, Troudet R, Courtois E, Grannec G, Latapie V, et al. CADPS functional (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint mutations in patients with bipolar disorder increase the sensitivity to stress. Mol Psychiatry. 2022;27(2):1145-1157. doi:10.1038/s41380-021-01151-9 1193. Arrúe A, González-Torres MA, Basterreche N, Arnaiz A, Olivas O, Zamalloa MI, Erkoreka L, Catalán A, Zumárraga M. GAD1 gene polymorphisms are associated with bipolar I disorder and with blood homovanillic acid levels but not with plasma GABA levels. Neurochem Int. 2019;124:152-161. doi:10.1016/j.neuint.2019.01.004 1194. Levchenko A, Vyalova NM, Nurgaliev T, Pozhidaev IV, Simutkin GG, Bokhan NA, Ivanova SA. NRG1, PIP4K2A, and HTR2C as Potential Candidate Biomarker Genes for Seve ral Clinical Subphenotypes of Depression and Bipo lar Disorder. Front Genet. 2020;11:936. doi:10.3389/fgene.2020.00936 1195. Jian J, Li C, Xu J, Qiao D, Mi G, Chen X, Tang M. Associations of serotonin receptor gene HTR3A, HTR3B, and HTR3A haplotypes with bipolar disorder in Chinese patients. Genet Mol Res. 2016;15(3):10.4238/gmr.15038671. doi:10.4238/gmr.15038671 1196. MacMullen CM, Vick K, Pacifico R, Fallahi-Sichani M, Davis RL. Novel, primate-specific PDE10A isoform highlights gene expression complexity in human striatum with implications on the molecular pathology of bipolar disorder. Transl Psychiatry. 2016;6(2):e742. doi:10.1038/tp.2016.3 1197. Lee SY, Chen SL, Chang YH, Chen SH, Chu CH, Huang SY, Tzeng NS, Wang CL, Lee IH, Yeh TL, et al. The DRD2/ANKK1 gene is associated with response to add-on dextromethorphan treatment in bipolar disorder. J Affect Disord. 2012;138(3):295-300. doi:10.1016/j.jad.2012.01.024 1198. Roedding AS, Tong SY, Au-Yeung W, Li PP, Warsh JJ. Chronic oxidative stress modulates TRPC3 and TRPM2 channel expression and function in rat primary cortical neurons: relevance to the pathophysiology of bipolar disorder. Brain Res. 2013;1517:16-27. doi:10.1016/j.brainres.2013.04.025 1199. Kowalczyk M, Kucia K, Owczarek A, Suchanek-Raif R, Paul- Samojedny M, Choreza P, Kowalski J. HSPB1 Gene Variants and Schizophrenia: A Case-Control Study in a Polish Population. Dis Markers. 2022;2022:4933011. doi:10.1155/2022/493301 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 1200. Greenbaum L, Alkelai A, Rigbi A, Kohn Y, Lerer B. Evidence for association of the GLI2 gene with tardive dyskinesia in patients with chronic schizophrenia. Mov Disord. 2010;25(16):2809-2817. doi:10.1002/mds.23377 1201. Li X, Wu X, Li W, Yan Q, Zhou P, Xia Y, Yao W, Zhu F. HERV-W ENV Induces Innate Immune Activa tion and Neuronal Apoptosis via linc01930/cGAS Axis in Recent-Onset Schizophrenia. Int J Mol Sci. 2023;24(3):3000. doi:10.3390/ijms24033000 1202. Yang H, Peng R, Yang M, Zhang J, Shi Z, Zhang X. Association between elevated serum matrix metalloproteinase-2 and tumor necrosis factor-α , and clinical symptoms in male patients with treatment-resistant and chronic medicated schizophrenia. BMC Psychiatry. 2024;24(1):173. doi:10.1186/s12888-024-05621-6 1203. Liu X, Low SK, Atkins JR, Wu JQ, Reay WR, Cairns HM, Green MJ, S c h a l l U , J a b l e n s k y A , M o w r y B , e t a l . W n t r e c e p t o r g e n e F Z D 1 w a s associated with schizophrenia in genome-wide SNP analysis of the Australian Schizophrenia Research Bank cohort. Aust N Z J Psychiatry. 2020;54(9):902-908. doi:10.1177/0004867419885443 1204. Pinheiro DS, Santos RDS, de Brito RB, Cruz AHDS, Ghedini PC, Reis AAS. GSTM1/GSTT1 double-null genotype increases risk of treatment-resistant schizophrenia: A ge netic association study in Brazilian patients. PLoS One. 2017;12(8):e0183812. doi:10.1371/journal.pone.0183812 1205. Xiong Y, Wei Z, Huo R, Wu X, Shen L, Li Y, Gong X, Wu Z, Feng G, Li W, et al. A pharmacogenetic study of risperidone on chemokine (C-C motif) ligand 2 (CCL2) in Chinese Han schizophrenia patients. Prog Neuropsychopharmacol Biol Psychiatry. 2014;51:153-158. doi:10.1016/j.pnpbp.2014.01.017 1206. Seshasubramanian V, Raghavan V, SathishKannan AD, Naganathan C, Ramachandran A, Arasu P, Rajendren P, John S, Mowry B, Rangaswamy T, et al. Association of HLA-A, -B, -C, -DRB1 and -DQB1 alleles at amino acid level in individuals with schizophrenia: A study from South India. Int J Immunogenet. 2020;47(6):501-511. doi:10.1111/iji.12507 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 1207. Sun L, Qiu Q, Ban C, Fan S, Xiao S, Li X. Decrease levels of bone morphogenetic protein 6 and noggin in chronic schizophrenia elderly. Cogn Neurodyn. 2023;17(3):695-701. doi:10.1007/s11571-022-09855-6 1208. Foldager L, Steffensen R, Thiel S, Als TD, Nielsen HJ, Nordentoft M, Mortensen PB, Mors O, Jensenius JC. MBL and MASP-2 concentrations in serum and MBL2 promoter polymorphisms are associated to schizophrenia. Acta Neuropsychiatr. 2012;24(4):199-207. doi: 10.1111/j.1601- 5215.2011.00618.x 1209. Miao J, Liu L, Yan C, Zhu X, Fan M, Yu P, Ji K, Huang Y, Wang Y, Zhu G. Association between AD ORA2A gene polymorphisms and schizophrenia in the North Chinese Han population. Neuropsychiatr Dis Treat. 2019;15:2451-2458. doi:10.2147/NDT.S205014 1210. Hattori S, Suda A, Miyauchi M, Shiraishi Y, Saeki T, Fukushima T, Fujibayashi M, Tsujita N, Ishii C, Ishii N, et al. The association of genetic polymorphisms in CYP1A2, UGT1A4, and ABCB1 with autonomic nervous system dysfunction in schizophrenia pa tients treated with olanzapine. BMC Psychiatry. 2020;20(1):72. doi:10.1186/s12888-020-02492-5 1211. Gross J, Grimm O, Ortega G, Teuber I, Lesch KP, Meyer J. Mutational analysis of the neuronal cadherin gene CELSR1 and exclusion as a candidate for catatonic schizophrenia in a large family. Psychiatr Genet. 2001;11(4):197-200. doi:10.1097/00041444-200112000-00003 1212. H a t a y a m a M , I s h i g u r o A , I w a y a m a Y , T a k a s h i m a N , S a k o o r i K , Toyota T, Nozaki Y, Odaka YS, Yamada K, Yoshikawa T, et al. Zic2 hypomorphic mutant mice as a schizophrenia model and ZIC2 mutations identified in schizophrenia patients. Sci Rep. 2011;1:16. doi:10.1038/srep00016 1213. Hsiung A, Naya FJ, Chen X, Shiang R. A schizophrenia associated CMYA5 allele displays differential binding with desmin. J Psychiatr Res. 2019;111:8-15. doi:10.1016/j.jpsychires.2019.01.007 1214. Mizoguchi T, Hara H, Shimazawa M. VGF has Roles in the Pathogenesis of Major Depressive Di sorder and Schizophrenia: Evidence from Transgenic Mouse Models. Cell Mol Neurobiol. 2019;39(6):721-727. doi:10.1007/s10571-019-00681-9 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 1215. Shen YC, Tsai HM, Cheng MC, Hsu SH, Chen SF, Chen CH. Genetic and functional analysis of the gene encoding GAP-43 in schizophrenia. Schizophr Res. 2012;134(2-3):239-245. doi:10.1016/j.schres.2011.11.016 1216. Xu FL, Yao J, Wang BJ. Asso ciation between RGS4 gene polymorphisms and schizophrenia: A pr otocol for systematic review and meta-analysis. Medicine (Baltimore). 2021;100(44):e27607. doi:10.1097/MD.0000000000027607 1217. Koga M, Ishiguro H, Horiuchi Y, Inada T, Ujike H, Itokawa M, Otowa T, Watanabe Y, Someya T, Arinami T. Replication study of association between ADC YAP1 gene polymorphisms and schizophrenia. Psychiatr Genet. 2010;20(3):123-125. doi:10.1097/YPG.0b013e32833a1f52 1218. Li XL, Yu Y, Hu Y, Wu HT, Li XS, Chen GY, Cheng Y. Fibroblast Growth Factor 9 as a Potential Biomarker for Schizophrenia. Front Psychiatry. 2022;13:788677. doi:10.3389/fpsyt.2022.788677 1219. Ma Y, Gao K, Sun X, Wang J, Yang Y, Wu J, Chai A, Yao L, Liu N, Yu H, et al. STON2 variations are involved in synaptic dysfunction and schizophrenia-like behaviors by regulating Syt1 trafficking. Sci Bull (Beijing). 2024;69(10):1458-1471. doi:10.1016/j.scib.2024.02.013 1220. Alshammari TK, Alshammari MA, Nenov MN, Hoxha E, Cambiaghi M, Marcinno A, James TF, Singh P, Labate D, Li J, et al. Genetic deletion of fibroblast growth factor 14 recapitu lates phenotypic alterations underlying cognitive impairment associated with schizophrenia. Transl Psychiatry. 2016;6(5):e806. doi:10.1038/tp.2016.66 1221. Ali D, Laighneach A, Corley E, Patlola SR, Mahoney R, Holleran L, McKernan DP, Kelly JP, Corvin AP, Hallahan B, et al. Direct targets of MEF2C are enriched for genes associated with schizophrenia and cognitive function and are involved in neuron development and mitochondrial function. PLoS Genet. 2024;20(9):e1011093. doi:10.1371/journal.pgen.1011093 1222. Zai CC, Zai GC, Tiwari AK, Manchia M, de Luca V, Shaikh SA, Strauss J, Kennedy JL. Association study of GABRG2 polymorphisms with suicidal behaviour in schizophrenia patients with alcohol use disorder. Neuropsychobiology. 2014;69(3):154-158. doi:10.1159/000358839 1223. Chen X, Zhang Q, Su Y, Zhao W, Li Y, Du B, Deng X, Ji F, Dong Q, Chen C, et al. Evidence for the contribution of HCN1 gene polymorphism (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint (rs1501357) to working memory at both behavioral and neural levels in schizophrenia patients and healthy controls. Schizophrenia (Heidelb). 2022;8(1):66. doi:10.1038/s41537-022-00271-7 1224. Bray NJ, Kirov G, Owen RJ, Jacobsen NJ, Georgieva L, Williams HJ, Norton N, Spurlock G, Jones S, Zammit S, et al. Screening the human protocadherin 8 (PCDH8) gene in schizophrenia. Genes Brain Behav. 2002;1(3):187-191. doi:10.1034/j.1601-183x.2002.10307.x 1225. Jiang J, Long J, Ling W, Huang G, Su L. Genetic variation in the 3'- untranslated region of PAK1 influen ces schizophrenia susceptibility. Exp Ther Med. 2017;13(3):1101-1108. doi:10.3892/etm.2017.4039 1226. Blennow K, Bogdanovic N, Heilig M, Grenfeldt B, Karlsson I, Davidsson P. Reduction of the synaptic protein rab3a in the thalamus and connecting brain regions in post-mor tem schizophrenic brains. J Neural Transm (Vienna). 2000;107(8-9):1085-1097. doi:10.1007/s007020070054 1227. Liu Y, Fu X, Tang Z, Li C, Xu Y, Zhang F, Zhou D, Zhu C. Altered expression of the CSMD1 gene in the peripheral blood of schizophrenia patients. BMC Psychiatry. 2019;19(1):113. doi:10.1186/s12888-019-2089-4 1228. Suddaby JS, Silver J, So J. Understanding the schizophrenia phenotype in the first patient with the full SCN2A phenotypic spectrum. Psychiatr Genet. 2019;29(3):91-94. doi:10.1097/YPG.0000000000000219 1229. Roberts E. GABAergic malfunction in the limbic system resulting from an aboriginal genetic defect in voltage-gated Na+-channel SCN5A is proposed to give rise to susceptibi lity to schizophrenia. Adv Pharmacol. 2006;54:119-145. doi:10.1016/s1054-3589(06)54006-2 1230. Håvik B, Degenhardt FA, Johansso n S, Fernandes CP, Hinney A, Scherag A, Lybæk H, Djurovic S, Christoforou A, Ersland KM, et al. DCLK1 variants are associated across schizophrenia and attention deficit/hyperactivity disorder. PLoS One. 2012;7(4):e35424. doi:10.1371/journal.pone.0035424 1231. Hattori E, Yamada K, Toyota T, Yoshitsugu K, Toru M, Shibuya H, Yoshikawa T. Association studies of the CT repeat polymorphism in the 5' upstream region of the cholecystokinin B receptor gene with panic disorder and schizophrenia in Japanese subj ects. Am J Med Genet. 2001;105(8):779- 782. doi:10.1002/ajmg.10043 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 1232. Liu Y, Ding M, Liu YP, Zhang XC, Xing JX, Xuan JF, Xia X, Yao J, Wang BJ. Functional analysis of haplot ypes and promoter activity at the 5' region of the human GABRB3 gene and associations with schizophrenia. Mol Genet Genomic Med. 2019;7(5):e652. doi:10.1002/mgg3.652 1233. Kim MJ, Biag J, Fass DM, Lewis MC, Zhang Q, Fleishman M, Gangwar SP, Machius M, Fromer M, Purcell SM, et al. Functional analysis of rare variants found in schizophrenia implicates a critical role for GIT1- PAK3 signaling in neuroplasticit y. Mol Psychiatry. 2017;22(3):417-429. doi:10.1038/mp.2016.98 1234. Demirel ÖF, Cetin İ , Turan Ş , Sa ğ lam T, Yıldız N, Duran A. Decreased Expression of α -Synuclein, Nogo-A and UCH-L1 in Patients with Schizophrenia: A Preliminary Serum Study. Psychiatry Investig. 2017;14(3):344-349. doi:10.4306/pi.2017.14.3.344 1235. Hu TM, Chen SJ, Hsu SH, Cheng MC. Functional analyses and effect of DNA methylation on the EGR1 gene in patients with schizophrenia. Psychiatry Res. 2019;275:276-282. doi:10.1016/j.psychres.2019.03.044 1236. Boiko AS, Ivanova SA, Pozhidaev IV, Freidin MB, Osmanova DZ, Fedorenko OY, Semke AV, Bokhan NA, Wilffert B, Loonen AJM. Pharmacogenetics of tardive dyskinesia in schizophrenia: The role of CHRM1 and CHRM2 mu scarinic receptors. World J Biol Psychiatry. 2020;21(1):72-77. doi:10.1080/15622975.2018.1548780 1237. Grubisha MJ, Sun X, MacDonald ML , Garver M, Sun Z, Paris KA, Patel DS, DeGiosio RA, Lewis DA, Yates NA, et al. MAP2 is differentially phosphorylated in schizophrenia, altering its function. Mol Psychiatry. 2021;26(9):5371-5388. doi:10.1038/s41380-021-01034-z 1238. Guo X, Zhang Y, Du J, Yang H, Ma Y, Li J, Yan M, Jin T, Liu X. Association analysis of ANK3 gene variants with schizophrenia in a northern Chinese Han population. Oncotarget. 2016;7(52):85888-85894. doi:10.18632/oncotarget.13043 1239. Guan F, Lin H, Chen G, Li L, Chen T, Liu X, Han J, Li T. Evaluation of association of common variants in HTR1A and HTR5A with schizophrenia and executive function. Sci Rep. 2016;6:38048. doi:10.1038/srep38048 1240. L i X , Z h an g W , Z h an g C , G o ng W , T an g J, Y i Z , W an g D , L u W , Fang Y, Chen X, et al. No association between genetic variants of the (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint LRRK2 gene and schizophrenia in Han Chinese. Neurosci Lett. 2014;566:210-215. doi:10.1016/j.neulet.2014.03.006 1241. Udawela M, Scarr E, Boer S, Um JY, Hannan AJ, McOmish C, Felder CC, Thomas EA, Dean B. Isoform specific differences in phospholipase C beta 1 expression in the prefrontal co rtex in schizophrenia and suicide. NPJ Schizophr. 2017;3:19. doi:10.1038/s41537-017-0020-x 1242. Ishizuka K, Yoshida T, Kawabata T, Imai A, Mori H, Kimura H, Inada T, Okahisa Y, Egawa J, Usami M, et al. Functional characterization of rare NRXN1 variants identified in autism spectrum disorders and schizophrenia. J Neurodev Disord. 2020;12(1):25.: 10.1186/s11689-020- 09325-2 1243. Morris JA, Kandpal G, Ma L, Austin CP. DISC1 (Disrupted-In- Schizophrenia 1) is a centrosome-ass ociated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation. Hum Mol Genet. 2003;12(13):1591-1608. doi:10.1093/hmg/ddg162 1244. Xu K, Zheng P, Zhao S, Feng J, Pu J, Wang J, Zhao S, Wang H, Chen J, Xie P. Altered MANF and RYR2 concentrations associated with hypolipidemia in the serum of patients with schizophrenia. J Psychiatr Res. 2023;163:142-149. doi:10.1016/j.jpsychires.2023.05.044 1245. Burhan AM, Anazodo UC, Marlatt NM, Palaniyappan L, Blair M, Finger E. Schizophrenia syndrome due to C9ORF72 mutation case report: a cautionary tale and role of hybrid brain imaging!. BMC Psychiatry. 2021;21(1):331. doi:10.1186/s12888-021-03341-9 1246. Chung Y, Dienel S, Belch M, Fish K, Ermentrout G, Lewis D, Chung D. Altered Rbfox1-Vamp1 pathway and prefrontal cortical dysfunction in schizophrenia. Preprint. Res Sq. 2023;rs.3.rs-2944372. doi: 10.21203/rs.3.rs- 2944372/v1 1247. Dienel SJ, Dowling KF, Barile Z, Bazmi HH, Liu A, Vespoli JC, Fish KN, Lewis DA. Diagnostic Specificity and Association With Cognition of Molecular Alterations in Prefrontal Somatostatin Neurons in Schizophrenia. JAMA Psychiatry. 2023;80(12):1235-1245. doi:10.1001/jamapsychiatry.2023.2972 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 1248. Reynolds GP. The neurochemical pathology of schizophrenia: post- mortem studies from dopamine to parv albumin. J Neural Transm (Vienna). 2022;129(5-6):643-647. doi:10.1007/s00702-021-02453-6 1249. Li Y, Wang K, Zhang P, Huang J, An H, Wang N, De Yang F, Wang Z, Tan S, Chen S, et al. Quantitative DNA Methylation Analysis of DLGAP2 Gene using Pyrosequencing in Schizophrenia with Tardive Dyskinesia: A Linear Mixed Model Approach. Sci Rep. 2018;8(1):17466. doi:10.1038/s41598-018-35718-4 1250. Chaumette B, Ferrafiat V, Ambala vanan A, Goldenberg A, Dionne- Laporte A, Spiegelman D, Dion PA, Gerardin P, Laurent C, Cohen D, Rapoport J, et al. Missense variants in ATP1A3 and FXYD gene family are associated with childhood-onset schizophrenia. Mol Psychiatry. 2020;25(4):821-830. doi:10.1038/s41380-018-0103-8 1251. Shen Q, Zhang J, Wang Y, Liu B, Li X, Zhao Q, Chen S, Ji J, Yang F, Wan C, et al. No association between the KCNH1, KCNJ10 and KCNN3 genes and schizophrenia in the Han Chinese population. Neurosci Lett. 2011;487(1):61-65. doi:10.1016/j.neulet.2010.09.074 1252. Noori-Daloii MR, Kheirollahi M, Mahbod P, Mohammadi F, Astaneh AN, Zarindast MR, Azimi C, Mohammadi MR. Alpha - and beta-synucleins mRNA expression in lymphocytes of schizophrenia patients. Genet Test Mol Biomarkers. 2010;14(5):725-729. doi:10.1089/gtmb.2010.0050 1253. Kordi-Tamandani DM, Dahmardeh N, Torkamanzehi A. Evaluation of hypermethylation and expression pattern of GMR2, GMR5, GMR8, and GRIA3 in patients with schizo phrenia. Gene. 2013;515(1):163-166. doi:10.1016/j.gene.2012.10.075 1254. Miyazawa A, Kanahara N, Kogure M, Otsuka I, Okazaki S, Watanabe Y, Yamasaki F, Nakata Y, Oda Y, Hishimoto A, et al. A preliminary genetic association study of GAD1 a nd GABAB receptor genes in patients with treatment-resistant schizophrenia. Mol Biol Rep. 2022;49(3):2015- 2024. doi:10.1007/s11033-021-07019-z 1255. Grubor M, Zivkovic M, Sagud M, Nikolac Perkovic M, Mihaljevic- Peles A, Pivac N, Muck-Seler D, Svob Strac D. TR1A, HTR1B, HTR2A, HTR2C and HTR6 Gene Polymorphisms and Extrapyramidal Side Effects in Haloperidol-Treated Patients with Schizophrenia. Int J Mol Sci. 2020;21(7):2345. doi:10.3390/ijms21072345 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 1256. Chen Q, Che R, Wang X, O'Neill FA, Walsh D, Tang W, Shi Y, He L, Kendler KS, Chen X. Asso ciation and expre ssion study of synapsin III and schizophrenia. Neurosci Lett. 2009;465(3):248-251. doi:10.1016/j.neulet.2009.09.032 1257. Gupta M, Jain S, Moily NS, Kaur H, Jajodia A, Purushottam M, Kukreti R. Genetic studies indicate a potential target 5-HTR(3B) for drug therapy in schizophrenia patients. Am J Med Genet B Neuropsychiatr Genet. 2012;159B(8):1006-1008. doi:10.1002/ajmg.b.32105 1258. Pozhidaev IV, Boiko AS, Loonen AJM, Paderina DZ, Fedorenko OY, Tenin G, Kornetova EG, Semke AV, Bokhan NA, Wilffert B, et al. Association of Cholinergic Muscarinic M4 Receptor Gene Polymorphism with Schizophrenia. Appl Clin Genet. 2020;13:97-105. doi:10.2147/TACG.S247174 1259. Davis KN, Tao R, Li C, Gao Y, Gondré-Lewis MC, Lipska BK, Shin JH, Xie B, Ye T, Weinberger DR, et al. Alternative Transcripts in the Human Prefrontal Cortex, and in Schizophrenia and Affective Disorders. PLoS One. 2016;11(2):e0148558. doi:10.1371/journal.pone.0148558 1260. Li JM, Lu CL, Cheng MC, Luu SU, Hsu SH, Chen CH. Genetic analysis of the DLGAP1 gene as a candidate gene for schizophrenia. Psychiatry Res. 2013;205(1-2):13-17. doi:10.1016/j.psychres.2012.08.014 1261. Braunewell KH, Dwary AD, Richter F, Trappe K, Zhao C, Giegling I, Schönrath K, Rujescu D. Association of VSNL1 with schizophrenia, frontal cortical function, and biological significance for its gene product as a modulator of cAMP levels and neuronal morphology. Transl Psychiatry. 2011;1(7):e22. doi:10.1038/tp.2011.20 1262. Marques TR, Natesan S, Niccolini F, Politis M, Gunn RN, Searle GE, Howes O, Rabiner EA, Kapur S. Phos phodiesterase 10A in Schizophrenia: A PET Study Using [(11)C]IMA107. Am J Psychiatry. 2016;173(7):714- 721. doi:10.1176/appi.ajp.2015.15040518 1263. Habibzadeh P, Nemati A, Dast sooz H, Taghipour-Sheshdeh A, Mariam Paul P, Sahraian A, Ali Faghihi M. Investigating the association between common DRD2/ANKK1 genetic polymorphisms and schizophrenia: a meta-analysis. J Genet. 2021;100:59. 1264. Gardella R, Sacchetti E, Legati A, Magri C, Traversa M, Gennarelli M. Compound heterozygosity for a hemizygous rare missense variant (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint (rs141999351) and a large CNV deletion affecting the FSTL5 gene in a patient with schizophrenia. Psychiatry Res. 2017;258:598-599. doi:10.1016/j.psychres.2016.10.057 1265. Harada S, Tachikawa H, Kawanishi Y. A possible association between an insertion/deletion polymorphism of the NQO2 gene and schizophrenia. Psychiatr Genet. 2003;13(4):205-209. doi:10.1097/00041444-200312000-00003 1266. Hartmann D, Fiedler J, Sonnenschein K, Just A, Pfanne A, Zimmer K, Remke J, Foinquinos A, Butzlaff M, Schimmel K, et al. MicroRNA-Based Therapy of GATA2-Deficient Vascular Disease. Circulation. 2016;134(24):1973-1990. doi:10.1161/CIRCULATIONAHA.116.022478 1267. de Jager SCA, Hoefer IE. Beyond the matrix: MMP2 as critical regulator of inflammation-mediated va scular dysfunction. Cardiovasc Res. 2017;113(14):1705-1707. doi:10.1093/cvr/cvx202 1268. Lawrie A, Spiekerkoetter E, Martinez EC, Ambartsumian N, Sheward WJ, MacLean MR, Harmar AJ, Schmidt AM, Lukanidin E, Rabinovitch M. Interdependent serotonin transporte r and receptor pathways regulate S100A4/Mts1, a gene associated with pulmonary vascular disease. Circ Res. 2005;97(3):227-235. doi:10.1161/01.RES.0000176025.57706.1e 1269. Mazzuca MQ, Khalil RA. Vascular endothelin receptor type B: structure, function and dysregulation in vascular disease. Biochem Pharmacol. 2012;84(2):147-162. doi:10.1016/j.bcp.2012.03.020 1270. Van Bergen T, Etienne I, Cunningham F, Moons L, Schlingemann RO, Feyen JHM, Stitt AW. The role of placental growth factor (PlGF) and its receptor system in retinal vascular diseases. Prog Retin Eye Res. 2019;69:116-136. doi:10.1016/j.preteyeres.2018.10.006 1271. Saint-Martin Willer A, Montani D, Capuano V, Antigny F. Orai1/STIMs modulators in pulmonary vascular diseases. Cell Calcium. 2024;121:102892. doi:10.1016/j.ceca.2024.102892 1272. Kuriakose J, Montezano AC, Touyz RM. ACE2/Ang-(1-7)/Mas1 axis and the vascular system: vasoprotection to COVID-19-associated vascular disease. Clin Sci (Lond). 2021;135(2):387-407. doi:10.1042/CS20200480 1273. Wang Y, Xu J, Chen J, Fan X, Zhang Y, Yu W, Liu J, Hui R. Promoter variants of VTN are associated with vascular disease. Int J Cardiol. 2013;168(1):163-168. doi:10.1016/j.ijcard.2012.09.100 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 1274. Fu Y, Liu JW, Wu J, Wu ZX, Li J, Ji HF, Liang NP, Zhang HJ, Lai ZQ, Dong YF. Inhibition of semaphorin-3a alleviates lipopolysaccharide- induced vascular injury. Microvasc Res. 2022;142:104346. doi:10.1016/j.mvr.2022.104346 1275. Guglielmotto M, Monteleone D, Vasciaveo V, Repetto IE, Manassero G, Tabaton M, Tamagno E. The Decrease of Uch-L1 Activity Is a Common Mechanism Responsible for A β 42 Accumulation in Alzheimer's and Vascular Disease. Front Aging Neurosci. 2017;9:320. doi:10.3389/fnagi.2017.00320 1276. Wang X, Athayde N, Trudinger B. Egr-1 transcription activation exists in placental endothelium when vascular disease is present. BJOG. 2006;113(6):683-687. doi:10.1111/j.1471-0528.2006.00928.x 1277. Zhang J, Chen J, Yang J, Xu C, Hu Q, Wu H, Cai W, Guo Q, Gao W, He C, et al. Suv39h1 downregulation inhibits neointimal hyperplasia after vascular injury. Athero sclerosis. 2019;288:76-84. doi:10.1016/j.atherosclerosis.2019.06.909 1278. Luo L, Cai Y, Zhang Y, Hsu CG, Korshunov VA, Long X, Knight PA, Berk BC, Yan C. Role of PDE10A in vascular smooth muscle cell hyperplasia and pathological vascul ar remodelling. Cardiovasc Res. 2022;118(12):2703-2717. 1279. Gauthier-Kemper A, Weissmann C, Golovyashkina N, Sebö-Lemke Z, Drewes G, Gerke V, Heinisch JJ, Brandt R. The frontotemporal dementia mutation R406W blocks tau's interactio n with the membrane in an annexin A2-dependent manner. J Cell Biol. 2011;192(4):647-661. doi:10.1083/jcb.201007161 1280. Tuna G, Yener GG, Oktay G, İş lekel GH, K İ rkalİ FG. Evaluation of Matrix Metalloproteinase-2 (MMP-2) and -9 (MMP-9) and Their Tissue Inhibitors (TIMP-1 and TIMP-2) in Plasma from Patients with Neurodegenerative Dementia. J Al zheimers Dis. 2018;66(3):1265-1273. doi:10.3233/JAD-180752 1281. Dhillon NK, Peng F, Bokhari S, Callen S, Shin SH, Zhu X, Kim KJ, Buch SJ. Cocaine-mediated alteration in tight junction protein expression and modulation of CCL2/CCR2 axis across the blood-brain barrier: implications for HIV-dementia. J Neuroimmune Pharmacol. 2008;3(1):52- 56. doi:10.1007/s11481-007-9091-1 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 1282. Yaowaluk T, Senanarong V, Limwongse C, Boonprasert R, Kijsanayotin P. Influence of CYP2D6, CYP3A5, ABCB1, APOE polymorphisms and nongenetic factors on donepezil treatment in patients with Alzheimer's disease and vascular dementia. Pharmgenomics Pers Med. 2019;12:209-224. 1283. Hansson O, Santillo AF, Meeter LH, Nilsson K, Landqvist Waldö M, Nilsson C, Blennow K, van Swieten JC, Janelidze S. SF placental growth factor - a novel candidate biomarker of frontotemporal dementia. Ann Clin Transl Neurol. 2019;6(5):863-872. doi:10.1002/acn3.763 1284. van Steenoven I, Noli B, Cocco C, Ferri GL, Oeckl P, Otto M, Koel- Simmelink MJA, Bridel C, van der Flier WM, Lemstra AW, et al. VGF Peptides in Cerebrospinal Fluid of Patients with Dementia with Lewy Bodies. Int J Mol Sci. 2019;20(19):4674. doi:10.3390/ijms20194674 1285. Ariaei A, Ghorbani A, Habibzadeh E, Moghaddam N, Chegeni Nezhad N, Abdoli A, Mazinanian S, Sadeghi M, Mayeli M. Investigating the association between the GAP-43 conc entration with diffusion tensor imaging indices in Alzheimer's dementia continuum. BMC Neurol. 2024;24(1):397. doi:10.1186/s12883-024-03904-9 1286. Bentivenga GM, Baiardi S, Mastrangelo A, Zenesini C, Mammana A, Polischi B, Capellari S, Parchi P. Diagnostic and prognostic value of cerebrospinal fluid SNAP-25 and neurogranin in Creutzfeldt-Jakob disease in a clinical setting cohort of rapidly progressive dementias. Alzheimers Res Ther. 2023;15(1):150. doi:10.1186/s13195-023-01300-y 1287. C r o cco P, D e R an g o F , B r u n o F , M alv as o A , M al ett a R , B r u n i A C , Passarino G, Rose G, Dato S. Genetic variability of FOXP2 and its targets CNTNAP2 and PRNP in frontotemporal dementia: A pilot study in a southern Italian population. Heliyon. 2024;10(11):e31624. doi:10.1016/j.heliyon.2024.e31624 1288. Shibata N, Motoi Y, Tomiyama H, Ohnuma T, Kuerban B, Tomson K, Komatsu M, Hattori N, Arai H. Lack of genetic association of the UCHL1 gene with Alzheimer's disease and Parkinson's disease with dementia. Dement Geriatr C ogn Disord. 2012;33(4):250-254. doi:10.1159/000339357 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 1289. Xie C, Miyasaka T. The Role of the Carboxyl-Terminal Sequence of Tau and MAP2 in the Pathogenesis of Dementia. Front Mol Neurosci. 2016;9:158. doi:10.3389/fnmol.2016.00158 1290. Yang D, Xie H, Wu S, Ying C, Chen Y, Ge Y, Yao R, Li K, Jiang Z, Chen G. Neurofilament light chain as a mediator between LRRK2 mutation and dementia in Parkinson's disease. NPJ Parkinsons Dis. 2023;9(1):132. doi:10.1038/s41531-023-00572-3 1291. Strittmatter M, Cramer H, Reuner C, Strubel D, Hamann G, Schimrigk K. Molecular forms of somatostatin-like immunoreactivity in the cerebrospinal fluid of patients with senile dementia of the Alzheimer type. Biol Psychiatry. 1997;41(11):1124-1130. doi: 10.1016/S0006- 3223(96)00211-9 1292. Zagórska A, Bucki A, Partyka A, Jastrz ę bska-Wię sek M, Siwek A, Głuch-Lutwin M, Mordyl B, Jaromin A, Walczak M, Wesołowska A, et al. Design, synthesi s, and behavioral evaluation of dual-acting compounds as phosphodiesterase type 10A (PDE10A) inhibitors and serotonin ligands targeting neuropsychiatric symptoms in dementia. Eur J Med Chem. 2022;233:114218. doi:10.1016/j.ejmech.2022.114218 1293. Chiasserini D, Biscetti L, Eusebi P, Salvadori N, Frattini G, Simoni S, De Roeck N, Tambasco N, Stoops E, Vanderstichele H, et al. Differential role of CSF fatty acid binding protein 3, α -synuclein, and Alzheimer's disease core biomarkers in Lewy body disorders and Alzheimer's dementia. Alzheimers Res Ther. 2017;9(1):52. doi:10.1186/s13195-017-0276-4 1294. L i R , S a n o T , M i z o k a m i A , F u k u d a T , S h i n j o T , I w a s h i t a M , Yamashita A, Sanui T, Nakatsu Y, Sotomaru Y, et al. miR-582-5p targets Skp1 and regulates NF- κ B signaling-mediated inflammation. Arch Biochem Biophys. 2023;734:109501. doi:10.1016/j.abb.2022.109501 1295. Pilar AV, Reid-Yu SA, Cooper CA, Mulder DT, Coombes BK. GogB is an anti-inflammatory effector that limits tissue damage during Salmonella infection through interaction with human FBXO22 and Skp1. PLoS Pathog. 2012;8(6):e1002773. doi:10.1371/journal.ppat.1002773 1296. Salas-Leal AC, Salas-Pacheco SM, Hernández-Cosaín EI, Vélez- Vélez LM, Antuna-Salcido EI, Castellanos-Juárez FX, Méndez-Hernández EM, Llave-León O, Quiñones-Canales G, Arias-Carrión O, et al. Differential expression of PSMC4, SK P1, and HSPA8 in Parkinso n's disease: insights (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint from a Mexican mestizo population. Front Mol Neurosci. 2023;16:1298560. doi:10.3389/fnmol.2023.1298560 1297. Kumar P, Dezso Z, MacKenzie C, Oestreicher J, Agoulnik S, Byrne M, Bernier F, Yanagimachi M, Aoshima K, Oda Y. irculating miRNA biomarkers for Alzheimer's disease. PLoS One. 2013;8(7):e69807. doi:10.1371/journal.pone.0069807 1298. Gámez-Valero A, Campdelacreu J, Vilas D, Ispierto L, Reñé R, Álvarez R, Armengol MP, Borràs FE, Beyer K. Exploratory study on microRNA profiles from plasma-derived extracellular vesicles in Alzheimer's disease and dementia with Lewy bodies. Transl Neurodegener. 2019;8:31. doi:10.1186/s40035-019-0169-5 1299. Li Y, Shaw CA, Sheffer I, Sule N, Powell SZ, Dawson B, Zaidi SN, Bucasas KL, Lupski JR, Wilhelmsen KC, Doody R, et al. Integrated copy number and gene expression analysis detects a CREB1 association with Alzheimer's disease. Transl Psychiatry. 2012;2(11):e192. doi:10.1038/tp.2012.119 1300. Shibata N, Ohnuma T, Higashi S, Higashi M, Usui C, Ohkubo T, Watanabe T, Kawashima R, Kitajima A, Ueki A, et al. Genetic association between USF 1 and USF 2 gene polymo rphisms and Japane se Alzheimer's disease. J Gerontol A Biol Sc i Med Sci. 2006;61(7):660-662. doi:10.1093/gerona/61.7.660 1301. Li H, Wang F, Guo X, Jiang Y. Decreased MEF2A Expression Regulated by Its Enhancer Methylation Inhibits Autophagy and May Play an Important Role in the Progression of Alzheimer's Disease. Front Neurosci. 2021;15:682247. doi:10.3389/fnins.2021.682247 1302. Yao Y, Kang SS, Xia Y, Wang ZH, Liu X, Muller T, Sun YE, Ye K. A delta-secretase-truncated APP fragment activates CEBPB, mediating Alzheimer's disease pathologies. Brain. 2021;144(6):1833-1852. doi:10.1093/brain/awab062 1303. Lingam I, Avdic-Belltheus A, Meehan C, Martinello K, Ragab S, Peebles D, Barkhuizen M, Tann CJ, Tachtsidis I, Wolfs TGAM, et al. Serial blood cytokine and chemokine mRNA and microRNA over 48 /i2 h are insult specific in a piglet model of inflammation-sensitized hypoxia-ischaemia. Pediatr Res. 2021;89(3):464-475. doi:10.1038/s41390-020-0986-3 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 1304. Han K, Wang FR, Yu MQ. MicroRNA-21-5p promotes the inflammatory response after spinal cord injury by targeting PLAG1. Eur Rev Med Pharmacol Sci. 2020;24(11):5878-5885. doi:10.26355/eurrev_202006_21480 1305. Jia P, Zhang W, Shi Y. NFIC attenu ates rheumatoid arthritis-induced inflammatory response in mice by regulating PTEN/SENP8 transcription. Tissue Cell. 2023;81:102013. doi:10.1016/j.tice.2023.102013 1306. Chen J, Bai Y, Xue K, Li Z, Zhu Z, Li Q, Yu C, Li B, Shen S, Qiao P, et al. CREB1-driven CXCR4hi neutroph ils promote skin inflammation in mouse models and human patients. Nat Commun. 2023;14(1):5894. doi:10.1038/s41467-023-41484-3 1307. Xiong Y, Wang L, Jiang W, Pang L, Liu W, Li A, Zhong Y, Ou W, Liu B, Liu SM. MEF2A alters the proliferation, inflammation-related gene expression profiles and its silencing induces cellular senescence in human coronary endothelial cells. BMC Mol Biol. 2019;20(1):8. doi:10.1186/s12867-019-0125-z 1308. van der Krieken SE, Popeijus HE, Mensink RP, Plat J. CCAAT/enhancer binding protein β in relation to ER stress, inflammation, and metabolic disturbances. Bi omed Res Int. 2015;2015:324815. doi:10.1155/2015/324815 1309. Cao Q, Guo Z, Du S, Ling H, Song C. Circular RNAs in the pathogenesis of athe rosclerosis. Life Sci. 2020;255:117837. doi:10.1016/j.lfs.2020.117837 1310. Ye Y, Jin Q, Gong Q, Li A, Sun M, Jiang S, Jin Y, Zhang Z, He J, Zhuang L. Bioinformatics and Experimental Analyses Reveal NFIC as an Upstream Transcriptional Regulator for Ischemic Cardiomyopathy. Genes (Basel). 2022;13(6):1051. doi:10.3390/genes13061051 1311. Zhang T, Ge J. Mechanism of CREB1 in cardiac function of rats with heart failure via regulating the microRNA-376a-3p/TRAF6 axis. Mamm Genome. 2022;33(3):490-501. doi:10.1007/s00335-022-09947-y 1312. Pu Y, Zhao Q, Men X, Jin W, Yang M. MicroRNA-325 facilitates atherosclerosis progression by mediating the SREBF1/LXR axis via KDM1A. Life Sci. 2021;277:119464. doi:10.1016/j.lfs.2021.119464 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 1313. Muhammad Sulaiman K. A Study of transcription factor MEF2A gene polymorphisms in patients with corona ry artery disease. Cell Mol Biol (Noisy-le-grand). 2024;70(1):80-86. doi:10.14715/cmb/2024.70.1.11 1314. Satoh T, Wang L, Espinosa-Diez C, Wang B, Hahn SA, Noda K, Rochon ER, Dent MR, Levine AR, Baust JJ, et al. Metabolic Syndrome Mediates ROS-miR-193b-NFYA-Depende nt Downregulation of Soluble Guanylate Cyclase and Contributes to Exercise-Induced Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction. Circulation. 2021;144(8):615-637. doi:10.1161/CIRCULATIONAHA.121.053889 1315. Liu C, Gao Q, Dong J, Cai H. Us f2 Deficiency Promotes Autophagy to Alleviate Cerebral Ischemia-Reperfusion Injury Through Suppressing YTHDF1-m6A-Mediated Cdc25A Translation. Mol Neurobiol. 2024;61(5):2556-2568. doi:10.1007/s12035-023-03735-8 1316. Cortes-Canteli M, Luna-Medina R, Sanz-Sancristobal M, Alvarez- Barrientos A, Santos A, Perez-Castillo A. CCAAT/enhancer binding protein beta deficiency provides cerebral prot ection following excitotoxic injury. J Cell Sci. 2008;121(Pt 8):1224-1234. doi:10.1242/jcs.025031 1317. Li J, Lv H, Che Y. microRNA-381-3p Confers Protection Against Ischemic Stroke Through Promoting Angiogenesis and Inhibiting Inflammation by Suppressing Cebpb and Map3k8. Cell Mol Neurobiol. 2020;40(8):1307-1319. doi:10.1007/s10571-020-00815-4 1318. Kim HK, Tyryshkin K, Elmi N, Dharsee M, Evans KR, Good J, Javadi M, McCormack S, Vaccarino AL, Zhang X, et al. Plasma microRNA expression levels and their targeted pathways in patients with major depressive disorder who are responsive to duloxetine treatment. J Psychiatr Res. 2019;110:38-44. doi:10.1016/j.jpsychires.2018.12.007 1319. Wang P, Yang Y, Yang X, Qiu X, Qiao Z, Wang L, Zhu X, Sui H, Ma J. CREB1 gene polymorphisms combined with environmental risk factors increase susceptibility to major depressive disorder (MDD). Int J Clin Exp Pathol. 2015;8(1):906-913. 1320. Resende LS, Amaral CE, Soares RB, Alves AS, Alves-Dos-Santos L, Britto LR, Chiavegatto S. Social stress in adolescents induces depression and brain-region-specific modulation of the transcription factor MAX. Transl Psychiatry. 2016;6(10):e914. doi:10.1038/tp.2016.202 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 1321. Cao D, Wang J, Ji Z, Shangguan Y, Guo W, Feng X, Xu K, Yang J. Profiling the mRNA and miRNA in Peripheral Blood Mononuclear Cells in Subjects with Active Tuberculosis. Infect Drug Resist. 2020;13:4223-4234. doi:10.2147/IDR.S278705 1322. de Klerk JA, Beulens JWJ, Bijkerk R, van Zonneveld AJ, Elders PJM, 't Hart LM, Slieker R. Circulating small non-coding RNAs are associated with the insulin-resistant and obesity-related type 2 diabetes clusters. Diabetes Obes Metab. 2024;26(10):4375-4385. doi:10.1111/dom.15786 1323. Kuryłowicz A, Wicik Z, Owczarz M, Jonas MI, Kotlarek M, Ś wierniak M, Lisik W, Jonas M, Noszczyk B, Puzianowska-Ku ź nicka M. NGS Reveals Molecular Pathways Affected by Obesity and Weight Loss- Related Changes in miRNA Levels in Adipose Tissue. Int J Mol Sci. 2017;19(1):66. doi:10.3390/ijms19010066 1324. Czogała W, Czogała M, Strojny W, W ą tor G, Wołkow P, Wójcik M, Bik Multanowski M, Tomasik P, W ę drychowicz A, Kowalczyk W, et al. Methylation and Expression of FTO and PLAG1 Genes in Childhood Obesity: Insight into Anthropometric Parameters and Glucose-Lipid Metabolism. Nutrients. 2021;13(5):1683. doi:10.3390/nu13051683 1325. Sukhatme MG, Kar A, Arasu UT, Lee SHT, Alvarez M, Garske KM, Gelev KZ, Rajkumar S, Das SS, Kaminska D, et al. ntegration of single cell omics with biobank data discovers trans effects of SREBF1 abdominal obesity risk variants on adipocyte expression of more than 100 genes. Preprint. medRxiv. 2024;2024.11.22.24317804. doi:10.1101/2024.11.22.24317804 1326. Bennett CE, Nsengimana J, Bostock JA, Cymbalista C, Futers TS, Knight BL, McCormack LJ, Prasad UK, Riches K, Rolton D, et al. CCAAT/enhancer binding protein alpha , beta and delta gene variants: associations with obesity related phe notypes in the Leeds Family Study. Diab Vasc Dis Res. 2010;7(3):195-203. doi:10.1177/1479164110366274 1327. Groen K, Maltby VE, Scott RJ, Tajouri L, Lechner-Scott J. Erythrocyte microRNAs show biomarker potential and implicate multiple sclerosis susceptibility genes. C lin Transl Med. 2020;10(1):74-90. doi:10.1002/ctm2.22 1328. Salemi M, Marchese G, Lanza G, Cosentino FII, Salluzzo MG, Schillaci FA, Ventola GM, Cordella A, Ravo M, Ferri R. Role and (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Dysregulation of miRNA in Patients with Parkinson's Disease. Int J Mol Sci. 2022;24(1):712. doi:10.3390/ijms24010712 1329. Liu T, Li G. miR-15b-5p transcription mediated by CREB1 protects against inflammation and apoptosis in Parkinson disease models by inhibiting AXIN2 and activating Wnt/ β -catenin. J Neuropathol Exp Neurol. 2023;82(12):995-1009. doi:10.1093/jnen/nlad084 1330. Yuan X, Cao B, Wu Y, Chen Y, Wei Q, Ou R, Yang J, Chen X, Zhao B, Song W, et al. Association anal ysis of SNP rs11868035 in SREBF1 with sporadic Parkinson's disease, sporadic amyotrophic lateral sclerosis and multiple system atrophy in a Chinese population. Neurosci Lett. 2018;664:128-132. doi:10.1016/j.neulet.2017.11.015 1331. Casado Gama H, Amorós MA, Andrade de Araújo M, Sha CM, Vieira MPS, Torres RGD, Souza GF, Junkes JA, Dokholyan NV, Leite Góes Gitaí D, et al. Systematic review and meta-analysis of dysregulated microRNAs derived from liquid biopsies as biomarkers for amyotrophic lateral sclerosis. Noncoding RNA Res. 2024;9(2):523-535. doi:10.1016/j.ncrna.2024.02.006 1332. Joilin G, Gray E, Thompson AG, Bobeva Y, Talbot K, Weishaupt J, Ludolph A, Malaspina A, Leigh PN, New bury SF, et al. Identification of a potential non-coding RNA biomarker signature for amyotrophic lateral sclerosis. Brain Commun. 2020;2(1):fcaa053. doi:10.1093/braincomms/fcaa053 1333. Zhao G, Fu Y, Yang C, Yang X, Hu X. Exploring the pathogenesis linking traumatic brain injury and epilepsy via bioinformatic analyses. Front Aging Neurosci. 2022;14:1047908. doi:10.3389/fnagi.2022.1047908 1334. Wang X, Sun Y, Tan Z, Che N, Ji A, Luo X, Sun X, Li X, Yang K, Wang G, et al. Serum MicroRNA-4521 is a Potential Biomarker for Focal Cortical Dysplasia with Refractory Epilepsy. Neurochem Res. 2016;41(4):905-912. doi:10.1007/s11064-015-1773-0 1335. Huang Y, Wu X, Guo J, Yuan J. Myocyte-specific enhancer binding factor 2A expression is downregulated during temporal lobe epilepsy. Int J Neurosci. 2016;126(9):786-796. doi:10.3109/00207454.2015.1062003 1336. M i r r a P , D e s i d e r i o A , S p i n e l l i R , N i g r o C , L o n g o M , P a r r i l l o L , D'Esposito V, Carissimo A, Hedjazifar S, Smith U, et al. Adipocyte precursor cells from first degree relatives of type 2 diabetic patients feature changes in hsa-mir-23a-5p, -193a-5p, and -193b-5p and insulin-like growth (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint factor 2 expression. FASEB J. 2021;35(4):e21357. doi:10.1096/fj.202002156RRR 1337. Shahin NN, Shaker OG, Mahmoud MO. GOAT rs10096097 and CREB1 rs6740584 single nucleotide poly morphisms are associated with type 2 diabetes mellitus in Eg yptians. Arch Pharm (Weinheim). 2024;357(8):e2400011. doi:10.1002/ardp.202400011 1338. Grarup N, Stender-Petersen KL, A ndersson EA, Jørgensen T, Borch- Johnsen K, Sandbaek A, Lauritzen T, Schmitz O, Hansen T, Pedersen O. Association of variants in the sterol regulatory element-binding factor 1 (SREBF1) gene with type 2 diabetes, glycemia, and insulin resistance: a study of 15,734 Danish subjects. Diabetes. 2008;57(4):1136-1142. doi:10.2337/db07-1534 1339. Lobanov SV, McAllister B, McDade-Kumar M, Landwehrmeyer GB, Orth M, Rosser AE; REGISTRY Investigators of the European Huntington’s disease network; Paulsen JS; PREDICT-HD Investigators of the Huntington Study Group; Lee JM, et al. Huntington's disease age at motor onset is modified by the tandem hexamer re peat in TCERG1. NPJ Genom Med. 2022;7(1):53. doi:10.1038/s41525-022-00317-w 1340. McCourt AC, Parker J, Silajdži ć E, Haider S, Sethi H, Tabrizi SJ, Warner TT, Björkqvist M. Analysis of White Adipose Tissue Gene Expression Reveals CREB1 Pathway Altered in Huntington's Disease. J Huntingtons Dis. 2015;4(4):371-382. doi:10.3233/JHD-150172 1341. Reynolds CA, Hong MG, Eriksson UK, Blennow K, Wiklund F, Johansson B, Malmberg B, Berg S, Alexeyenko A, Grönberg H, et al. nalysis of lipid pathway genes indicat es association of sequence variation near SREBF1/TOM1L2/ATPAF2 with dementia risk. Hum Mol Genet. 2010;19(10):2068-2078. doi:10.1093/hmg/ddq079 1342. W a n g X , Z h a n g G , L u W , Z h a n g Y , F a n W , T a n g W , Z h a n g C . Common variants in CREB1 gene confer risk for bipolar disorder in Han Chinese. Asian J Psychiatr. 2021;59:102648. doi:10.1016/j.ajp.2021.102648 1343. Pan B, Han B, Zhu X, Wang Y, Ji H, Weng J, Liu Y. Dysfunctional microRNA-144-3p/ZBTB20/ERK/CREB1 signalling pathway is associated with MK-801-induced schizophrenia-like abnormalities. Brain Res. 2023;1798:148153. doi:10.1016/j.brainres.2022.148153 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 1344. Y a n g L , C h e n J , L i Y , W a n g Y , L i a n g S , S h i Y , S h i S , X u Y . Association between SCAP and SR EBF1 gene polymorphisms and metabolic syndrome in schizophrenia patients treated with atypical antipsychotics. World J Biol Psychiatry. 2016;17(6):467-474. doi:10.3109/15622975.2016.1165865 Table 1 The statistical metrics for key differentially expressed genes (DEGs) Gene Symbol logFC pValue tvalue Regulation Gene Name HSPA1A 4.149241 0.014769 2.528066 Up heat shock protein family A (Hsp70) member 1A TGFB2-OT1 3.381762 0.000852 3.555385 Up TGFB2 overlapping transcript 1 KCNA6 3.006283 0.003607 3.058974 Up potassium voltage-gated channel subfamily A member 6 ZNF623 2.386691 0.008608 2.738206 Up zinc finger protein 623 ATP6V1G2 2.273082 0.000717 3.61263 Up ATPase H+ transporting V1 subunit G2 SAMD11 2.255065 1.36E-05 4.839089 Up sterile alpha motif domain containing 11 GSTM1 2.192769 0.033159 2.192524 Up glutathione S-transferase mu 1 SOX7 1.920759 0.021668 2.372539 Up SRY-box transcription factor 7 TLCD2 1.905676 0.034084 2.180587 Up TLC domain containing 2 G0S2 1.901098 0.004447 2.983563 Up G0/G1 switch 2 NOTUM 1.898857 0.000175 4.065471 Up notum, palmitoleoyl-protein carboxylesterase FOXJ1 1.886664 0.001687 3.32526 Up forkhead box J1 PHRF1 1.886309 0.018904 2.428581 Up PHD and ring finger domains 1 CCDC80 1.876431 0.001479 3.37009 Up coiled-coil domain containing 80 MICA 1.830944 0.00062 3.660083 Up MHC class I polypeptide-related sequence A LCN10 1.814854 0.002455 3.195242 Up lipocalin 10 C2CD4B 1.77082 0.001336 3.404682 Up C2 calcium dependent domain containing 4B NPC1L1 1.739011 0.009887 2.68517 Up NPC1 like intracellular cholesterol transporter 1 HLA-DQB1 1.723753 0.02891 2.251475 Up major histocompatibility complex, class II, DQ beta 1 FOXL2 1.722495 0.000345 3.84986 Up forkhead box L2 AMMECR1L 1.683627 0.038172 2.131008 Up AMMECR1 like CCDC102A 1.677237 0.000129 4.15967 Up coiled-coil domain containing 102A FLT4 1.661451 0.000152 4.108419 Up fms related receptor tyrosine kinase 4 SMOC2 1.617379 0.008786 2.730385 Up SPARC related modular calcium binding 2 GPR17 1.583478 0.015722 2.503086 Up G protein-coupled receptor 17 LTF 1.558295 0.007088 2.811574 Up lactotransferrin SERPINH1 1.534214 0.013771 2.555856 Up serpin family H member 1 ESPNL 1.5325 0.004627 2.969081 Up espin like (which was not certified by peer review) is the author/funder. 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The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint RRAD 1.532149 0.001531 3.358399 Up RRAD, Ras related glycolysis inhibitor and calcium channel regulator OTOS 1.526164 0.00206 3.256253 Up otospiralin MT1G 1.515497 0.025682 2.301637 Up metallothionein 1G DDIT4L 1.511141 0.006478 2.845207 Up DNA damage inducible transcript 4 like P2RY2 1.50816 0.014473 2.536125 Up purinergic r eceptor P2Y2 CLCNKA 1.491382 0.006419 2.848636 Up chloride voltage-gated channel Ka CDA 1.48822 0.001308 3.411764 Up cytidinedeaminase ZBTB12 1.48597 0.018513 2.437106 Up zinc finger and BTB domain containing 12 ENG 1.485039 0.000665 3.637246 Up endoglin SLC23A3 1.480762 0.003304 3.090362 Up solute carrier family 23 member 3 FAM167B 1.46885 0.010718 2.654017 Up family with sequence similarity 167 member B ARHGEF5 1.455913 0.008956 2.723109 Up Rho guanine nucleotide exchange factor 5 NEU1 1.451818 2.58E-05 4.649018 Up neuraminidase 1 SMAD6 1.422975 0.000989 3.505757 Up SMAD family member 6 MLKL 1.400681 0.001919 3.280794 Up mixed lineage kinase domain like pseudokinase NKX1-2 1.399173 0.000355 3.840655 Up NK1 homeobox 2 HSPB1 1.389515 0.008407 2.747175 Up heat shock protein family B (small) member 1 SPACDR 1.384947 0.007477 2.791498 Up sperm acrosome developmental regulator MOSMO 1.374777 0.010815 2.650522 Up modulator of smoothened AMIGO2 1.37203 0.009597 2.696625 Up adhesion molecule with Ig like domain 2 PRX 1.355774 0.001076 3.477679 Up periaxin LEF1 1.355546 0.000833 3.562986 Up lymphoid enhancer binding factor 1 GLI2 1.354663 0.01905 2.425443 Up GLI family zinc finger 2 DNAJB1 1.351002 0.022244 2.361683 Up DnaJ heat shock protein family (Hsp40) member B1 PABPC4L 1.350311 0.006532 2.842156 Up poly(A) binding protein cytoplasmic 4 like FOXF2 1.350043 0.000849 3.556548 Up forkhead box F2 NANOS1 1.349238 0.000882 3.544182 Up nanos C2HC-type zinc finger 1 ZNF366 1.345489 0.002793 3.149857 Up zinc finger protein 366 SLC1A7 1.334827 0.049611 2.013538 Up solute carrier family 1 member 7 LRTOMT 1.33451 0.00641 2.849158 Up leucine rich transmembrane and O- methyltransferase domain containing ABHD16A 1.327616 0.007779 2.776609 Up abhydrolase domain containing 16A, phospholipase ANO2 1.326823 0.00629 2.856164 Up anoctamin 2 ZAP70 1.323334 0.001372 3.395575 Up zeta chain of T cell receptor associated protein kinase 70 ALX4 1.313713 0.015449 2.510107 Up ALX homeobox 4 OTOG 1.312914 0.006884 2.822523 Up otogelin OSR1 1.30742 0.022136 2.363703 Up odd-skipped related transcription factor 1 FOXF1 1.302946 0.006651 2.835379 Up forkhead box F1 SCARF1 1.30188 0.004979 2.942327 Up scavenger r eceptor class F member 1 PPBP 1.301236 0.004629 2.968949 Up pro-platelet basic protein MSX1 1.298881 0.005365 2.914969 Up mshhomeobox 1 RAMP2 1.289091 0.012943 2.580346 Up receptor activity modifying protein 2 (which was not certified by peer review) is the author/funder. 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The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint ANKRD37 1.286802 0.007741 2.778458 Up ankyrin repeat domain 37 CCDC168 1.286216 0.003477 3.072096 Up coiled-coil domain containing 168 LVRN 1.281864 0.020961 2.386236 Up laeverin C1QTNF5 1.277174 0.000158 4.097364 Up C1q and TNF related 5 SERPINA5 1.275781 0.022383 2.3591 Up serpin family A member 5 MRGPRE 1.274929 0.000838 3.561141 Up MAS related GPR family member E FOXC1 1.273865 0.002006 3.265414 Up forkhead box C1 CLEC18A 1.261735 0.000181 4.055035 Up C-type lectin domain family 18 member A EPHX1 1.260743 0.003522 3.067535 Up epoxide hydrolase 1 CCL2 1.258196 0.031504 2.214646 Up C-C motif chemokine ligand 2 MBOAT7 1.250478 0.001198 3.441661 Up membrane bound O-acyltransferase domain containing 7 ADAMTSL5 1.246684 0.000266 3.932719 Up ADAMTS like 5 SCARF2 1.239488 0.047029 2.037822 Up scavenger r eceptor class F member 2 FCGBP 1.238872 0.030185 2.233012 Up Fc gamma binding protein AEBP1 1.234388 0.001952 3.274964 Up AE binding protein 1 PGR 1.232681 0.01705 2.470474 Up progesterone receptor ADCY4 1.225058 0.001437 3.380047 Up adenylatecyclase 4 SYCE2 1.22367 0.006308 2.855133 Up synaptonemal complex central element protein 2 TEAD2 1.221922 0.004825 2.953834 Up TEA domain transcription factor 2 NUPR1 1.216256 0.005401 2.912539 Up nuclear protein 1, transcriptional regulator GPSM3 1.21073 0.004306 2.995192 Up G protein signaling modulator 3 TRPV4 1.207102 0.001822 3.298763 Up transient receptor potential cation channel subfamily V member 4 RIPOR3 1.206058 0.001679 3.326809 Up RIPOR family member 3 MASP2 1.204261 0.019084 2.424717 Up MBL associated serine protease 2 ROM1 1.199636 0.025583 2.303263 Up retinal outer segment membrane protein 1 GATA2 1.197816 0.006921 2.820513 Up GATA binding protein 2 LGR6 1.19553 0.004875 2.950067 Up leucine rich repeat containing G protein- coupled receptor 6 CDKN1C 1.195334 0.045369 2.054046 Up cyclin dependent kinase inhibitor 1C NUTM2B 1.194944 0.005453 2.909025 Up NUT family member 2B CASP7 1.194221 0.00179 3.304801 Up caspase 7 TRABD2B 1.194219 0.04291 2.079063 Up TraB domain containing 2B FLT1 1.193978 0.003741 3.045889 Up fms related receptor tyrosine kinase 1 TBX1 1.191866 0.002969 3.128289 Up T-box transcription factor 1 EGFL8 1.190474 0.016141 2.492534 Up EGF like domain multiple 8 TRIP10 1.18973 0.001741 3.31443 Up thyroid hormone receptor interactor 10 FOXQ1 1.188919 0.00017 4.073147 Up forkhead box Q1 TFAP2C 1.188349 0.005566 2.90144 Up transcription factor AP-2 gamma MKNK2 1.187865 0.004932 2.94583 Up MAPK interacting serine/threonine kinase 2 OSCAR 1.18543 0.016557 2.482311 Up osteoclast associated Ig-like receptor HIC1 1.179404 0.007961 2.767824 Up HIC ZBTB transcriptional repressor 1 SECTM1 1.175892 0.018572 2.435794 Up secreted and transmembrane 1 ANKRD53 1.173086 0.00205 3.258026 Up ankyrin repeat domain 53 (which was not certified by peer review) is the author/funder. 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The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint ORAI2 1.171851 0.006092 2.868082 Up ORAI calcium release-activated calcium modulator 2 DLL4 1.170977 0.002889 3.137923 Up delta like canonical Notch ligand 4 SYDE1 1.168773 0.001082 3.47582 Up synapse defective Rho GTPase homolog 1 S100A4 1.166986 0.016164 2.491973 Up S100 calcium binding protein A4 MCUB 1.166718 0.006693 2.833057 Up mitochondrial calcium uniporter dominant negative subunit beta TBX3 1.165657 0.008631 2.737167 Up T-box transcription factor 3 CCRL2 1.165608 0.016341 2.487591 Up C-C motif chemokine r eceptor like 2 GAS1 1.160359 0.001128 3.461882 Up growth arrest specific 1 PRRG2 1.158664 0.002386 3.205164 Up proline rich and Gla domain 2 SMAD9 1.155664 0.01885 2.429755 Up SMAD family member 9 MAFF 1.152268 0.009135 2.715513 Up MAF bZIP transcription factor F CHURC1- FNTB 1.151101 0.016262 2.489536 Up CHURC1-FNTB readthrough APLN 1.150376 0.001736 3.315353 Up apelin ANXA2 1.146668 0.009848 2.686715 Up annexin A2 PROSER2 1.146067 0.008004 2.76582 Up proline and serine rich 2 SIX2 1.145783 0.036472 2.151024 Up SIX homeobox 2 CGNL1 1.14219 0.004014 3.020559 Up cingulin like 1 TP63 1.141348 0.004449 2.983357 Up tumor protein p63 SAMD4A 1.140967 0.000233 3.974544 Up sterile alpha motif domain containing 4A ARHGAP11B 1.140431 0.00483 2.953443 Up Rho GTPase activating protein 11B LIMS2 1.140203 0.002117 3.246837 Up LIM zinc finger domain containing 2 GAREM2 1.139877 0.00321 3.100578 Up GRB2 associated regulator of MAPK1 subtype 2 PODN 1.139282 0.008706 2.733877 Up podocan HSD17B1 1.138351 0.004828 2.95362 Up hydroxysteroid 17-beta dehydrogenase 1 SLC5A3 1.134496 0.013885 2.552594 Up solute carrier family 5 member 3 GABRR2 1.133917 0.003285 3.09243 Up gamma-aminobutyric acid type A receptor subunit rho2 PLEKHG4B 1.13351 0.008075 2.762472 Up pleckstrin homology and RhoGEF domain containing G4B SALL3 1.132245 0.021719 2.371574 Up spalt like transcription factor 3 NDNF 1.131191 0.008067 2.762818 Up neuron derived neurotrophic factor NFKB2 1.130087 0.005272 2.921405 Up nuclear factor kappa B subunit 2 BCL6B 1.129207 0.017224 2.466378 Up BCL6B transcription repressor SKIC2 1.128342 0.004153 3.008324 Up SKI2 subunit of superkiller complex SMTN 1.126927 0.001114 3.465956 Up smoothelin VSIG2 1.126544 0.014904 2.524439 Up V-set and immunoglobulin domain containing 2 GDF11 1.124801 0.002151 3.241275 Up growth differentiation factor 11 PCAT19 1.124336 0.005755 2.889119 Up prostate cancer associated transcript 19 FLOT1 1.12052 0.01745 2.461099 Up flotillin 1 PIRT 1.118138 0.025372 2.306739 Up phosphoinositide interacting regulator of transient receptor potential channels CLEC18B 1.116421 0.005614 2.898296 Up C-type lectin domain family 18 member B TIE1 1.112101 0.005148 2.930135 Up tyrosine kinase with immunoglobulin like and EGF like domains 1 TNFRSF10D 1.110766 0.019635 2.413086 Up TNF receptor superfamily member 10d (which was not certified by peer review) is the author/funder. 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The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint TUBAL3 1.108463 0.007923 2.769668 Up tubulin alpha like 3 HPSE2 1.108352 0.00676 2.829303 Up heparanase 2 (inactive) PPP2R1B 1.10773 0.000854 3.554935 Up protein phosphatase 2 scaffold subunit Abeta KIT 1.107729 0.03544 2.163586 Up KIT proto-oncogene, receptor tyrosine kinase SMTNL2 1.105379 0.040546 2.104315 Up smoothelin like 2 MYCT1 1.102668 0.008936 2.723961 Up MYC target 1 BTNL9 1.102347 0.006055 2.870337 Up butyrophilin like 9 MEDAG 1.092903 0.022738 2.352564 Up mesenteric estrogen dependent adipogenesis LRRC32 1.090509 0.012415 2.59671 Up leucine rich repeat containing 32 NHEJ1 1.089862 0.003804 3.039945 Up non-homologous end joining factor 1 GPER1 1.085035 0.001443 3.37857 Up G protein-coupled estrogen receptor 1 TMEM54 1.083939 5.03E-05 4.448603 Up transmembrane protein 54 NWD1 1.083211 0.000707 3.617194 Up NACHT and WD repeat domain containing 1 MPG 1.0808 0.013811 2.554728 Up N-methylpurine DNA glycosylase RUNX3 1.079143 0.03406 2.180892 Up RUNX family transcription factor 3 RGS9BP 1.076534 0.002902 3.136414 Up regulator of G protein signaling 9 binding protein ITGB5 1.076145 0.000283 3.913599 Up integrin subunit beta 5 SLC7A2 1.073162 0.015178 2.51718 Up solute carrier family 7 member 2 ATP10A 1.073015 0.004337 2.992621 Up ATPase phospholipid transporting 10A (putative) DPEP2 1.071511 0.006189 2.862186 Up dipeptidase 2 DSP 1.068185 0.007614 2.784677 Up desmoplakin DXO 1.066688 0.003442 3.075755 Up decappingexoribonuclease MFSD2A 1.066658 0.002521 3.185958 Up major facilitator superfamily domain containing 2A ALPL 1.06569 0.007124 2.809714 Up alkaline phosphatase, biomineralization associated RTL9 1.065649 0.022704 2.35319 Up retrotransposon Gag like 9 RGL2 1.061967 0.00027 3.928165 Up ral guanine nucleotide dissociation stimulator like 2 CYP1A1 1.061172 0.02255 2.356015 Up cytochrome P450 family 1 subfamily A member 1 CCDC141 1.059179 0.006691 2.833163 Up coiled-coil domain containing 141 ADORA2A 1.051817 0.010151 2.675033 Up adenosine A2a receptor HNF4G 1.050752 0.043518 2.072761 Up hepatocyte nuclear factor 4 gamma PRICKLE4 1.050474 0.038203 2.130646 Up prickle planar cell polarity protein 4 FOXO4 1.048717 0.000419 3.787568 Up forkhead box O4 PYGM 1.048448 0.00073 3.60688 Up glycogen phosphorylase, muscle associated LSR 1.046709 0.015884 2.498988 Up lipolysis stimulated lipoprotein receptor HSP90AA1 1.041471 0.004266 2.998561 Up heat shock protein 90 alpha family class A member 1 PRELP 1.041013 0.004317 2.994268 Up proline and arginine rich end leucine rich repeat protein HGFAC 1.040979 0.028903 2.251576 Up HGF activator SLC6A12 1.039043 0.002511 3.187336 Up solute carrier family 6 member 12 CACNA1H 1.035066 0.000906 3.535237 Up calcium voltage-gated channel subunit alpha1 H APOBEC3F 1.034591 0.000235 3.97235 Up apolipoprotein B mRNA editing enzyme catalytic subunit 3F (which was not certified by peer review) is the author/funder. 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The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint SHISA3 1.026422 0.031136 2.219692 Up shisa family member 3 GBP2 1.024907 0.013941 2.550995 Up guanylate binding protein 2 WNK4 1.024792 0.038583 2.126281 Up WNK lysine deficient protein kinase 4 KCNG2 1.022692 0.005874 2.881546 Up potassium voltage-gated channel modifier subfamily G member 2 TMEM204 1.021692 0.00991 2.684271 Up transmembrane protein 204 SIX5 1.021067 0.003562 3.063527 Up SIX homeobox 5 HSPA12B 1.019112 0.004329 2.993311 Up heat shock protein family A (Hsp70) member 12B CCL16 1.017769 0.025084 2.31155 Up C-C motif chemokine ligand 16 DIO3 1.01673 0.009582 2.697211 Up iodothyroninedeiodinase 3 KANK2 1.016204 0.001807 3.301473 Up KN motif and ankyrin repeat domains 2 HSPB7 1.01552 0.004453 2.983077 Up heat shock protein family B (small) member 7 EVA1B 1.013791 0.010467 2.663188 Up eva-1 homolog B NOG 1.013273 0.005574 2.90089 Up noggin PTGER4 1.012911 0.034792 2.171639 Up prostaglandin E receptor 4 SLCO4A1 1.01269 0.009313 2.708154 Up solute carrier organic anion transporter family member 4A1 MS4A14 1.012306 0.033099 2.193302 Up membrane spanning 4-domains A14 EPHA2 1.011832 0.010997 2.644063 Up EPH receptor A2 RBMS2 1.010902 0.00368 3.051849 Up RNA binding motif single stranded interacting protein 2 C11orf91 1.006757 0.029103 2.248636 Up chromosome 11 open reading frame 91 FAM89A 1.00647 0.002888 3.138093 Up family with sequence similarity 89 member A ZFP36L2 1.006289 0.002877 3.13942 Up ZFP36 ring finger protein like 2 ITPRIP 1.003532 0.009459 2.702178 Up inositol 1,4,5-trisphosphate receptor interacting protein TAB2 1.002925 0.023994 2.330152 Up TGF-beta activated kinase 1 (MAP3K7) binding protein 2 PRKD2 1.002547 0.002028 3.26163 Up protein kinase D2 TMPRSS7 1.001336 0.010731 2.653556 Up transmembrane serine protease 7 GNG12 0.999929 0.017695 2.455449 Up G protein subunit gamma 12 CCDC194 0.998806 0.037809 2.13521 Up coiled-coil domain containing 194 SOX21 0.998345 0.006806 2.826823 Up SRY-box transcription factor 21 MFNG 0.996529 0.011474 2.627551 Up MFNG O-fucosylpeptide 3-beta-N- acetylglucosaminyltransferase FAM110D 0.995791 0.010498 2.662037 Up family with sequence similarity 110 member D STUM 0.993152 0.03253 2.20081 Up stum, mechanosensory transduction mediator homolog PZP 0.991772 0.02282 2.351064 Up PZP alpha-2-macroglobulin like C15orf62 0.990928 0.010583 2.65892 Up chromosome 15 open reading frame 62 CD34 0.990688 0.020577 2.393859 Up CD34 molecule DPPA4 0.987102 0.049737 2.012385 Up developmental pluripotency associated 4 KCNQ1 0.986506 0.04947 2.014833 Up potassium voltage-gated channel subfamily Q member 1 LMAN1L 0.986054 0.013619 2.560257 Up lectin, mannose binding 1 like KRT19 0.985331 0.025416 2.306017 Up keratin 19 ITIH5 0.984336 0.001769 3.308835 Up inter-alpha-trypsin inhibitor heavy chain 5 SRPX2 0.98275 0.022346 2.359776 Up sushi repeat containing protein X-linked 2 (which was not certified by peer review) is the author/funder. 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The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint NQO1 0.982266 0.026252 2.292392 Up NAD(P)H quinone dehydrogenase 1 TMEM92 0.980752 0.017005 2.471549 Up transmembrane protein 92 PAQR5 0.980659 0.024106 2.32821 Up progestin and adipoQ receptor family member 5 SETD9 0.978771 0.002339 3.21208 Up SET domain containing 9 YAP1 0.978696 0.008106 2.760993 Up Yes1 associated transcriptional regulator OLFML1 0.976707 0.009496 2.700663 Up olfactomedin like 1 SLC15A3 0.975913 0.009119 2.716197 Up solute carrier family 15 member 3 ESAM 0.972978 0.008601 2.738512 Up endothelial cell adhesion molecule CDK2AP1 0.972132 0.003266 3.094421 Up cyclin dependent kinase 2 associated protein 1 PLSCR2 0.971319 0.03939 2.117137 Up phospholipid scramblase 2 AK4 0.970351 0.001825 3.298225 Up adenylate kinase 4 GSDMD 0.970153 0.002244 3.226553 Up gasdermin D DES 0.969958 0.040295 2.107069 Up desmin ATP5MGL 0.967433 0.001161 3.452078 Up ATP synthase membrane subunit g like BACE2 0.966642 0.001236 3.430949 Up beta-secretase 2 ZC3H11B 0.966065 0.01182 2.615957 Up zinc finger CCCH-type containing 11B PEAR1 0.964952 0.023153 2.345046 Up platelet endothelial aggregation receptor 1 DOK2 0.962644 0.046568 2.04227 Up docking protein 2 CYP27B1 0.96255 0.037189 2.142485 Up cytochrome P450 family 27 subfamily B member 1 ADRA2C 0.961678 0.001398 3.389361 Up adrenoceptor alpha 2C TTN 0.961317 0.002735 3.157215 Up titin DHX16 0.958103 0.011238 2.635618 Up DEAH-box helicase 16 TRIM34 0.956067 0.001614 3.340409 Up tripartite motif containing 34 COL8A2 0.955364 0.009624 2.695543 Up collagen type VIII alpha 2 chain MMRN2 0.954608 0.007207 2.805328 Up multimerin 2 ECM2 0.951991 0.011993 2.610277 Up extracellular matrix protein 2 CXCR1 0.951791 0.046706 2.04094 Up C-X-C motif chemokine receptor 1 ISYNA1 0.951734 0.002518 3.186346 Up inositol-3-phosphate synthase 1 DHH 0.951144 0.017464 2.460782 Up desert hedgehog signaling molecule STIP1 0.947971 0.005213 2.925569 Up stress induced phosphoprotein 1 NPR1 0.947495 0.008934 2.724039 Up natriuretic peptide receptor 1 NES 0.945507 0.001593 3.344808 Up nestin LSM2 0.945275 0.008328 2.75076 Up LSM2 homolog, U6 small nuclear RNA and mRNA degradation associated RCN1 0.945041 0.04963 2.013368 Up reticulocalbin 1 MEX3A 0.944984 0.020045 2.404618 Up mex-3 RNA binding family member A MROH6 0.944756 0.012172 2.604476 Up maestro heat like repeat family member 6 CSF1 0.94253 0.007709 2.77998 Up colony stimulating factor 1 CDC42BPG 0.941158 0.018584 2.435533 Up CDC42 binding protein kinase gamma TMEM47 0.940914 0.005774 2.887909 Up transmembrane protein 47 NXN 0.939936 0.009874 2.685693 Up nucleoredoxin PDYN 0.938558 0.005624 2.897631 Up prodynorphin CMTM3 0.93726 0.001885 3.287021 Up CKLF like MARVEL transmembrane domain containing 3 (which was not certified by peer review) is the author/funder. 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The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint LRATD2 0.933556 0.000961 3.515565 Up LRAT domain containing 2 TRIM5 0.932464 0.002081 3.252745 Up tripartite motif containing 5 CHKA-DT 0.932235 0.02234 2.359885 Up CHKA divergent transcript VANGL2 0.930701 0.001161 3.452001 Up VANGL planar cell polarity protein 2 SLC39A8 0.929357 0.007228 2.804267 Up solute carrier family 39 member 8 FAM124B 0.928174 0.010087 2.677472 Up family with sequence similarity 124 member B LRRC3 0.928007 0.012916 2.581156 Up leucine rich repeat containing 3 COL1A2 0.927022 0.024808 2.316195 Up collagen type I alpha 2 chain C2 0.926615 0.01586 2.499588 Up complement C2 FZD1 0.926187 0.002483 3.191162 Up frizzled class receptor 1 PIP5K1C 0.925853 0.005655 2.895609 Up phosphatidylinositol-4-phosphate 5-kinase type 1 gamma SP5 0.925737 0.0394 2.117025 Up Sp5 transcription factor EFNB1 0.925407 0.001297 3.414633 Up ephrin B1 SLC6A16 0.925195 0.003658 3.054016 Up solute carrier family 6 member 16 SQOR 0.923925 0.010517 2.661353 Up sulfidequinoneoxidoreductase SMAD7 0.923089 0.001186 3.445055 Up SMAD family member 7 CDC42EP5 0.922648 0.037552 2.138208 Up CDC42 effector protein 5 ABCB1 0.92119 0.020123 2.403021 Up ATP binding cassette subfamily B member 1 ANXA3 0.92113 0.02643 2.289532 Up annexin A3 MMP14 0.920084 0.003632 3.056488 Up matrix metallopeptidase 14 SLC12A7 0.917694 0.012137 2.605589 Up solute carrier family 12 member 7 TINAGL1 0.917052 0.00978 2.689369 Up tubulointerstitial nephritis antigen like 1 SYPL2 0.916953 0.013133 2.574602 Up synaptophysin like 2 C17orf67 0.916664 0.001731 3.316301 Up chromosome 17 open reading frame 67 RRAS 0.914001 0.004746 2.959892 Up RAS related TNFRSF18 0.912683 0.02153 2.375182 Up TNF receptor superfamily member 18 PEX12 0.912174 0.011814 2.61614 Up peroxisomal biogenesis factor 12 CELSR1 0.912102 0.000882 3.544235 Up cadherin EGF LAG seven-pass G-type receptor 1 DDAH2 0.911632 0.011632 2.622212 Up dimethylargininedimethylaminohydrolase 2 EMP3 0.908913 0.016102 2.493501 Up epithelial membrane protein 3 ID3 0.908675 0.020182 2.401805 Up inhibitor of DNA binding 3 ZIC5 0.908645 0.02368 2.335661 Up Zic family member 5 TGFB2 0.907103 0.005973 2.875391 Up transforming growth factor beta 2 CLTB 0.906539 0.000312 3.881841 Up clathrin light chain B PCDH18 0.906064 0.002543 3.182853 Up protocadherin 18 LCAT 0.904912 0.002628 3.17138 Up lecithin-cholesterol acyltransferase ADAM33 0.904712 0.002171 3.238104 Up ADAM metallopeptidase domain 33 KCNN3 0.904465 0.005813 2.885402 Up potassium calcium-activated channel subfamily N member 3 IL2RG 0.903778 0.011972 2.610951 Up interleukin 2 receptor subunit gamma ITPR3 0.90365 0.017526 2.459344 Up inositol 1,4,5-trisphosphate receptor type 3 PRKX 0.903406 0.005713 2.891851 Up protein kinase cAMP-dependent X-linked catalytic subunit NFATC1 0.903227 0.01482 2.526692 Up nuclear factor of activated T cells 1 (which was not certified by peer review) is the author/funder. 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The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint RNA5S12 0.90099 0.02632 2.29129 Up RNA, 5S ribosomal 12 RNA5S11 0.90099 0.02632 2.29129 Up RNA, 5S ribosomal 11 RNA5S3 0.90099 0.02632 2.29129 Up RNA, 5S ribosomal 3 RNA5S1 0.90099 0.02632 2.29129 Up RNA, 5S ribosomal 1 RNA5S5 0.90099 0.02632 2.29129 Up RNA, 5S ribosomal 5 RNA5S10 0.90099 0.02632 2.29129 Up RNA, 5S ribosomal 10 RNA5S8 0.90099 0.02632 2.29129 Up RNA, 5S ribosomal 8 RNA5S17 0.90099 0.02632 2.29129 Up RNA, 5S ribosomal 17 RNA5S4 0.90099 0.02632 2.29129 Up RNA, 5S ribosomal 4 RNA5S6 0.90099 0.02632 2.29129 Up RNA, 5S ribosomal 6 RNA5S14 0.90099 0.02632 2.29129 Up RNA, 5S ribosomal 14 RNA5S2 0.90099 0.02632 2.29129 Up RNA, 5S ribosomal 2 RNA5S15 0.90099 0.02632 2.29129 Up RNA, 5S ribosomal 15 RNA5S16 0.90099 0.02632 2.29129 Up RNA, 5S ribosomal 16 RNA5S7 0.90099 0.02632 2.29129 Up RNA, 5S ribosomal 7 RNA5S13 0.90099 0.02632 2.29129 Up RNA, 5S ribosomal 13 NAIP 0.900498 0.005102 2.933464 Up NLR family apoptosis inhibitory protein CGAS 0.898364 0.021126 2.38301 Up cyclic GMP-AMP synthase FBXL7 0.897947 0.001729 3.316773 Up F-box and leucine rich repeat protein 7 SHE 0.897255 0.003238 3.097537 Up Src homology 2 domain containing E C21orf62 0.895882 0.007184 2.806557 Up chromosome 21 open reading frame 62 MAPK4 0.893293 0.001036 3.490374 Up mitogen-activated protein kinase 4 FAM83G 0.893209 0.007072 2.812422 Up family with sequence similarity 83 member G SLC16A3 0.89258 0.026184 2.293486 Up solute carrier family 16 member 3 PROM1 0.891505 0.025524 2.304231 Up prominin 1 DUSP1 0.891268 0.020293 2.399566 Up dual specificity phosphatase 1 TERLR1 0.89093 0.004992 2.941415 Up TERT regulating lncRNA 1 ASPN 0.889761 0.023116 2.345699 Up asporin TPRG1 0.888638 0.004392 2.988004 Up tumor protein p63 regulated 1 RNA5-8SN5 0.88855 0.040416 2.105743 Up RNA, 5.8S ribosomal N5 RNA5-8SN3 0.88855 0.040416 2.105743 Up RNA, 5.8S ribosomal N3 RNA5-8SN4 0.88855 0.040416 2.105743 Up RNA, 5.8S ribosomal N4 RNA5-8SN1 0.88855 0.040416 2.105743 Up RNA, 5.8S ribosomal N1 RNA5-8SN2 0.88855 0.040416 2.105743 Up RNA, 5.8S ribosomal N2 CDH23 0.88842 0.002084 3.252221 Up cadherin related 23 CYYR1 0.886979 0.028173 2.262471 Up cysteine and tyrosine rich 1 CARD10 0.885219 0.03822 2.130446 Up caspase recruitment domain family member 10 ORAI1 0.884766 0.011565 2.624446 Up ORAI calcium release-activated calcium modulator 1 ARHGEF19 0.884506 0.012864 2.582759 Up Rho guanine nucleotide exchange factor 19 EMCN 0.884441 0.01442 2.537606 Up endomucin PLA2G5 0.884288 0.009085 2.717608 Up phospholipase A2 group V NEAT1 0.884286 0.010418 2.665021 Up nuclear paraspeckle assembly transcript 1 (which was not certified by peer review) is the author/funder. 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The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint TBX15 0.882748 0.02331 2.342219 Up T-box transcription factor 15 CLIC5 0.88186 0.004425 2.985338 Up chloride intracellular channel 5 GGN 0.881647 0.009017 2.720517 Up gametogenetin C8orf88 0.880559 0.000173 4.067767 Up chromosome 8 open reading frame 88 TCAP 0.879998 0.023 2.34779 Up titin-cap SERTAD1 0.879226 0.013874 2.552925 Up SERTA domain containing 1 BST2 0.878676 0.023825 2.333102 Up bone marrow stromal cell antigen 2 RDH10 0.878622 0.008747 2.732109 Up retinol dehydrogenase 10 YBX3 0.877075 0.031145 2.219578 Up Y-box binding protein 3 MYRFL 0.876928 0.011868 2.614364 Up myelin regulatory factor like ARHGEF16 0.876589 0.002066 3.255218 Up Rho guanine nucleotide exchange factor 16 SOX17 0.873843 0.035062 2.168267 Up SRY-box transcription factor 17 LY75 0.873283 0.039464 2.116303 Up lymphocyte antigen 75 CDK2AP2 0.871899 0.006753 2.829716 Up cyclin dependent kinase 2 associated protein 2 AQP6 0.87107 0.006614 2.837496 Up aquaporin 6 BMP6 0.870228 0.03407 2.180762 Up bone morphogenetic protein 6 ARHGEF15 0.870089 0.016713 2.478537 Up Rho guanine nucleotide exchange factor 15 BCAM 0.86841 0.005195 2.926801 Up basal cell adhesion molecule (Lutheran blood group) FGF11 0.86825 0.003956 3.025824 Up fibroblast growth factor 11 SLC29A4 0.867702 0.008302 2.751941 Up solute carrier family 29 member 4 MRGPRF 0.865973 0.002634 3.170502 Up MAS related GPR family member F SPR 0.865636 0.027137 2.278362 Up sepiapterinreductase CMTM8 0.865581 0.025243 2.308888 Up CKLF like MARVEL transmembrane domain containing 8 LATS2 0.864575 0.020319 2.399033 Up large tumor suppressor kinase 2 ZIC2 0.864506 0.016899 2.474068 Up Zic family member 2 RFLNB 0.862396 0.00477 2.958054 Up refilin B RGS16 0.862308 0.00715 2.808319 Up regulator of G protein signaling 16 MMP23B 0.861711 0.024533 2.320858 Up matrix metallopeptidase 23B EFNA4 0.861112 0.036806 2.147021 Up ephrin A4 TSPAN11 0.860908 0.005973 2.875383 Up tetraspanin 11 METTL7B 0.859718 0.028224 2.2617 Up methyltransferase like 7B OLFM2 0.853388 0.004605 2.970828 Up olfactomedin 2 SEMA3G 0.852317 0.007622 2.784276 Up semaphorin 3G SERHL2 0.8523 0.002674 3.165195 Up serine hydrolase like 2 CFAP47 0.844559 0.017724 2.454783 Up cilia and flagella associated protein 47 SLC7A5 0.843468 0.014502 2.535332 Up solute carrier family 7 member 5 LILRA2 0.843191 0.038393 2.128461 Up leukocyte immunoglobulin like receptor A2 FAM131C 0.842357 0.000821 3.567696 Up family with sequence similarity 131 member C NFATC4 0.840307 0.005502 2.905737 Up nuclear factor of activated T cells 4 EDN3 0.839325 0.038962 2.121965 Up endothelin 3 FENDRR 0.839231 0.022791 2.351595 Up FOXF1 adjacent non-coding developmental regulatory RNA IL12A 0.838297 0.047909 2.02942 Up interleukin 12A (which was not certified by peer review) is the author/funder. 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The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint ESPL1 0.837905 0.018031 2.447824 Up extra spindle pole bodies like 1, separase FAM27E3 0.837762 0.017295 2.464717 Up family with sequence similarity 27 member E3 AHRR 0.836907 0.042521 2.083126 Up aryl hydrocarbon r eceptor repressor TCF7L1 0.8368 0.002067 3.255076 Up transcription factor 7 like 1 CAVIN1 0.836663 0.003739 3.046156 Up caveolae associated protein 1 CMTM7 0.834266 0.020768 2.390041 Up CKLF like MARVEL transmembrane domain containing 7 ST8SIA6 0.83372 0.002594 3.175878 Up ST8 alpha-N-acetyl-neuraminide alpha-2,8- sialyltransferase 6 CFAP300 0.833264 0.015217 2.51616 Up cilia and flagella associated protein 300 VAX2 0.832643 0.026445 2.289291 Up ventral anterior homeobox 2 KLF4 0.83234 0.027365 2.274829 Up KLF transcription factor 4 SLC12A3 0.831629 0.038225 2.130389 Up solute carrier family 12 member 3 MID1IP1 0.831031 0.010169 2.674326 Up MID1 interacting protein 1 IL17RD 0.830837 0.031975 2.208247 Up interleukin 17 receptor D FGD5 0.829992 0.003235 3.097851 Up FYVE, RhoGEF and PH domain containing 5 SLC43A3 0.82908 0.005812 2.885488 Up solute carrier family 43 member 3 SMAGP 0.828337 0.00252 3.186013 Up small cell adhesion glycoprotein CPLANE2 0.828192 0.000256 3.945709 Up ciliogenesis and planar polarity effector complex subunit 2 RHOQ 0.8259 0.003631 3.056667 Up ras homolog family member Q PPP1R13L 0.825168 0.007989 2.766514 Up protein phosphatase 1 regulatory subunit 13 like C1QL1 0.824638 0.011817 2.616032 Up complement C1q like 1 RCC1 0.824262 0.009104 2.716817 Up regulator of chromosome condensation 1 PGF 0.822594 0.031062 2.220722 Up pl acental growth factor MECOM 0.820437 0.027971 2.265526 Up MDS1 and EVI1 complex locus CDKN2C 0.817349 0.001164 3.45123 Up cyclin dependent kinase inhibitor 2C EDNRB 0.817198 0.004117 3.011448 Up endothelin r eceptor type B MDGA1 0.816787 0.000173 4.069133 Up MAM domain containing glycosylphosphatidylinositol anchor 1 RASL12 0.816698 0.010597 2.65841 Up RAS like family 12 IFI27L2 0.816029 0.029639 2.240829 Up interferon alpha inducible protein 27 like 2 STEAP3 0.814893 0.009873 2.68571 Up STEAP3 metalloreductase KIF1C 0.812965 0.007253 2.802933 Up kinesin family member 1C C9orf153 0.812227 0.019675 2.412254 Up chromosome 9 open reading frame 153 EPAS1 0.812074 0.007212 2.805087 Up endothelial PAS domain protein 1 LMO2 0.809637 0.002599 3.175271 Up LIM domain only 2 ARSF 0.808014 0.02088 2.387837 Up arylsulfatase F TAS1R3 0.807945 0.041453 2.094474 Up taste 1 receptor member 3 NECTIN2 0.807075 0.007109 2.810488 Up nectin cell adhesion molecule 2 WWTR1 0.806987 0.012076 2.607564 Up WW domain containing transcription regulator 1 CASS4 0.804783 0.009338 2.707135 Up Cas scaffold protein family member 4 RASIP1 0.803676 0.006253 2.858365 Up Ras interacting protein 1 RNF152 0.803555 0.005806 2.885839 Up ring finger protein 152 FGR 0.802382 0.03326 2.191207 Up FGR proto-oncogene, Src family tyrosine kinase (which was not certified by peer review) is the author/funder. 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The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint PECAM1 0.800222 0.027295 2.275912 Up platelet and endothelial cell adhesion molecule 1 MMP2 0.799852 0.038186 2.130843 Up matrix metallopeptidase 2 HSPA2 0.799116 0.03462 2.173789 Up heat shock protein family A (Hsp70) member 2 SIX4 0.798852 0.005244 2.923393 Up SIX homeobox 4 ACVRL1 0.795456 0.01794 2.449882 Up activin A receptor like type 1 HMGN5 0.794832 0.001636 3.335775 Up high mobility group nucleosome binding domain 5 FN1 0.794514 0.017846 2.452017 Up fibronectin 1 ZFPM1 0.793987 0.003564 3.0633 Up zinc finger protein, FOG family member 1 EBF4 0.793097 0.017395 2.462367 Up EBF family member 4 PHETA2 0.791164 0.013564 2.561846 Up PH domain containing endocytic trafficking adaptor 2 USHBP1 0.789213 0.01285 2.583183 Up USH1 protein network component harmonin binding protein 1 PLPP4 0.788743 0.004243 3.000571 Up phospholipid phosphatase 4 DDR2 0.788576 0.005025 2.938979 Up discoidin domain receptor tyrosine kinase 2 LMCD1 0.7884 0.008264 2.753686 Up LIM and cysteine rich domains 1 MAP1LC3C 0.787786 0.041586 2.093052 Up microtubule associated protein 1 light chain 3 gamma JMJD6 0.787257 0.001667 3.329343 Up jumonji domain containing 6, arginine demethylase and lysine hydroxylase ZC3H12A 0.786732 0.044857 2.05915 Up zinc finger CCCH-type containing 12A RASSF3 0.786693 0.01257 2.591846 Up Ras association domain family member 3 INHBB 0.786327 0.014253 2.54223 Up inhibin subunit beta B RASA4 0.785832 0.005468 2.907958 Up RAS p21 protein activator 4 ITGA5 0.785718 0.029495 2.242909 Up integrin subunit alpha 5 CLIC1 0.784247 0.033084 2.193507 Up chloride intracellular channel 1 SLC2A9 0.783281 0.00604 2.87123 Up solute carrier family 2 member 9 ZSWIM9 0.782972 0.00078 3.584665 Up zinc finger SWIM-type containing 9 ARHGAP42 0.782454 0.031479 2.214985 Up Rho GTPase activating protein 42 FZD2 0.782331 0.028348 2.259826 Up frizzled class receptor 2 CEBPA-DT 0.781679 0.002468 3.193331 Up CEBPA divergent transcript LRP10 0.781037 0.009485 2.701129 Up LDL receptor related protein 10 TGFB1I1 0.77889 0.001815 3.300093 Up transforming growth factor beta 1 induced transcript 1 POMZP3 0.778886 0.026422 2.289663 Up POM121 and ZP3 fusion HYAL4 0.77875 0.042709 2.08116 Up hyaluronidase 4 CLDN9 0.778696 0.022792 2.351579 Up claudin 9 C11orf96 0.778464 0.034523 2.17502 Up chromosome 11 open reading frame 96 S100A10 0.77816 0.048474 2.024091 Up S100 calcium binding protein A10 KANK3 0.778011 0.030727 2.22538 Up KN motif and ankyrin repeat domains 3 SAMD9 0.777941 0.033993 2.181748 Up sterile alpha motif domain containing 9 ABCC2 0.777677 0.002268 3.222813 Up ATP binding cassette subfamily C member 2 ADAT3 0.776802 0.006615 2.837442 Up adenosine deaminasetRNA specific 3 PLPPR4 -2.28818 0.008824 -2.72875 Down phospholipid phosphatase related 4 HCG18 -2.24464 0.00085 -3.55618 Down HLA complex group 18 ZBTB41 -2.23271 0.003996 -3.02222 Down zinc finger and BTB domain containing 41 (which was not certified by peer review) is the author/funder. 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The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint HLA-DRB1 -2.20002 0.003538 -3.06594 Down major histocompatibility complex, class II, DR beta 1 RNVU1-7 -2.10776 0.021842 -2.36923 Down RNA, variant U1 small nuclear 7 LY6G5B -2.08247 0.0052 -2.92647 Down lymphocyte antigen 6 family member G5B GTF2H4 -2.0333 0.001629 -3.33723 Down general transcription factor IIH subunit 4 KAT14 -2.03076 0.007002 -2.81619 Down lysine acetyltransferase 14 TRIM26 -1.97525 0.025475 -2.30504 Down tripartite motif containing 26 MPO -1.91726 0.000854 -3.55458 Down myeloperoxidase PWWP4 -1.8984 0.000481 -3.7431 Down PWWP domain containing 4 CSNK2B -1.89153 0.019376 -2.41852 Down casein kinase 2 beta NPIPA5 -1.80979 0.019026 -2.42596 Down nuclear pore complex interacting protein family member A5 VAMP1 -1.78452 0.006879 -2.82279 Down vesicle associated membrane protein 1 PCSK1 -1.77462 0.001243 -3.429 Down proproteinconvertasesubtilisin/kexin type 1 NUAK1 -1.66698 0.00507 -2.93574 Down NUAK family kinase 1 VARS2 -1.59785 0.033237 -2.1915 Down valyl-tRNAsynthetase 2, mitochondrial SST -1.5798 0.00362 -3.05768 Down somatostatin FLT3 -1.57441 0.000254 -3.94816 Down fms related r eceptor tyrosine kinase 3 VGF -1.48561 0.003858 -3.03487 Down VGF nerve growth factor inducible DNAJC5G -1.47579 0.006779 -2.82829 Down DnaJ heat shock protein family (Hsp40) member C5 gamma GAP43 -1.47385 0.017274 -2.46519 Down growth associated protein 43 MAS1 -1.47146 0.047326 -2.03497 Down MAS1 proto-oncogene, G protein-coupled receptor RPH3A -1.39566 0.000738 -3.60323 Down rabphilin 3A PVALB -1.39117 0.024927 -2.31417 Down parvalbumin TARBP1 -1.38426 0.000663 -3.63813 Down TAR (HIV-1) RNA binding protein 1 UMODL1 -1.37982 0.00618 -2.86277 Down uromodulin like 1 RPP21 -1.36804 0.013949 -2.55077 Down ribonuclease P/MRP subunit p21 TAC1 -1.35023 0.011625 -2.62242 Down tachykinin precursor 1 RFX8 -1.34964 0.003637 -3.05602 Down regulatory factor X8 ZNF112 -1.3333 0.005638 -2.89669 Down zinc finger protein 112 LY75-CD302 -1.33029 0.033984 -2.18185 Down LY75-CD302 readthrough PRORP -1.32416 0.027271 -2.27628 Down protein only RNase P catalytic subunit CIP2A -1.32257 0.002071 -3.25436 Down cellular inhibitor of PP2A LAMB1 -1.29982 0.041593 -2.09297 Down laminin subunit beta 1 THY1 -1.28919 0.018993 -2.42668 Down Thy-1 cell surface antigen TAFA1 -1.28618 0.007103 -2.8108 Down TAFA chemokine like family member 1 SCN8A -1.28616 0.003259 -3.09524 Down sodium voltage-gated channel alpha subunit 8 STMN2 -1.27819 0.042411 -2.08429 Down stathmin 2 FAM66E -1.27564 0.001291 -3.41621 Down family with sequence similarity 66 member E OPN4 -1.2498 0.005573 -2.90096 Down opsin 4 CHGB -1.24927 0.003961 -3.02541 Down chromogranin B AK8 -1.24269 0.000703 -3.61923 Down adenylate kinase 8 CKMT1A -1.21464 0.013226 -2.57181 Down creatine kinase, mitochondrial 1A THCAT155 -1.21262 0.003333 -3.08719 Down thyroid cancer-associated transcript 155 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint CORO6 -1.20997 0.0442 -2.06579 Down coronin 6 PNMA3 -1.20285 0.001989 -3.2684 Down PNMA family member 3 RBM11 -1.20244 0.001481 -3.36963 Down RNA binding motif protein 11 FAM156B -1.1947 0.0065 -2.84395 Down family with sequence similarity 156 member B DLAT -1.18101 0.02872 -2.25429 Down dihydrolipoamide S-acetyltransferase TRANK1 -1.1741 0.002897 -3.13693 Down tetratricopeptide repeat and ankyrin repeat containing 1 SYT2 -1.17241 0.002068 -3.25491 Down synaptotagmin 2 MDH1B -1.17202 0.002154 -3.24085 Down malate dehydrogenase 1B NELL1 -1.1633 0.000527 -3.71355 Down neural EGFL like 1 SPARCL1 -1.15799 0.005105 -2.93324 Down SPARC like 1 CFAP221 -1.15736 0.002029 -3.26146 Down cilia and flagella associated protein 221 VSNL1 -1.15178 0.015649 -2.50495 Down visinin like 1 CNTN5 -1.14795 0.008998 -2.72131 Down contactin 5 NEUROD6 -1.14631 0.006128 -2.86587 Down neuronal differentiation 6 ABCC12 -1.13973 0.013901 -2.55215 Down ATP binding cassette subfamily C member 12 C11orf21 -1.13045 0.002705 -3.16118 Down chromosome 11 open reading frame 21 NAP1L5 -1.1302 0.001789 -3.30505 Down nucleosome assembly protein 1 like 5 CAMK1G -1.129 0.000162 -4.0886 Down calcium/calmodulin dependent protein kinase IG RGS4 -1.12067 0.012097 -2.60688 Down regulator of G protein signaling 4 RXFP1 -1.11321 0.004831 -2.95338 Down relaxin family peptide receptor 1 CDKL5 -1.1096 0.000156 -4.10099 Down cyclin dependent kinase like 5 ABCF2-H2BK1 -1.10676 0.017797 -2.45312 Down ABCF2-H2BK1 readthrough PCYOX1L -1.09446 0.004024 -3.01969 Down prenylcysteine oxidase 1 like FPGT-TNNI3K -1.09118 0.017299 -2.4646 Down FPGT-TNNI3K readthrough LYRM9 -1.08964 0.004983 -2.9421 Down LYR motif containing 9 VWDE -1.08857 0.013468 -2.56467 Down von Willebrand factor D and EGF domains CLGN -1.08148 0.005749 -2.88949 Down calmegin KCNIP4 -1.0801 0.009415 -2.70399 Down potassium voltage-gated channel interacting protein 4 IL1RAPL2 -1.07954 0.002614 -3.17316 Down interleukin 1 r eceptor accessory protein like 2 GEN1 -1.07753 0.011891 -2.61359 Down GEN1 Holliday junction 5' flap endonuclease SMN1 -1.07407 0.035122 -2.16752 Down survival of motor neuron 1, telomeric SORCS1 -1.07082 0.01367 -2.55879 Down sortilin related VPS10 domain containing receptor 1 ADGRF2 -1.07054 0.025838 -2.29909 Down adhesion G protein-coupled receptor F2 SLC17A6 -1.07044 0.017863 -2.45162 Down solute carrier family 17 member 6 SLC8A3 -1.07009 0.01161 -2.62293 Down solute carrier family 8 member A3 ADCYAP1 -1.06957 0.016282 -2.48904 Down adenylatecyclase activating polypeptide 1 TMEM132E- DT -1.06813 0.005486 -2.90678 Down TMEM132E divergent transcript OCA2 -1.06339 0.001542 -3.35593 Down OCA2 melanosomaltransmembrane protein SVEP1 -1.06012 0.000844 -3.55852 Down sushi, von Willebrand factor type A, EGF and pentraxin domain containing 1 ICA1 -1.05835 0.001046 -3.4872 Down islet cell autoantigen 1 FAM218A -1.05726 0.001355 -3.4 Down family with sequence similarity 218 member A (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint UNC13C -1.05692 0.003311 -3.0896 Down unc-13 homolog C ERICH3 -1.05092 0.002382 -3.2057 Down glutamate rich 3 SCG2 -1.04914 0.013528 -2.56292 Down secretogranin II ZNF891 -1.04814 0.008346 -2.74993 Down zinc finger protein 891 SV2C -1.04804 0.002064 -3.25556 Down synaptic vesicle glycoprotein 2C CDH18 -1.04648 0.003863 -3.03438 Down cadherin 18 ALOX12B -1.03825 0.025828 -2.29926 Down arachidonate 12-lipoxygenase, 12R type CARNS1 -1.03793 0.040493 -2.10489 Down carnosine synthase 1 GAS2 -1.03479 0.007327 -2.79915 Down growth arrest specific 2 MEG3 -1.0345 0.016407 -2.48598 Down maternally expressed 3 CKMT1B -1.03298 0.013683 -2.55841 Down creatine kinase, mitochondrial 1B CROT -1.03204 0.006926 -2.82027 Down carnitine O-octanoyltransferase NAP1L2 -1.02971 0.00561 -2.89852 Down nucleosome assembly protein 1 like 2 STAT4 -1.0296 0.003954 -3.02598 Down signal transducer and activator of transcription 4 OVGP1 -1.02583 0.003099 -3.1131 Down oviductal glycoprotein 1 MSLNL -1.02147 0.006999 -2.81632 Down mesothelin like BEX1 -1.02138 0.003384 -3.08182 Down brain expressed X-linked 1 SERPINI1 -1.01729 0.006317 -2.8546 Down serpin family I member 1 SOSTDC1 -1.01589 0.021824 -2.36958 Down sclerostin domain containing 1 FGF9 -1.01278 0.002133 -3.24428 Down fibroblast growth factor 9 MDH1 -1.01175 0.00863 -2.73723 Down malate dehydrogenase 1 DQX1 -1.00898 0.048982 -2.01935 Down DEAQ-box RNA dependent ATPase 1 NEGR1 -1.00784 0.004562 -2.97426 Down neuronal growth regulator 1 IQGAP3 -1.00773 0.024517 -2.32113 Down IQ motif containing GTPase activating protein 3 TNNI3K -1.00735 0.005006 -2.94039 Down TNNI3 interacting kinase SYT1 -1.00522 0.007335 -2.79872 Down synaptotagmin 1 RNF148 -1.00159 0.00137 -3.39606 Down ring finger protein 148 TRHDE -1.00005 0.034736 -2.17233 Down thyrotropin releasing hormone degrading enzyme SNAP25 -0.99637 0.031201 -2.2188 Down synaptosome associated protein 25 THEMIS -0.99627 0.038606 -2.12602 Down thymocyte selection associated SUV39H1 -0.99581 0.042935 -2.0788 Down SUV39H1 histone lysine methyltransferase RSPH4A -0.9934 0.018534 -2.43663 Down radial spoke head component 4A AGBL4-IT1 -0.99072 0.008284 -2.75276 Down AGBL4 intronic transcript 1 ATP2B1 -0.99028 0.01652 -2.48319 Down ATPase plasma membrane Ca2+ transporting 1 PDE10A -0.98495 0.002123 -3.24578 Down phosphodiesterase 10A GVQW3 -0.9841 0.009357 -2.70633 Down GVQW motif containing 3 FLRT3 -0.98232 0.006664 -2.83467 Down fibronectinleucine rich transmembrane protein 3 GLMN -0.97976 0.002248 -3.22595 Down glomulin, FKBP associated protein KCNH5 -0.97936 0.005944 -2.87716 Down potassium voltage-gated channel subfamily H member 5 TAGLN3 -0.97715 0.004012 -3.02081 Down transgelin 3 NCR3LG1 -0.97569 0.001517 -3.36143 Down natural killer cell cytotoxicity receptor 3 ligand 1 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint EXT1 -0.97216 0.002502 -3.18861 Down exostosinglycosyltransferase 1 NAP1L3 -0.97078 0.003637 -3.05602 Down nucleosome assembly protein 1 like 3 TTC23L -0.96998 0.006719 -2.83163 Down tetratricopeptide repeat domain 23 like SPTLC2 -0.96883 0.019953 -2.4065 Down serine palmitoyltransferase long chain base subunit 2 DLGAP2 -0.96801 0.025455 -2.30538 Down DLG associated protein 2 ACTR2 -0.96677 0.021429 -2.37712 Down actin related protein 2 DYNLT5 -0.96422 0.019534 -2.4152 Down dynein light chain Tctex-type family member 5 SLC27A2 -0.96281 0.02749 -2.27289 Down solute carrier family 27 member 2 GABRA1 -0.95933 0.021983 -2.36657 Down gamma-aminobutyric acid type A receptor subunit alpha1 H2BC15 -0.95826 0.032737 -2.19807 Down H2B clustered histone 15 MSH5 -0.95709 0.031476 -2.21503 Down mutS homolog 5 FGF12 -0.95626 0.00275 -3.15537 Down fibroblast growth factor 12 KCNB2 -0.95523 0.01113 -2.63938 Down potassium voltage-gated channel subfamily B member 2 INHA -0.95442 0.044407 -2.06369 Down inhibin subunit alpha VTN -0.95398 0.002884 -3.13859 Down vitronectin NOXA1 -0.95318 0.00667 -2.83433 Down NADPH oxidase activator 1 FGF14 -0.95216 0.01217 -2.60454 Down fibroblast growth factor 14 ATP1A3 -0.94665 0.00243 -3.19882 Down ATPase Na+/K+ transporting subunit alpha 3 OPCML -0.94631 0.003547 -3.06503 Down opioid binding protein/cell adhesion molecule like SCG5 -0.94616 0.004488 -2.98021 Down secretogranin V TCEAL6 -0.94554 0.008062 -2.76306 Down transcription elongation factor A like 6 PTH2R -0.94497 0.003616 -3.05808 Down parathyroid hormone 2 receptor TRMT9B -0.94325 0.0009 -3.53723 Down tRNAmethyltransferase 9B (putative) PRMT8 -0.94192 0.017445 -2.46123 Down protein arginine methyltransferase 8 DPH6 -0.94088 0.013073 -2.57642 Down diphthamine biosynthesis 6 CPNE4 -0.93498 0.003848 -3.03578 Down copine 4 PKD2L1 -0.93335 0.027562 -2.27178 Down polycystin 2 like 1, transient receptor potential cation channel IARS1 -0.92449 0.025838 -2.29909 Down isoleucyl-tRNAsynthetase 1 SLC6A7 -0.92045 0.003054 -3.11825 Down solute carrier family 6 member 7 SYT4 -0.91933 0.013906 -2.55199 Down synaptotagmin 4 STX16- NPEPL1 -0.91928 0.03474 -2.17229 Down STX16-NPEPL1 readthrough (NMD candidate) SERTM1 -0.91896 0.017202 -2.46689 Down serine rich and transmembrane domain containing 1 MEF2C -0.91574 0.016771 -2.47713 Down myocyte enhancer factor 2C NRN1 -0.91458 0.002995 -3.12516 Down neuritin 1 STXBP5L -0.91434 0.011167 -2.6381 Down syntaxin binding protein 5L DBET -0.91094 0.002553 -3.1815 Down D4Z4 binding element transcript GABRG2 -0.9062 0.010498 -2.66205 Down gamma-aminobutyric acid type A receptor subunit gamma2 KCNK4-TEX40 -0.90555 0.028626 -2.25567 Down KCNK4-TEX40 readthrough RTCA -0.90291 0.033979 -2.18192 Down RNA 3'-terminal phosphate cyclase HCN1 -0.90068 0.027849 -2.26739 Down hyperpolarization activated cyclic nucleotide gated potassium channel 1 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint EPM2AIP1 -0.90025 0.006321 -2.85437 Down EPM2A interacting protein 1 STYK1 -0.89835 0.00923 -2.71159 Down serine/threonine/tyrosine kinase 1 PCP4 -0.89227 0.022083 -2.3647 Down Purkinje cell protein 4 PCDH8 -0.88991 0.003402 -3.07991 Down protocadherin 8 NIPAL2 -0.88963 0.029589 -2.24156 Down NIPA like domain containing 2 FCGR1A -0.88958 0.019881 -2.40797 Down Fc gamma receptor Ia ST8SIA3 -0.88938 0.012426 -2.59636 Down ST8 alpha-N-acetyl-neuraminide alpha-2,8- sialyltransferase 3 KCNH1 -0.88937 0.003124 -3.11025 Down potassium voltage-gated channel subfamily H member 1 YPEL4 -0.88893 0.000948 -3.51998 Down yippee like 4 PARP2 -0.88879 0.000552 -3.69838 Down poly(ADP-ribose) polymerase 2 RCOR3 -0.88824 0.000225 -3.98554 Down REST corepressor 3 ROBO2 -0.88651 0.004138 -3.00964 Down roundabout guidance receptor 2 TRIM45 -0.88634 0.007929 -2.76938 Down tripartite motif containing 45 C2orf16 -0.88624 0.013131 -2.57467 Down chromosome 2 open reading frame 16 CSMD3 -0.88287 0.011067 -2.64159 Down CUB and Sushi multiple domains 3 OSGEP -0.88172 0.000269 -3.92994 Down O-sialoglycoproteinendopeptidase MGAT4C -0.88026 0.004489 -2.98013 Down MGAT4 family member C PCDH11X -0.87924 0.003222 -3.09933 Down protocadherin 11 X-linked RTKN2 -0.87897 0.005757 -2.88898 Down rhotekin 2 RNU5A-1 -0.87711 0.003671 -3.05272 Down RNA, U5A small nuclear 1 DOP1A -0.87634 0.004367 -2.9901 Down DOP1 leucine zipper like protein A ZNF449 -0.87571 0.003193 -3.10248 Down zinc finger protein 449 TCERG1 -0.87558 0.026545 -2.2877 Down transcription elongation regulator 1 TRIM66 -0.87552 0.009854 -2.68647 Down tripartite motif containing 66 PAK1 -0.87433 0.005153 -2.92978 Down p21 (RAC1) activated kinase 1 GSTA4 -0.87335 0.002473 -3.19263 Down glutathione S-transferase alpha 4 CES4A -0.87313 0.00934 -2.70702 Down carboxylesterase 4A RBM3 -0.87297 0.000916 -3.5314 Down RNA binding motif protein 3 ZNF441 -0.87247 0.004843 -2.9525 Down zinc finger protein 441 GOLGA8B -0.86931 0.030726 -2.2254 Down golgin A8 family member B RAB3C -0.86879 0.009123 -2.71605 Down RAB3C, member RAS oncogene family TMEM233 -0.86671 0.043506 -2.07288 Down transmembrane protein 233 NMNAT2 -0.86578 0.002742 -3.15644 Down nicotinamide nucleotide adenylyltransferase 2 GPR61 -0.8647 0.021519 -2.3754 Down G protein-coupled receptor 61 RAB3A -0.86443 0.003879 -3.03291 Down RAB3A, member RAS oncogene family CSRNP3 -0.86436 0.014299 -2.54095 Down cysteine and serine rich nuclear protein 3 TECTA -0.86397 0.025115 -2.31103 Down tectorin alpha SLC44A5 -0.8634 0.009916 -2.68406 Down solute carrier family 44 member 5 SYCP2L -0.86335 0.024949 -2.31381 Down synaptonemal complex protein 2 like SNCB -0.86175 0.008631 -2.73719 Down synuclein beta SPIN2B -0.86099 0.009993 -2.68106 Down spindlin family member 2B HAPLN1 -0.86085 0.046529 -2.04265 Down hyaluronan and proteoglycan link protein 1 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint STMN4 -0.85848 0.008073 -2.76254 Down stathmin 4 NSF -0.85747 0.026481 -2.28872 Down N-ethylmaleimide sensitive factor, vesicle fusing ATPase GRIA3 -0.85645 0.008114 -2.76065 Down glutamate ionotropic receptor AMPA type subunit 3 SIDT1 -0.85644 0.003401 -3.07998 Down SID1 transmembrane family member 1 PRLHR -0.85543 0.025587 -2.3032 Down prolactin releasing hormone receptor CAP2 -0.85492 0.003957 -3.0257 Down cyclase associated actin cytoskeleton regulatory protein 2 ZMYND12 -0.85479 0.01675 -2.47764 Down zinc finger MYND-type containing 12 RIMS2 -0.85449 0.004648 -2.96745 Down regulating synaptic membrane exocytosis 2 THSD7B -0.8541 0.037772 -2.13565 Down thrombospondin type 1 domain containing 7B NEFM -0.8521 0.013795 -2.55518 Down neurofilament medium chain UBXN10 -0.85128 0.0012 -3.441 Down UBX domain protein 10 ZNF304 -0.84933 0.045985 -2.04797 Down zinc finger protein 304 DSN1 -0.84776 0.002032 -3.26108 Down DSN1 component of MIS12 kinetochore complex UBLCP1 -0.84628 0.011977 -2.61078 Down ubiquitin like domain containing CTD phosphatase 1 NIPSNAP3B -0.84502 0.005671 -2.89457 Down nipsnap homolog 3B PLEKHH1 -0.84363 0.037823 -2.13505 Down pleckstrin homology, MyTH4 and FERM domain containing H1 CFAP69 -0.84335 0.004944 -2.94496 Down cilia and flagella associated protein 69 ATAT1 -0.84267 0.0448 -2.05973 Down alpha tubulin acetyltransferase 1 DDX39B -0.84118 0.00014 -4.13501 Down DExD-box helicase 39B RGS7 -0.84084 0.002861 -3.14133 Down regulator of G protein signaling 7 AHI1 -0.84058 0.01605 -2.49482 Down Abelson helper integration site 1 PPP3CA -0.8386 0.004834 -2.95315 Down protein phosphatase 3 catalytic subunit alpha EXOC1 -0.83567 0.005934 -2.87778 Down exocyst complex component 1 CADPS -0.83532 0.007582 -2.78629 Down calcium dependent secretion activator DIRAS3 -0.83531 0.00631 -2.85503 Down DIRAS family GTPase 3 CSMD1 -0.83519 0.016033 -2.49524 Down CUB and Sushi multiple domains 1 STMN1 -0.8321 0.007049 -2.81366 Down stathmin 1 SCN2A -0.82984 0.013132 -2.57464 Down sodium voltage-gated channel alpha subunit 2 ZSCAN1 -0.82978 0.01921 -2.42202 Down zinc finger and SCAN domain containing 1 AA06 -0.82895 0.029587 -2.24158 Down uncharacterized LOC100506677 GAD1 -0.82739 0.004722 -2.96171 Down glutamate decarboxylase 1 LRRC7 -0.82732 0.024539 -2.32076 Down leucine rich repeat containing 7 SCN5A -0.82714 0.046565 -2.04231 Down sodium voltage-gated channel alpha subunit 5 CRHR2 -0.82626 0.013459 -2.56492 Down corticotropin releasing hormone receptor 2 ZNF544 -0.82593 0.042342 -2.08501 Down zinc finger protein 544 ENO2 -0.82379 0.002352 -3.21016 Down enolase 2 DCLK1 -0.81755 0.004621 -2.96957 Down doublecortin like kinase 1 MIAT -0.81704 0.028927 -2.25122 Down myocardial infarction associated transcript CHML -0.81531 0.04708 -2.03732 Down CHM like Rab escort protein CCKBR -0.81514 0.009193 -2.71311 Down cholecystokinin B receptor ATP1B1 -0.81457 0.018085 -2.44661 Down ATPase Na+/K+ transporting subunit beta 1 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint MCF2 -0.8145 0.016691 -2.47906 Down MCF.2 cell line derived transforming sequence CNTNAP2 -0.81392 0.018307 -2.44166 Down contactin associated protein 2 SRI -0.81219 0.011113 -2.63999 Down sorcin TRIM9 -0.81214 0.001411 -3.3862 Down tripartite motif containing 9 ADAT2 -0.81077 0.010241 -2.67162 Down adenosine deaminasetRNA specific 2 UNC50 -0.80877 0.001248 -3.42771 Down unc-50 inner nuclear membrane RNA binding protein ALKBH8 -0.80496 0.026834 -2.28312 Down alkB homolog 8, tRNAmethyltransferase SPTSSB -0.80454 0.021716 -2.37163 Down serine palmitoyltransferase small subunit B PLCH1 -0.80435 0.041878 -2.08993 Down phospholipase C eta 1 KCNH8 -0.80397 0.023839 -2.33286 Down potassium voltage-gated channel subfamily H member 8 VWA5B2 -0.80378 0.010687 -2.65516 Down von Willebrand factor A domain containing 5B2 TTC8 -0.80371 0.011973 -2.61091 Down tetratricopeptide repeat domain 8 HHIP -0.80153 0.002578 -3.17803 Down hedgehog interacting protein RFESD -0.80028 0.042809 -2.08012 Down Rieske Fe-S domain containing GABRB3 -0.79986 0.039405 -2.11697 Down gamma-aminobutyric acid type A receptor subunit beta3 SEC16B -0.7991 0.01812 -2.44582 Down SEC16 homolog B, endoplasmic reticulum export factor SLC25A14 -0.79901 0.00324 -3.09731 Down solute carrier family 25 member 14 TP53TG5 -0.79805 0.016711 -2.47857 Down TP53 target 5 NEK10 -0.79805 0.015119 -2.51873 Down NIMA related kinase 10 SLC25A12 -0.79603 0.001855 -3.29248 Down solute carrier family 25 member 12 TTC21B -0.796 0.00915 -2.71491 Down tetratricopeptide repeat domain 21B SCN1A -0.79555 0.041546 -2.09348 Down sodium voltage-gated channel alpha subunit 1 RBFOX2 -0.79526 0.000538 -3.70681 Down RNA binding fox-1 homolog 2 SLIT2 -0.79472 0.005044 -2.93763 Down slit guidance ligand 2 ZC2HC1A -0.79375 0.000761 -3.59284 Down zinc finger C2HC-type containing 1A RSAD2 -0.79307 0.026904 -2.28201 Down radical S-adenosyl methionine domain containing 2 HAUS7 -0.7919 0.000752 -3.597 Down HAUS augmin like complex subunit 7 SLC4A8 -0.79168 0.021252 -2.38055 Down solute carrier family 4 member 8 AGBL4 -0.79117 0.016804 -2.47634 Down AGBL carboxypeptidase 4 PLK4 -0.79052 0.029935 -2.23659 Down polo like kinase 4 RORB -0.79014 0.00451 -2.97842 Down RAR related orphan r eceptor B ALDH1L2 -0.78998 0.001893 -3.28557 Down aldehyde dehydrogenase 1 family member L2 PAK3 -0.78827 0.003278 -3.09316 Down p21 (RAC1) activated kinase 3 SOWAHB -0.78778 0.00791 -2.77026 Down sosondowahankyrin repeat domain family member B SEMA3A -0.78739 0.006671 -2.83428 Down semaphorin 3A GNG3 -0.7845 0.014509 -2.53515 Down G protein subunit gamma 3 PRR16 -0.7844 0.007995 -2.76624 Down proline rich 16 SV2B -0.78389 0.00981 -2.68818 Down synaptic vesicle glycoprotein 2B FAM81A -0.78334 0.005676 -2.89425 Down family with sequence similarity 81 member A ATP6V1E1 -0.78246 0.002992 -3.12553 Down ATPase H+ transporting V1 subunit E1 UCHL1 -0.78175 0.008278 -2.75306 Down ubiquitin C-terminal hydrolase L1 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint MAP7D2 -0.78002 0.031797 -2.21065 Down MAP7 domain containing 2 SLC4A10 -0.77937 0.015568 -2.50704 Down solute carrier family 4 member 10 GOT1 -0.77868 0.01036 -2.66715 Down glutamic-oxalo acetic transaminase 1 NECAB1 -0.77793 0.004416 -2.98604 Down N-terminal EF-hand calcium binding protein 1 SPAG6 -0.77491 0.033028 -2.19423 Down sperm associated antigen 6 ELAVL4 -0.77453 0.008066 -2.76288 Down ELAV like RNA binding protein 4 BTBD8 -0.77056 0.015302 -2.51393 Down BTB domain containing 8 ZNF711 -0.76987 0.028177 -2.2624 Down zinc finger protein 711 R3HDM1 -0.76973 0.019257 -2.42103 Down R3H domain containing 1 RAB6C -0.76886 0.039852 -2.11197 Down RAB6C, member RAS oncogene family GK -0.76882 0.017572 -2.45827 Down glycerol kinase ADAM23 -0.76845 0.006682 -2.83365 Down ADAM metallopeptidase domain 23 ZNF385D -0.76761 0.004718 -2.962 Down zinc finger protein 385D MSTO1 -0.76618 0.015417 -2.51094 Down misato mitochondrial distribution and morphology regulator 1 TC2N -0.76572 0.03599 -2.15685 Down tandem C2 domains, nuclear ASB2 -0.76491 0.039125 -2.12012 Down ankyrin repeat and SOCS box containing 2 ANKK1 -0.76382 0.029604 -2.24134 Down ankyrin repeat and kinase domain containing 1 HTR2C -0.76362 0.017768 -2.45377 Down 5-hydroxytryptamine receptor 2C NCALD -0.76305 0.012906 -2.58149 Down neurocalcin delta ZFP37 -0.76237 0.00465 -2.96732 Down ZFP37 zinc finger protein EGR1 -0.76201 0.015412 -2.51106 Down early growth response 1 OR2L3 -0.76141 0.028147 -2.26286 Down olfactory receptor family 2 subfamily L member 3 CCDC15 -0.76068 0.024043 -2.32929 Down coiled-coil domain containing 15 ALDH1A3 -0.75914 0.012634 -2.58984 Down aldehyde dehydrogenase 1 family member A3 SYN3 -0.75873 0.003083 -3.11499 Down synapsin III GABRB2 -0.75647 0.007487 -2.79099 Down gamma-aminobutyric acid type A receptor subunit beta2 SLC16A7 -0.75585 0.002788 -3.15051 Down solute carrier family 16 member 7 CHRM1 -0.75573 0.002164 -3.2392 Down cholinergic receptor muscarinic 1 HSPA14 -0.75564 0.008114 -2.76063 Down heat shock protein family A (Hsp70) member 14 PAX5 -0.75531 0.024115 -2.32805 Down paired box 5 COL25A1 -0.75389 0.025044 -2.31221 Down collagen type XXV alpha 1 chain CNTNAP5 -0.75368 0.009659 -2.69417 Down contactin associated protein family member 5 NAPB -0.75234 0.017193 -2.4671 Down NSF attachment protein beta NDUFAF7 -0.7515 0.007071 -2.81248 Down NADH:ubiquinoneoxidoreductase complex assembly factor 7 TUBB3 -0.75149 0.002604 -3.17459 Down tubulin beta 3 class III BEX5 -0.75095 0.044407 -2.06369 Down brain expressed X-linked 5 GNL1 -0.74952 0.049197 -2.01735 Down G protein nucleolar 1 (putative) STRBP -0.74914 0.002666 -3.16625 Down spermatid perinuclear RNA binding protein SPDEF -0.74834 0.03996 -2.11078 Down SAM pointed domain containing ETS transcription factor FAXC -0.74819 0.011561 -2.6246 Down failed axon connections homolog, metaxin like GST domain containing LAMP5 -0.74795 0.049794 -2.01186 Down lysosomal associated membrane protein family member 5 (which was not certified by peer review) is the author/funder. 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The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint TTC12 -0.74715 0.010399 -2.6657 Down tetratricopeptide repeat domain 12 SLITRK3 -0.74694 0.006291 -2.85611 Down SLIT and NTRK like family member 3 EIF5A2 -0.74671 0.013531 -2.56283 Down eukaryotic translation initiation factor 5A2 MAP2 -0.74629 0.004324 -2.9937 Down microtubule associated protein 2 CITED2 -0.74528 0.001054 -3.48453 Down Cbp/p300 interacting transactivator with Glu/Asp rich carboxy-terminal domain 2 NLRP2B -0.74477 0.033602 -2.18676 Down NLR family pyrin domain containing 2B PCSK2 -0.74465 0.009055 -2.71888 Down proproteinconvertasesubtilisin/kexin type 2 GPATCH2 -0.7444 0.003953 -3.02612 Down G-patch domain containing 2 MYBPHL -0.74419 0.002735 -3.15731 Down myosin binding protein H like PREP -0.74247 0.042423 -2.08416 Down prolylendopeptidase PTPRO -0.7424 0.028999 -2.25016 Down protein tyrosine phosphatase r eceptor type O PRMT9 -0.74236 0.021135 -2.38283 Down protein arginine methyltransferase 9 CIT -0.74129 0.015558 -2.50729 Down citron rho-interacting serine/threonine kinase DYNC2LI1 -0.74055 0.005615 -2.8982 Down dynein cytoplasmic 2 light intermediate chain 1 SLITRK4 -0.73822 0.019092 -2.42454 Down SLIT and NTRK like family member 4 RAB3B -0.73788 0.009327 -2.70757 Down RAB3B, member RAS oncogene family ANK3 -0.73632 0.00967 -2.69372 Down ankyrin 3 C11orf87 -0.73623 0.006117 -2.86652 Down chromosome 11 open reading frame 87 C2CD5 -0.73622 0.01064 -2.65686 Down C2 calcium dependent domain containing 5 NAALAD2 -0.73616 0.039152 -2.11981 Down N-acetylated alpha-linked acidic dipeptidase 2 CDK7 -0.73528 0.004512 -2.97826 Down cyclin dependent kinase 7 PYROXD1 -0.73512 0.004409 -2.98662 Down pyridine nucleotide-disulphide oxidoreductase domain 1 FSTL5 -0.73489 0.024805 -2.31625 Down follistatin like 5 HMGCR -0.73399 0.046517 -2.04277 Down 3-hydroxy-3-methylglutaryl-CoA reductase ITFG1 -0.73054 0.017692 -2.45552 Down integrin alpha FG-GAP repeat containing 1 PDP1 -0.73029 0.004413 -2.98634 Down pyruvate dehydrogenase phosphatase catalytic subunit 1 CD200 -0.73025 0.00936 -2.7062 Down CD200 molecule RMND1 -0.72884 0.005477 -2.90736 Down required for meiotic nuclear division 1 homolog HTR5A -0.72882 0.014342 -2.53976 Down 5-hydroxytryptamine r eceptor 5A LRRK2 -0.72729 0.013561 -2.56195 Down leucine rich repeat kinase 2 NSG2 -0.72652 0.003814 -3.03901 Down neuronal vesicle trafficking associated 2 CCSER1 -0.72633 0.021549 -2.37482 Down coiled-coil serine rich protein 1 GLRB -0.72469 0.009361 -2.70616 Down glycine receptor beta NUP35 -0.72343 0.006133 -2.8656 Down nucleoporin 35 STX1B -0.72317 0.006041 -2.87115 Down syntaxin 1B PTPRT-DT -0.72204 0.017456 -2.46095 Down PTPRT divergent transcript ATP6V1B2 -0.72098 0.00981 -2.68819 Down ATPase H+ transporting V1 subunit B2 SYTL2 -0.7206 0.004864 -2.95093 Down synaptotagmin like 2 PLCB1 -0.72017 0.024854 -2.31541 Down phospholipase C beta 1 OR2L5 -0.71969 0.04497 -2.05802 Down olfactory receptor family 2 subfamily L member 5 CCPG1 -0.71858 0.000925 -3.52808 Down cell cycle progression 1 (which was not certified by peer review) is the author/funder. 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The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint NRXN1 -0.71812 0.025793 -2.29982 Down neurexin 1 NQO2 -0.71702 0.000678 -3.63089 Down N- ribosyldihydronicotinamide:quinonereductase 2 ATP2B2 -0.71558 0.003959 -3.0256 Down ATPase plasma membrane Ca2+ transporting 2 FMN1 -0.71519 0.006551 -2.84106 Down formin 1 PLA2G7 -0.715 0.034044 -2.1811 Down phospholipase A2 group VII HTR3B -0.71426 0.001885 -3.28699 Down 5-hydroxytryptamine receptor 3B CISD1 -0.71406 0.006717 -2.83171 Down CDGSH iron sulfur domain 1 C20orf203 -0.71269 0.020043 -2.40465 Down chromosome 20 open reading frame 203 SH3GL2 -0.71211 0.029752 -2.2392 Down SH3 domain containing GRB2 like 2, endophilin A1 CHRM4 -0.71197 0.00292 -3.1342 Down cholinergic receptor muscarinic 4 LNCOC1 -0.70914 0.004554 -2.97486 Down lncRNA associated with ovarian cancer 1 NELL2 -0.709 0.025363 -2.30689 Down neural EGFL like 2 VWC2L -0.70894 0.02655 -2.28763 Down von Willebrand factor C domain containing 2 like CYP4X1 -0.70744 0.005183 -2.92768 Down cytochrome P450 family 4 subfamily X member 1 PARM1 -0.70623 0.007727 -2.77914 Down prostate androgen-regulated mucin-like protein 1 CHN1 -0.70609 0.012687 -2.5882 Down chimerin 1 SRSF5 -0.70553 0.002226 -3.22934 Down serine and arginine rich splicing factor 5 FHAD1 -0.70546 0.020175 -2.40195 Down forkhead associated phosphopeptide binding domain 1 SCART1 -0.7025 0.035045 -2.16847 Down scavenger receptor family member expressed on T cells 1 RNF133 -0.70053 0.02337 -2.34115 Down ring finger protein 133 ENTPD3 -0.69868 0.004725 -2.96149 Down ectonucleoside triphosphate diphosphohydrolase 3 LANCL2 -0.69846 0.027557 -2.27186 Down LanC like glutathione S-transferase 2 DMXL2 -0.69659 0.004755 -2.95917 Down Dmx like 2 ZNF540 -0.69557 0.009323 -2.70775 Down zinc finger protein 540 FASTKD3 -0.69516 0.03717 -2.1427 Down FAST kinase domains 3 LNX1 -0.69514 0.013506 -2.56356 Down ligand of numb-protein X 1 TSPAN7 -0.69477 0.02575 -2.30052 Down tetraspanin 7 GPRASP1 -0.69287 0.002721 -3.15913 Down G protein-coupled receptor associated sorting protein 1 NSMAF -0.69267 0.016083 -2.494 Down neutral sphingomyelinase activation associated factor ABCA5 -0.69251 0.01249 -2.59434 Down ATP binding cassette subfamily A member 5 CLSTN3 -0.69159 0.005685 -2.89368 Down calsyntenin 3 GAD2 -0.69125 0.039866 -2.11182 Down glutamate decarboxylase 2 TRIM67 -0.69103 0.029154 -2.24788 Down tripartite motif containing 67 ZNF365 -0.69086 0.018706 -2.43288 Down zinc finger protein 365 SKOR1 -0.69065 0.032556 -2.20047 Down SKI family transcriptional corepressor 1 MAP1A -0.69018 0.015508 -2.50859 Down microtubule associated protein 1A LRRTM2 -0.69011 0.0222 -2.3625 Down leucine rich repeat transmembrane neuronal 2 MYL5 -0.68916 0.044508 -2.06266 Down myosin light chain 5 ABCA10 -0.68868 0.033377 -2.18968 Down ATP binding cassette subfamily A member 10 DPYS -0.68786 0.036965 -2.14513 Down dihydropyrimidinase (which was not certified by peer review) is the author/funder. 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The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint KYAT3 -0.6874 0.032815 -2.19704 Down kynurenine aminotransferase 3 LGALS8 -0.68701 0.002975 -3.12756 Down galectin 8 ABRACL -0.68688 0.014361 -2.53922 Down ABRA C-terminal like CCER2 -0.68685 0.028577 -2.25641 Down coiled-coil glutamate rich protein 2 C5orf34 -0.68676 0.026537 -2.28782 Down chromosome 5 open reading frame 34 SLC35A1 -0.68644 0.035124 -2.16749 Down solute carrier family 35 member A1 KDM4D -0.68549 0.021538 -2.37503 Down lysine demethylase 4D TTC39C -0.68527 0.025683 -2.30162 Down tetratricopeptide repeat domain 39C TRPC3 -0.68403 0.034243 -2.17856 Down transient receptor potential cation channel subfamily C member 3 RYR2 -0.68348 0.030393 -2.23007 Down ryanodine receptor 2 MED23 -0.68347 0.012278 -2.60107 Down mediator complex subunit 23 PPL -0.68283 0.047326 -2.03497 Down periplakin UPP2 -0.68228 0.011795 -2.61678 Down uridinephosphorylase 2 FASTKD2 -0.6819 0.002769 -3.15298 Down FAST kinase domains 2 BEX4 -0.6819 0.007081 -2.81195 Down brain expressed X-linked 4 MYSM1 -0.68134 0.006089 -2.86825 Down Myb like, SWIRM and MPN domains 1 CCDC184 -0.68075 0.02264 -2.35435 Down coiled-coil domain containing 184 RNF128 -0.68028 0.011381 -2.6307 Down ring finger protein 128 VPS13A -0.67928 0.011253 -2.63509 Down vacuolar protein sorting 13 homolog A ATP1A1 -0.67921 0.011228 -2.63598 Down ATPase Na+/K+ transporting subunit alpha 1 KALRN -0.67908 0.01211 -2.60646 Down kalirinRhoGEF kinase CLASP2 -0.67844 0.01211 -2.60648 Down cytoplasmic linker associated protein 2 CPLANE1 -0.67829 0.026527 -2.28799 Down ciliogenesis and planar polarity effector complex subunit 1 SEC61A2 -0.67792 0.014803 -2.52717 Down SEC61 translocon subunit alpha 2 PHF14 -0.67785 0.041126 -2.098 Down PHD finger protein 14 GPR149 -0.67772 0.025117 -2.31099 Down G protein-coupled receptor 149 CENATAC -0.67767 0.005305 -2.91915 Down centrosomal AT-AC splicing factor FABP3 -0.67698 0.037594 -2.13771 Down fatty acid binding protein 3 MTR -0.67672 0.000967 -3.51355 Down 5-methyltetrahydrofolate-homocysteine methyltransferase TAF9 -0.67609 0.024936 -2.31402 Down TATA-box binding protein associated factor 9 PHF24 -0.67443 0.00466 -2.96651 Down PHD finger protein 24 RELL2 -0.67429 0.023512 -2.33863 Down RELT like 2 DGKB -0.67426 0.012273 -2.60122 Down diacylglycerol kinase beta FARSB -0.67364 0.001985 -3.26911 Down phenylalanyl-tRNAsynthetase subunit beta VDAC3 -0.67301 0.012952 -2.58007 Down voltage dependent anion channel 3 RNF165 -0.67278 0.00407 -3.01555 Down ring finger protein 165 AP1G2 -0.67271 0.017901 -2.45077 Down adaptor related protein complex 1 subunit gamma 2 ODAD4 -0.6726 0.042462 -2.08375 Down outer dynein arm docking complex subunit 4 ZNF780B -0.67212 0.009043 -2.71939 Down zinc finger protein 780B TCEAL5 -0.67157 0.006785 -2.82797 Down transcription elongation factor A like 5 ZIM2 -0.67153 0.041275 -2.09639 Down zinc finger imprinted 2 SKP1 -0.67085 0.007158 -2.80793 Down S-phase kinase associated protein 1 (which was not certified by peer review) is the author/funder. 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The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint TEKT3 -0.67062 0.034003 -2.18162 Down tektin 3 DHX36 -0.67049 0.001856 -3.29242 Down DEAH-box helicase 36 PLCXD3 -0.67022 0.007109 -2.81047 Down phosphatidylinositol specific phospholipase C X domain containing 3 PLK2 -0.67008 0.024615 -2.31946 Down polo like kinase 2 COG1 -0.66994 0.000964 -3.51442 Down component of oligomericgolgi complex 1 SERPINB8 -0.66991 0.02609 -2.295 Down serpin family B member 8 DNAH1 -0.66991 0.031517 -2.21446 Down dynein axonemal heavy chain 1 TUBB2A -0.66942 0.005408 -2.91206 Down tubulin beta 2A class IIa CACNA1E -0.66886 0.004428 -2.98511 Down calcium voltage-gated channel subunit alpha1 E MAGEE1 -0.66868 0.001522 -3.36042 Down MAGE family member E1 FAM228A -0.66818 0.008539 -2.74127 Down family with sequence similarity 228 member A ARPP21 -0.6678 0.044898 -2.05874 Down cAMP regulated phosphoprotein 21 C9orf72 -0.66767 0.024416 -2.32286 Down C9orf72-SMCR8 complex subunit DLGAP1 -0.66746 0.005813 -2.88545 Down DLG associated protein 1 GTF2H3 -0.66677 0.001717 -3.31903 Down general transcription factor IIH subunit 3 ARMCX5 -0.66641 0.019471 -2.41651 Down armadillo repeat containing X-linked 5 WSB1 -0.66627 0.026415 -2.28977 Down WD repeat and SOCS box containing 1 PDE1A -0.66614 0.015975 -2.49669 Down phosphodiesterase 1A KIFAP3 -0.66582 0.020768 -2.39004 Down kinesin associated protein 3 ZRANB3 -0.66533 0.005802 -2.88611 Down zinc finger RANBP2-type containing 3 PLRG1 -0.66494 0.027915 -2.26639 Down pleiotropic regulator 1 UNC80 -0.66479 0.006736 -2.83065 Down unc-80 homolog, NALCN channel complex subunit ZNF502 -0.6647 0.002678 -3.16465 Down zinc finger protein 502 CDK14 -0.66455 0.009864 -2.68606 Down cyclin dependent kinase 14 (which was not certified by peer review) is the author/funder. 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The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Table 2 The enriched GO terms of the up and down regulated differentially expressed genes GO ID CATEGORY GO Name adjusted_p_v alue negative_log10_of_adjuste d_p_value Gene Count Gene Up regulated genes GO:0050896 BP response to stimulus 3.95E-21 20.40375707 126 HSP90AA1,FN1,KIT,YAP1,PECAM 1,ITGB5,DHX16,ZAP70,TTN,DNAJ B1,SMAD7,RRAS,STIP1,HSPA1A, LEF1,PGR,EPHA2,ITPR3,KLF4,CO L1A2,HSPA2,HSPB1,FLT1,NFKB2, TAB2,PPP2R1B,FLT4,ITGA5,GNG 12,FOXO4,GLI2,GATA2,ADCY4,A NXA2,CYP1A1,RHOQ,WWTR1,CA SP7,CGAS,MMP2,EPAS1,SMAD6,F ZD2,SERPINH1,FZD1,TGFB2,LAT S2,GSTM1,VANGL2,RUNX3,CDK N1C,CCL2,LTF,MAP1LC3C,FGR,H SD17B1,DSP,KCNQ1,HLA- DQB1,S100A10,SMAD9,EFNB1,DU SP1,MECOM,TCF7L1,EDN3,ACVR L1,DLL4,BMP6,SOX17,NFATC1,T BX3,MLKL,S100A4,TP63,TRIP10,Z FPM1,MASP2,ABCC2,KRT19,MSX 1,TGFB1I1,DHH,APOBEC3F,ADO RA2A,CYP27B1,ABCB1,MMP14,A SPN,SLC7A5,NAIP,WNK4,HIC1,T RIM5,JMJD6,FLOT1,YBX3,FOXJ1, FOXC1,FOXF1,HGFAC,CACNA1H ,TEAD2,CSF1,PTGER4,ENG,MAP K4,RASIP1,CELSR1,RASA4,OLFM 2,GAS1,TCAP,NPR1,TIE1,ID3,EDN RB,ARHGEF16,RRAD,NFATC4,SL C12A3,EFNA4,RGL2,PGF,EPHX1, ORAI1 GO:0065007 BP biological regulation 3.21E-12 11.49352852 135 HSP90AA1,FN1,KIT,YAP1,LSM2,P ECAM1,ITGB5,ZAP70,TTN,DNAJB 1,SMAD7,RRAS,HSPA1A,LEF1,PG R,EPHA2,ITPR3,KLF4,COL1A2,HS PA2,HSPB1,ESPL1,FLT1,NFKB2,T AB2,PPP2R1B,FLT4,ITGA5,GNG12 ,FOXO4,GLI2,GATA2,ADCY4,AN XA2,CYP1A1,RHOQ,WWTR1,CAS P7,CGAS,MMP2,EPAS1,SMAD6,F ZD2,NES,FZD1,TGFB2,LATS2,RC C1,VANGL2,RUNX3,CDKN1C,CC L2,LTF,LMO2,FGR,HSD17B1,DSP, (which was not certified by peer review) is the author/funder. 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The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint KCNQ1,S100A10,SMAD9,EFNB1,D USP1,MECOM,TCF7L1,EDN3,ACV RL1,DLL4,BMP6,SOX17,NFATC1, TBX3,MLKL,S100A4,TP63,TRIP10, ZFPM1,MASP2,ABCC2,KRT19,MS X1,TGFB1I1,DHH,APOBEC3F,SER PINA5,ADORA2A,CYP27B1,ABCB 1,FOXL2,CDKN2C,MMP14,ASPN, SLC7A5,NAIP,WNK4,HIC1,TRIM5, JMJD6,FLOT1,ZIC2,YBX3,FOXJ1, DES,FOXC1,FOXF1,HGFAC,CACN A1H,TEAD2,CSF1,ATP6V1G2,PTG ER4,KCNG2,ENG,MAPK4,RASIP1, RDH10,CELSR1,RASA4,OLFM2,G AS1,ECM2,PPP1R13L,NPR1,TIE1,I D3,EDNRB,ARHGEF16,RRAD,NF ATC4,SLC12A3,MDGA1,EFNA4,R GL2,PGF,ORAI1,FOXF2 GO:0005737 CC cytoplasm 7.53125E-05 4.123133079 115 HSP90AA1,FN1,KIT,YAP1,LSM2,P ECAM1,ITGB5,DHX16,ZAP70,TTN ,DNAJB1,SMAD7,STIP1,HSPA1A, LEF1,PGR,ITPR3,KLF4,COL1A2,H SPA2,HSPB1,ESPL1,FLT1,LRTOM T,NFKB2,TAB2,PPP2R1B,FLT4,IT GA5,CLTB,FOXO4,GLI2,GATA2,A DCY4,ANXA2,CYP1A1,RHOQ,AT P5MGL,WWTR1,CASP7,CGAS,M MP2,EPAS1,SMAD6,FZD2,NES,SE RPINH1,TGFB2,LATS2,GSTM1,RC C1,RUNX3,CDKN1C,LTF,MAP1LC 3C,TUBAL3,FGR,PYGM,HSD17B1, DSP,KCNQ1,HLA- DQB1,S100A10,SMAD9,EFNB1,DU SP1,MECOM,TCF7L1,NFATC1,ML KL,S100A4,TP63,TRIP10,KRT19,T GFB1I1,DHH,APOBEC3F,SERPIN A5,CYP27B1,COL8A2,ABCB1,CD KN2C,MMP14,SLC7A5,NAIP,WNK 4,TRIM5,JMJD6,FLOT1,ZIC2,YBX 3,DES,FOXC1,HGFAC,KCNA6,TE AD2,CSF1,ATP6V1G2,MAPK4,RA SIP1,RDH10,RASA4,OLFM2,TCAP ,PPP1R13L,ID3,ARHGEF16,RRAD, NFATC4,SLC12A3,MDGA1,PRICK LE4,RGL2,FBXL7,EPHX1 GO:0016020 CC membran e 0.031323662 1.504127464 86 HSP90AA1,FN1,KIT,YAP1,PECAM 1,ITGB5,ZAP70,SMAD7,RRAS,PG R,EPHA2,ITPR3,HSPA2,HSPB1,FL T1,LRTOMT,TAB2,PPP2R1B,FLT4, ITGA5,GNG12,CLTB,GLI2,ADCY4 ,ANXA2,CYP1A1,RHOQ,ATP5MG L,WWTR1,CGAS,MMP2,FZD2,SER PINH1,FZD1,VANGL2,LTF,MAP1L C3C,FGR,DSP,KCNQ1,HLA- DQB1,S100A10,EFNB1,ACVRL1,D LL4,MLKL,TRIP10,ABCC2,KRT19, DHH,SERPINA5,ADORA2A,CYP2 7B1,ABCB1,MMP14,SLC7A5,NAIP ,WNK4,JMJD6,FLOT1,DES,KCNA6 (which was not certified by peer review) is the author/funder. 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The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint ,CACNA1H,CSF1,ATP6V1G2,PTG ER4,KCNG2,ENG,RDH10,PRRG2, CELSR1,RASA4,OLFM2,GAS1,OR AI2,NPR1,TIE1,EDNRB,ABHD16A, RRAD,SLC12A3,MDGA1,EFNA4,P GF,EPHX1,ORAI1 GO:0036094 MF small molecule binding 7.67834E-05 4.114732511 77 HSP90AA1,KIT,ITGB5,DHX16,ZA P70,TTN,SMAD7,RRAS,HSPA1A,P GR,EPHA2,ITPR3,KLF4,COL1A2,H SPA2,FLT1,TAB2,FLT4,ITGA5,GLI 2,GATA2,ADCY4,ANXA2,CYP1A1 ,RHOQ,CGAS,MMP2,SMAD6,LAT S2,GSTM1,RCC1,RUNX3,LTF,LM O2,TUBAL3,FGR,PYGM,HSD17B1 ,KCNQ1,S100A10,SMAD9,MECOM ,ACVRL1,DLL4,MLKL,S100A4,HS PA12B,TP63,ZFPM1,MASP2,ABCC 2,TGFB1I1,DHH,APOBEC3F,SERPI NA5,CYP27B1,ABCB1,MMP14,AS PN,NAIP,WNK4,HIC1,TRIM5,JMJ D6,ZIC2,CACNA1H,ENG,MAPK4, PRRG2,CELSR1,RASA4,NPR1,TIE 1,ID3,RRAD,SLC12A3,PRICKLE4 GO:0042802 MF identical protein binding 0.000159686 3.796732628 36 HSP90AA1,FN1,KIT,PECAM1,TTN ,PGR,COL1A2,HSPB1,FLT4,FOXO 4,ANXA2,WWTR1,CGAS,SMAD6, TGFB2,GSTM1,LMO2,HSD17B1,S1 00A10,MECOM,MLKL,S100A4,TP6 3,TRIP10,MASP2,APOBEC3F,ADO RA2A,TRIM5,JMJD6,DES,CSF1,EN G,MAPK4,RASIP1,PPP1R13L,ORA I1 Down regulated genes GO:0007275 BP multicellula r organism developme nt 1.16E-09 8.936560173 152 PLPPR4,HLA- DRB1,KAT14,PCSK1,VGF,GAP43, MAS1,UMODL1,RFX8,LAMB1,TH Y1,TAFA1,SCN8A,STMN2,OPN4,A K8,SYT2,NELL1,CNTN5,NEUROD 6,RGS4,RXFP1,CDKL5,IL1RAPL2, SLC17A6,SLC8A3,ADCYAP1,SVE P1,SCG2,GAS2,NAP1L2,BEX1,SER PINI1,SOSTDC1,FGF9,NEGR1,SYT 1,SNAP25,ATP2B1,FLRT3,GLMN, TAGLN3,EXT1,GABRA1,FGF12,IN HA,VTN,FGF14,OPCML,SYT4,ME F2C,NRN1,GABRG2,RTCA,HCN1, PCP4,PCDH8,PARP2,ROBO2,TRIM 45,CSMD3,PAK1,NMNAT2,RAB3A ,TECTA,HAPLN1,STMN4,RIMS2,Z NF304,ATAT1,AHI1,PPP3CA,CSM D1,STMN1,SCN2A,SCN5A,DCLK1 ,CCKBR,MCF2,CNTNAP2,SRI,TTC 8,HHIP,GABRB3,TTC21B,SCN1A, RBFOX2,SLIT2,AGBL4,PLK4,ROR B,PAK3,SEMA3A,UCHL1,SLC4A1 0,NECAB1,SPAG6,ELAVL4,ADAM 23,ASB2,EGR1,ALDH1A3,GABRB (which was not certified by peer review) is the author/funder. 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The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 2,CHRM1,PAX5,TUBB3,SPDEF,SL ITRK3,MAP2,CITED2,PCSK2,MYB PHL,PTPRO,CIT,DYNC2LI1,SLITR K4,ANK3,HTR5A,LRRK2,GLRB,S TX1B,PLCB1,NRXN1,ATP2B2,FM N1,SH3GL2,NELL2,VWC2L,CHN1, CLSTN3,TRIM67,ZNF365,MAP1A, LRRTM2,LGALS8,TTC39C,RYR2, MYSM1,VPS13A,KALRN,CLASP2, CPLANE1,PHF14,GPR149,MTR,RN F165,ODAD4,DHX36,PLK2,TUBB2 A,C9ORF72,KIFAP3 GO:0032502 BP developme ntal process 3.19E-08 7.495787075 187 PLPPR4,HLA- DRB1,KAT14,PCSK1,FLT3,VGF,G AP43,MAS1,UMODL1,RFX8,LAM B1,THY1,TAFA1,SCN8A,STMN2,O PN4,AK8,RBM11,SYT2,NELL1,SP ARCL1,CFAP221,CNTN5,NEURO D6,RGS4,RXFP1,CDKL5,VWDE,IL 1RAPL2,SLC17A6,SLC8A3,ADCY AP1,OCA2,SVEP1,UNC13C,SCG2, CDH18,ALOX12B,GAS2,NAP1L2,S TAT4,BEX1,SERPINI1,SOSTDC1,F GF9,NEGR1,IQGAP3,SYT1,SNAP2 5,THEMIS,SUV39H1,ATP2B1,FLR T3,GLMN,TAGLN3,EXT1,SPTLC2, GABRA1,FGF12,INHA,VTN,FGF14 ,OPCML,IARS1,SYT4,MEF2C,NRN 1,GABRG2,RTCA,HCN1,PCP4,PCD H8,KCNH1,PARP2,ROBO2,TRIM4 5,CSMD3,RTKN2,ZNF449,PAK1,N MNAT2,RAB3A,TECTA,HAPLN1, STMN4,CAP2,RIMS2,ZNF304,CFA P69,ATAT1,AHI1,PPP3CA,DIRAS3 ,CSMD1,STMN1,SCN2A,SCN5A,D CLK1,MIAT,CCKBR,MCF2,CNTN AP2,SRI,TTC8,HHIP,GABRB3,TTC 21B,SCN1A,RBFOX2,SLIT2,RSAD 2,AGBL4,PLK4,RORB,PAK3,SEM A3A,ATP6V1E1,UCHL1,SLC4A10, NECAB1,SPAG6,ELAVL4,ADAM2 3,ASB2,HTR2C,EGR1,ALDH1A3,G ABRB2,CHRM1,PAX5,TUBB3,STR BP,SPDEF,TTC12,SLITRK3,EIF5A 2,MAP2,CITED2,PCSK2,MYBPHL, PTPRO,CIT,DYNC2LI1,SLITRK4,A NK3,FSTL5,HTR5A,LRRK2,GLRB, STX1B,ATP6V1B2,PLCB1,NRXN1, ATP2B2,FMN1,SH3GL2,NELL2,V WC2L,CHN1,ABCA5,CLSTN3,TRI M67,ZNF365,MAP1A,LRRTM2,LG ALS8,TTC39C,RYR2,PPL,MYSM1, VPS13A,KALRN,CLASP2,CPLANE 1,PHF14,GPR149,FABP3,MTR,VD AC3,RNF165,ODAD4,DHX36,PLK2 ,DNAH1,TUBB2A,C9ORF72,KIFAP 3 GO:0030054 CC cell 6.28E-23 22.20213075 120 PLPPR4,VAMP1,PCSK1,SST,VGF, GAP43,RPH3A,PVALB,TAC1,THY (which was not certified by peer review) is the author/funder. 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The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint junction 1,SCN8A,SYT2,SPARCL1,CNTN5, CDKL5,IL1RAPL2,SLC17A6,SLC8 A3,ICA1,UNC13C,SV2C,CDH18,IQ GAP3,SYT1,SNAP25,THEMIS,ATP 2B1,FLRT3,EXT1,DLGAP2,ACTR2 ,GABRA1,FGF12,ATP1A3,SLC6A7, SYT4,MEF2C,NRN1,STXBP5L,GA BRG2,HCN1,PCDH8,KCNH1,PAK1 ,RAB3C,NMNAT2,RAB3A,SNCB,H APLN1,NSF,GRIA3,CAP2,RIMS2,N EFM,ATAT1,AHI1,PPP3CA,CADPS ,SCN2A,GAD1,SCN5A,CRHR2,DC LK1,ATP1B1,CNTNAP2,TRIM9,G ABRB3,SCN1A,SLC4A8,PAK3,SE MA3A,GNG3,SV2B,FAM81A,ATP6 V1E1,SLC4A10,ELAVL4,BTBD8,A DAM23,HTR2C,SYN3,GABRB2,SL C16A7,CHRM1,NAPB,LAMP5,SLI TRK3,PTPRO,SLITRK4,RAB3B,AN K3,HTR5A,LRRK2,GLRB,STX1B, ATP6V1B2,PLCB1,NRXN1,ATP2B 2,FMN1,HTR3B,SH3GL2,CHRM4, VWC2L,DMXL2,CLSTN3,GAD2,M AP1A,LRRTM2,PPL,ATP1A1,KAL RN,CLASP2,DGKB,VDAC3,PLCX D3,CACNA1E,MAGEE1,C9ORF72, DLGAP1 GO:0005886 CC plasma membrane 5.69E-07 6.245120873 165 PLPPR4,HLA- DRB1,LY6G5B,VAMP1,FLT3,GAP 43,MAS1,RPH3A,UMODL1,CIP2A, THY1,SCN8A,OPN4,SYT2,CNTN5, CAMK1G,RGS4,RXFP1,CDKL5,KC NIP4,IL1RAPL2,SLC17A6,SLC8A3, UNC13C,SV2C,CDH18,NEGR1,IQ GAP3,SYT1,TRHDE,SNAP25,SUV3 9H1,ATP2B1,FLRT3,KCNH5,NCR3 LG1,DLGAP2,SLC27A2,GABRA1, KCNB2,INHA,VTN,NOXA1,ATP1 A3,OPCML,PTH2R,PRMT8,CPNE4, PKD2L1,SLC6A7,SYT4,NRN1,STX BP5L,GABRG2,HCN1,STYK1,PCD H8,FCGR1A,KCNH1,ROBO2,CSM D3,RTKN2,PAK1,RAB3C,TMEM23 3,GPR61,RAB3A,TECTA,SLC44A5, NSF,GRIA3,SIDT1,PRLHR,CAP2,R IMS2,THSD7B,RGS7,PPP3CA,EXO C1,DIRAS3,SCN2A,GAD1,LRRC7, SCN5A,CRHR2,ENO2,DCLK1,CCK BR,ATP1B1,CNTNAP2,SRI,PLCH1, KCNH8,TTC8,HHIP,GABRB3,SLC 25A14,SCN1A,HAUS7,SLC4A8,PL K4,PAK3,GNG3,SV2B,ATP6V1E1, UCHL1,SLC4A10,BTBD8,ADAM23 ,HTR2C,OR2L3,GABRB2,SLC16A7 ,CHRM1,COL25A1,LAMP5,SLITR K3,PTPRO,SLITRK4,RAB3B,ANK3 ,C2CD5,NAALAD2,CDK7,ITFG1,C D200,HTR5A,LRRK2,GLRB,NUP35 ,STX1B,ATP6V1B2,SYTL2,OR2L5, NRXN1,ATP2B2,FMN1,HTR3B,SH (which was not certified by peer review) is the author/funder. 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The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 3GL2,CHRM4,VWC2L,PARM1,SC ART1,ENTPD3,LANCL2,TSPAN7, ABCA5,CLSTN3,GAD2,LRRTM2,S LC35A1,TRPC3,RYR2,PPL,ATP1A 1,CLASP2,GPR149,RELL2,DGKB, CACNA1E,MAGEE1,DLGAP1,KIF AP3,UNC80,CDK14 GO:0043167 MF ion binding 1.15845E-06 5.936124465 189 ZBTB41,TRIM26,MPO,NUAK1,VA RS2,FLT3,GAP43,RPH3A,PVALB, UMODL1,RPP21,ZNF112,PRORP,S CN8A,AK8,PNMA3,TRANK1,SYT2 ,NELL1,SPARCL1,VSNL1,ABCC12 ,CAMK1G,RXFP1,CDKL5,ABCF2- H2BK1,FPGT- TNNI3K,VWDE,CLGN,KCNIP4,GE N1,SLC8A3,SVEP1,UNC13C,ZNF8 91,CDH18,ALOX12B,CARNS1,BE X1,DQX1,TNNI3K,SYT1,RNF148,T RHDE,SUV39H1,ATP2B1,PDE10A, EXT1,SPTLC2,ACTR2,SLC27A2,M SH5,ATP1A3,SCG5,PRMT8,DPH6, CPNE4,PKD2L1,IARS1,SYT4,RTC A,HCN1,STYK1,PCP4,PCDH8,ST8 SIA3,YPEL4,TRIM45,OSGEP,MGA T4C,ZNF449,TRIM66,PAK1,ZNF44 1,RAB3C,NMNAT2,RAB3A,SNCB, NSF,ZMYND12,RIMS2,ZNF304,UB LCP1,DDX39B,PPP3CA,EXOC1,C ADPS,DIRAS3,ZSCAN1,GAD1,ZN F544,ENO2,DCLK1,SRI,TRIM9,AD AT2,ALKBH8,PLCH1,HHIP,RFESD ,NEK10,SLC25A12,SLIT2,ZC2HC1 A,RSAD2,AGBL4,PLK4,RORB,PA K3,GOT1,NECAB1,ZNF711,RAB6C ,GK,ZNF385D,ANKK1,HTR2C,NC ALD,ZFP37,EGR1,ALDH1A3,SYN3 ,HSPA14,TUBB3,BEX5,GNL1,CIT, RAB3B,C2CD5,NAALAD2,CDK7,P YROXD1,FSTL5,HMGCR,PDP1,HT R5A,LRRK2,GLRB,ATP6V1B2,SY TL2,PLCB1,NRXN1,NQO2,ATP2B2 ,CISD1,NELL2,CYP4X1,CHN1,RN F133,ENTPD3,LANCL2,ZNF540,L NX1,ABCA5,CLSTN3,GAD2,TRIM 67,ZNF365,MYL5,ABCA10,DPYS, KYAT3,KDM4D,TRPC3,RYR2,BE X4,MYSM1,RNF128,ATP1A1,KAL RN,PHF14,FABP3,MTR,PHF24,DG KB,FARSB,RNF165,ZNF780B,ZIM 2,DHX36,PLK2,DNAH1,TUBB2A,C ACNA1E,GTF2H3,PDE1A,ZRANB 3,ZNF502,CDK14 GO:0043168 MF anion binding 0.0001546 3.810791607 86 NUAK1,VARS2,FLT3,GAP43,RPH3 A,SCN8A,AK8,TRANK1,SYT2,AB CC12,CAMK1G,CDKL5,ABCF2- H2BK1,FPGT- TNNI3K,CARNS1,DQX1,TNNI3K,S YT1,ATP2B1,PDE10A,SPTLC2,AC TR2,SLC27A2,MSH5,ATP1A3,SCG (which was not certified by peer review) is the author/funder. 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The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint 5,DPH6,IARS1,RTCA,HCN1,STYK 1,ST8SIA3,PAK1,RAB3C,NMNAT2 ,RAB3A,NSF,DDX39B,EXOC1,DIR AS3,GAD1,DCLK1,NEK10,PLK4,P AK3,GOT1,RAB6C,GK,ANKK1,AL DH1A3,SYN3,HSPA14,TUBB3,GN L1,CIT,RAB3B,CDK7,PYROXD1,H MGCR,LRRK2,GLRB,ATP6V1B2,S YTL2,PLCB1,NQO2,ATP2B2,CISD 1,ENTPD3,LANCL2,ABCA5,GAD2, ABCA10,KYAT3,TRPC3,RYR2,AT P1A1,KALRN,FABP3,DGKB,FARS B,DHX36,PLK2,DNAH1,TUBB2A, ZRANB3,CDK14 Table 3 The enriched pathway terms of the up and down regulated differentially expressed genes Pathway ID Pathway Name adjusted_p_ value negative_log10_of_adjust ed_p_value Gene Count Gene Up regulated genes REAC:R-HSA-162582 Signal Transduction 2.59E-08 7.586277137 65 HSP90AA1,FN1,KIT,YAP1,ITG B5,ZAP70,DNAJB1,SMAD7,ST IP1,LEF1,PGR,EPHA2,ITPR3,C OL1A2,HSPB1,FLT1,TAB2,PPP 2R1B,FLT4,ITGA5,GNG12,CL TB,FOXO4,GLI2,ADCY4,RHO Q,WWTR1,MMP2,EPAS1,SMA D6,FZD2,FZD1,TGFB2,LATS2, VANGL2,RUNX3,CCL2,TUBA L3,DSP,SMAD9,DUSP1,MECO M,TCF7L1,EDN3,ACVRL1,DL L4,SOX17,NFATC1,TRIP10,DH H,ADORA2A,FLOT1,HGFAC, ATP6V1G2,PTGER4,MAPK4,R DH10,RASA4,GAS1,ID3,EDNR B,ARHGEF16,RRAD,RGL2,PG F REAC:R-HSA-397014 Muscle contraction 0.001058341 2.97537425 12 ITGB5,TTN,ITPR3,ANXA2,W WTR1,KCNQ1,DES,CACNA1H ,TCAP,ORAI2,NPR1,ORAI1 REAC:R-HSA-9006934 Signaling by Receptor Tyrosine Kinases 0.003972621 2.400922828 18 HSP90AA1,FN1,KIT,YAP1,PG R,ITPR3,COL1A2,HSPB1,FLT1 ,TAB2,PPP2R1B,FLT4,ADORA 2A,HGFAC,ATP6V1G2,ID3,RR AD,PGF REAC:R-HSA-109582 Hemostasis 0.015840211 1.80023904 19 FN1,PECAM1,TTN,ITPR3,COL 1A2,PPP2R1B,ITGA5,GNG12,G ATA2,ANXA2,TGFB2,TUBAL 3,FGR,S100A10,ZFPM1,SERPI (which was not certified by peer review) is the author/funder. 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The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint NA5,SLC7A5,ORAI2,ORAI1 REAC:R-HSA-195721 Signaling by WNT 0.017580784 1.75496175 12 LEF1,ITPR3,PPP2R1B,GNG12, CLTB,FZD2,FZD1,VANGL2,R UNX3,TCF7L1,SOX17,NFATC 1 REAC:R-HSA-1474244 Extracellular matrix organization 0.025433553 1.594592972 11 FN1,PECAM1,ITGB5,COL1A2, ITGA5,MMP2,SERPINH1,TGF B2,COL8A2,MMP14,ASPN Down regulated genes REAC:R-HSA-5576891 Cardiac conduction 1.98007E-06 5.703319324 13 SCN5A,RYR2,SCN2A,SCN1A, SCN8A,ATP1A1,ATP1A3,ATP 2B2,ATP2B1,ATP1B1,FGF14,F GF12,SRI REAC:R-HSA-112316 Neuronal System 2.51263E-06 5.599871714 21 SNAP25,NSF,TUBB2A,GNG3, TUBB3,SYT1,RAB3A,GRIA3,N RXN1,GAD2,GAD1,DLGAP1,C ACNA1E,SYT2,KCNB2,SYN3, PLCB1,GABRB3,DLGAP2,GA BRB2,LRRTM2 REAC:R-HSA-112315 Transmission across Chemical Synapses 6.58789E-05 4.181253733 15 SNAP25,NSF,TUBB2A,GNG3, TUBB3,SYT1,RAB3A,GRIA3,G AD2,GAD1,CACNA1E,SYN3,P LCB1,GABRB3,GABRB2 REAC:R-HSA-983712 Ion channel transport 0.002710765 2.566908054 10 ATP6V1B2,RYR2,ATP6V1E1, ATP1A1,ATP1A3,ATP2B2,ATP 2B1,ATP1B1,SRI,TRPC3 REAC:R-HSA-9675108 Nervous system development 0.005628954 2.249572309 18 ANK3,ACTR2,SCN5A,TUBB2 A,PAK1,TUBB3,SCN2A,LAMB 1,SCN1A,HMGCR,SCN8A,SH3 GL2,KALRN,PAK3,SLIT2,ROB O2,SEMA3A,TRPC3 REAC:R-HSA-5663205 Infectious disease 0.017468304 1.757749269 24 SKP1,TAF9,CDK7,H2BC15,GT F2H4,GTF2H3,SNAP25,ACTR2 ,TUBB2A,GNG3,STX1B,TUBB 3,VAMP1,SYT1,NUP35,FCGR1 A,SH3GL2,ATP1A1,ATP1A3,S YT2,PLK2,ATP1B1,SV2C,SV2 B Table 4 Topology table for up and down regulated genes Regulation Node Degree Betweenness Stress Closeness Up HSP90AA1 412 0.331748 3.3E+08 0.364335 Up FN1 151 0.051517 55951306 0.29276 Up KIT 107 0.025536 9005534 0.307407 Up YAP1 98 0.021899 16566854 0.288116 Up LSM2 97 0.012707 7183354 0.246369 Up PECAM1 95 0.027311 15598130 0.285389 (which was not certified by peer review) is the author/funder. 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The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Up ITGB5 89 0.019065 10823778 0.2632 Up DHX16 87 0.006795 7680748 0.242817 Up ZAP70 84 0.020196 14434054 0.27588 Up TTN 82 0.022649 15929072 0.268318 Up DNAJB1 79 0.00724 4527968 0.301469 Up SMAD7 79 0.023933 12249154 0.291294 Up RRAS 77 0.020444 23708134 0.258534 Up STIP1 77 0.010281 3740162 0.299124 Up HSPA1A 72 0.006524 4403126 0.303322 Up LEF1 70 0.014415 9742488 0.276771 Up PGR 70 0.017751 10178210 0.311226 Up EPHA2 69 0.021947 7616462 0.298612 Up ITPR3 68 0.019343 18949700 0.276348 Up KLF4 68 0.01472 11190300 0.283057 Up COL1A2 67 0.012102 4568578 0.254401 Up HSPA2 65 0.008224 2662732 0.290895 Up HSPB1 64 0.017318 15454858 0.317703 Up ESPL1 60 0.013489 6685380 0.250654 Up FLT1 58 0.003177 2562430 0.261664 Up LRTOMT 56 0.008281 6446570 0.233587 Up NFKB2 55 0.009331 6295740 0.281281 Up TAB2 54 0.010248 9176286 0.266213 Up PPP2R1B 53 0.011781 4253812 0.254958 Up FLT4 52 0.001855 1563378 0.251674 Up ITGA5 52 0.005695 3427082 0.25452 Up GNG12 51 0.006008 7389770 0.217469 Up CLTB 50 0.01384 13710394 0.232221 Up FOXO4 49 0.006871 10748042 0.26882 Up GLI2 49 0.024173 12043054 0.283451 Up GATA2 48 0.009184 7348172 0.260672 Up ADCY4 47 0.011675 15177860 0.251947 Up ANXA2 47 0.016961 13826622 0.28878 Up CYP1A1 47 0.024307 10892992 0.253806 Up RHOQ 46 0.011169 4034056 0.257688 Up ATP5MGL 46 0.014235 8195802 0.215303 Up WWTR1 45 0.003202 2701564 0.266911 Up CASP7 44 0.011044 7838022 0.272221 Up CGAS 44 0.005352 11621556 0.225656 Up MMP2 43 0.01023 5291268 0.290463 Up EPAS1 42 0.010661 3106168 0.295398 Up SMAD6 40 0.002268 1241912 0.250474 Up FZD2 39 0.005417 5968842 0.245169 Up NES 39 0.009746 3886682 0.279159 Up SERPINH1 39 0.008666 6132574 0.254454 Up FZD1 38 0.004448 4967756 0.24425 Up TGFB2 38 0.005502 3456016 0.265129 Up LATS2 38 0.005622 3681742 0.268998 Up GSTM1 37 0.009107 2221432 0.228731 Up RCC1 37 0.010461 9618220 0.244446 Up VANGL2 36 0.009535 4508478 0.241139 Up RUNX3 36 0.005861 3907114 0.268672 Up CDKN1C 36 0.0059 2575264 0.274084 Up CCL2 35 0.00964 3836526 0.249095 Up LTF 35 0.011048 9198250 0.236367 Up LMO2 35 0.006484 3494992 0.245046 Up MAP1LC3C 35 0.012003 5588556 0.227061 Up TUBAL3 33 0.003243 2422636 0.25407 Up FGR 32 0.004805 2532834 0.286057 Up PYGM 30 0.006312 8543430 0.245206 Up HSD17B1 30 0.00426 2515692 0.208904 Up DSP 30 0.006533 4060330 0.246394 Up KCNQ1 29 0.007088 5503300 0.251454 Up HLA-DQB1 29 0.006178 1698602 0.25448 Up S100A10 28 0.005224 1469632 0.252259 Up SMAD9 28 8.90E-04 415468 0.247029 Up EFNB1 27 0.007689 4284116 0.248664 Up DUSP1 27 0.002586 2743748 0.266053 Up MECOM 26 0.003811 2444116 0.259275 Up TCF7L1 26 0.001281 1022458 0.24926 Up EDN3 26 0.007731 7367014 0.193849 (which was not certified by peer review) is the author/funder. 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The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Up ACVRL1 26 0.002133 750930 0.250616 Up DLL4 25 0.005242 2298644 0.258973 Up BMP6 25 0.002674 1418790 0.228634 Up SOX17 25 0.003327 910874 0.256242 Up NFATC1 25 0.002674 1329822 0.260867 Up TBX3 24 0.004447 1550508 0.260784 Up MLKL 24 0.003586 661900 0.276426 Up S100A4 24 0.005845 2855694 0.277588 Up HSPA12B 23 5.63E-04 213422 0.277715 Up TP63 23 0.003467 1818626 0.264512 Up TRIP10 22 0.004064 2368940 0.239191 Up ZFPM1 22 0.002089 1372496 0.238409 Up MASP2 22 0.006972 2040132 0.202521 Up ABCC2 22 0.005714 3339104 0.225844 Up KRT19 21 0.003614 1048462 0.268112 Up MSX1 21 0.005651 3074290 0.214537 Up TGFB1I1 21 0.003102 916034 0.265749 Up DHH 21 0.004871 2005552 0.22468 Up APOBEC3F 20 0.003972 1224604 0.204342 Up SERPINA5 19 0.004552 24449500 0.190433 Up ADORA2A 19 0.005036 4063672 0.239613 Up CYP27B1 18 0.002865 1872814 0.254998 Up COL8A2 18 0.002495 2274174 0.201203 Up ABCB1 18 0.005 2929012 0.241366 Up FOXL2 18 0.003634 1805108 0.235467 Up CDKN2C 16 0.001251 998572 0.251687 Up MMP14 16 0.002025 1858998 0.242107 Up ASPN 16 7.16E-04 383744 0.216649 Up SLC7A5 15 0.004566 2045024 0.215502 Up NAIP 15 0.003326 1247474 0.236299 Up WNK4 13 0.003148 916772 0.217314 Up HIC1 13 0.001492 953204 0.247292 Up TRIM5 13 0.002298 1483978 0.220821 Up JMJD6 13 0.001116 1194080 0.231901 Up FLOT1 12 0.002949 1951616 0.234935 Up ZIC2 11 0.001198 459526 0.215075 Up YBX3 10 0.00218 749988 0.235683 Up FOXJ1 10 0.002514 612922 0.219847 Up DES 10 0.00121 319774 0.24335 Up FOXC1 10 0.001656 354088 0.251157 Up FOXF1 8 0.001274 442252 0.225312 Up HGFAC 7 9.03E-04 370528 0.225146 Up KCNA6 6 8.87E-04 829840 0.190107 Up CACNA1H 6 3.49E-04 199244 0.242191 Up TEAD2 5 3.69E-05 46644 0.231692 Up CSF1 4 5.28E-06 23196 0.240155 Up ATP6V1G2 2 0 0 0.192946 Up PTGER4 2 7.00E-08 84 0.180232 Up KCNG2 2 9.47E-06 10176 0.186237 Up ENG 2 2.43E-05 4930 0.212244 Up MAPK4 2 9.51E-06 4202 0.245947 Up RASIP1 1 0 0 0.205433 Up RDH10 1 0 0 0.175827 Up PRRG2 1 0 0 0.223682 Up CELSR1 1 0 0 0.194296 Up RASA4 1 0 0 0.205433 Up OLFM2 1 0 0 0.193465 Up GAS1 1 0 0 0.183467 Up TCAP 1 0 0 0.211563 Up ECM2 1 0 0 0.200583 Up ORAI2 1 0 0 0.216524 Up PPP1R13L 1 0 0 0.20919 Up NPR1 1 0 0 0.188792 Up TIE1 1 0 0 0.222035 Up ID3 1 0 0 0.198763 Up EDNRB 1 0 0 0.162379 Up ARHGEF16 1 0 0 0.229958 Up ABHD16A 1 0 0 0.202655 Up RRAD 1 0 0 0.215854 Up NFATC4 1 0 0 0.217604 (which was not certified by peer review) is the author/funder. 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The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Up SLC12A3 1 0 0 0.178526 Up MDGA1 1 0 0 0.226472 Up PRICKLE4 1 0 0 0.194296 Up EFNA4 1 0 0 0.229958 Up RGL2 1 0 0 0.205433 Up FBXL7 1 0 0 0.242745 Up PGF 1 0 0 0.207405 Up EPHX1 1 0 0 0.202437 Up ORAI1 1 0 0 0.216524 Up FOXF2 1 0 0 0.183889 Down SKP1 199 0.070684 26927550 0.320538 Down EIF5A2 160 0.050446 78530446 0.25777 Down TAF9 160 0.037517 18387236 0.279558 Down DDX39B 141 0.035937 36971660 0.254149 Down CDK7 136 0.02791 22833198 0.279638 Down PLRG1 132 0.026894 22725890 0.250899 Down H2BC15 129 0.02747 40803386 0.263983 Down SEC61A2 110 0.017258 26359526 0.242673 Down GTF2H4 108 0.005426 4930418 0.252429 Down MED23 108 0.008873 7193154 0.259937 Down LRRK2 107 0.036607 24311442 0.315568 Down GTF2H3 104 0.004084 3318070 0.253898 Down SNAP25 98 0.032441 19736590 0.261552 Down SUV39H1 96 0.020265 23012784 0.26444 Down TCERG1 80 0.019382 17644130 0.259289 Down SRSF5 78 0.012469 17636146 0.234811 Down PLK4 76 0.02204 12740236 0.257024 Down ANK3 76 0.027163 15120894 0.286057 Down ACTR2 74 0.020618 23249388 0.263101 Down PPP3CA 73 0.02563 17665202 0.27811 Down FLT3 72 0.008082 6196950 0.275755 Down EGR1 69 0.013312 18218852 0.275258 Down NSF 66 0.010088 3020688 0.234969 Down SCN5A 63 0.013935 5839408 0.269949 Down RTCA 61 0.014035 10031336 0.233732 Down TUBB2A 60 0.011767 8903740 0.281022 Down PAK1 57 0.016453 6642310 0.304267 Down MYSM1 57 0.013733 15649402 0.250333 Down DQX1 55 0.010089 6556852 0.235819 Down GNG3 53 0.006601 7640394 0.218422 Down ATP6V1B2 52 0.012394 17971322 0.239039 Down STX1B 51 0.003375 2627738 0.23939 Down RYR2 51 0.009482 5614804 0.258918 Down TUBB3 50 0.010008 3112238 0.290428 Down ENO2 50 0.016186 10220232 0.2651 Down DLAT 49 0.015356 7473230 0.234102 Down VAMP1 49 0.001243 436186 0.225198 Down SYT1 48 0.013247 6304394 0.254242 Down CSNK2B 48 0.011334 8822638 0.267877 Down SMN1 47 0.01445 11032158 0.26374 Down HLA-DRB1 46 0.013564 5885448 0.26165 Down GNL1 46 0.011154 5806374 0.225625 Down NAPB 45 7.12E-04 252222 0.216141 Down ATP6V1E1 41 0.006263 9470862 0.236379 Down RAB3A 40 0.012805 8328118 0.246332 Down PARP2 40 0.008522 5192346 0.250013 Down GRIA3 40 0.009484 6833460 0.239861 Down HSPA14 39 0.002131 661700 0.276849 Down TEKT3 39 0.018873 10587676 0.216361 Down NRXN1 39 0.010329 4908658 0.220552 Down SCN2A 39 0.00527 3303488 0.254493 Down LAMB1 38 0.001249 1140898 0.220224 Down MYL5 38 0.00599 5912158 0.237044 Down SCN1A 37 0.003954 1562880 0.245675 Down STAT4 37 0.008984 5199728 0.262903 Down GAD2 37 0.011492 3161516 0.247555 Down NUP35 36 0.010017 4683956 0.228463 Down FCGR1A 36 0.007319 4492710 0.251999 Down DSN1 36 0.008536 5697012 0.225022 Down AP1G2 35 0.006174 3518330 0.208672 (which was not certified by peer review) is the author/funder. 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The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Down MEF2C 35 0.004675 4297274 0.255518 Down IARS1 34 0.012131 4019176 0.220005 Down EXOC1 34 0.00761 4201490 0.247605 Down RBFOX2 34 0.008396 5244808 0.245539 Down GAD1 33 0.006124 1803704 0.234473 Down VDAC3 33 0.006881 13258408 0.233286 Down DLGAP1 32 0.005186 2246220 0.237297 Down HMGCR 31 0.009995 5551748 0.241581 Down CHML 31 0.007292 4555202 0.231286 Down GOT1 31 0.008139 2743078 0.208921 Down UBLCP1 30 0.003775 2387996 0.237044 Down SCN8A 30 0.001804 1760756 0.25 Down MAP2 30 0.006918 4304670 0.268717 Down RGS4 30 0.005679 8175476 0.249949 Down UCHL1 29 0.00401 4640212 0.306693 Down PDE10A 29 0.006758 2751630 0.232719 Down SH3GL2 29 0.006272 3162582 0.267818 Down ATP1A1 29 0.004868 8285510 0.240581 Down PVALB 28 0.006348 1786680 0.249057 Down ALDH1A3 28 0.005678 1488464 0.213328 Down GEN1 28 0.007053 3690664 0.205494 Down ATP1A3 28 0.003899 5971992 0.238293 Down VTN 27 0.004554 2927376 0.237217 Down CACNA1E 26 0.004408 3042884 0.23189 Down KALRN 25 0.004496 3106758 0.241461 Down AHI1 25 0.006639 5041052 0.234844 Down RGS7 25 0.003446 1710074 0.236768 Down SYT2 25 0.001559 640028 0.226252 Down FGF9 25 0.003504 1440734 0.248033 Down NEFM 24 0.002659 1735210 0.248866 Down TTC8 24 0.00825 3037596 0.223355 Down MSH5 23 0.00746 3218116 0.234551 Down PAX5 22 0.002303 1260182 0.248058 Down ATP2B2 21 0.002769 2487270 0.243253 Down CNTNAP2 21 0.004905 1441942 0.234304 Down FASTKD2 21 0.007028 2073946 0.222106 Down ATP2B1 20 0.00219 3441182 0.235683 Down PAK3 19 1.98E-04 85320 0.243471 Down MDH1B 19 0.002601 1209440 0.212947 Down CIT 19 0.002448 2238854 0.230316 Down STMN1 19 0.004024 1948708 0.271479 Down TRIM66 19 0.002065 4729006 0.221071 Down DHX36 18 0.003066 3004952 0.221381 Down IQGAP3 17 0.002194 2262706 0.244091 Down LNX1 16 0.002705 3005710 0.235342 Down TARBP1 15 0.0038 1934228 0.227675 Down SLIT2 15 0.002991 1605730 0.233397 Down ZRANB3 14 0.002104 886186 0.222958 Down LRRC7 14 0.00111 401628 0.216812 Down PRMT8 14 0.001704 962642 0.227941 Down RBM3 12 0.001459 1452996 0.219019 Down GK 11 0.002523 902064 0.221582 Down PLK2 10 8.84E-04 290958 0.232774 Down SPAG6 10 0.003682 2041884 0.151201 Down DCLK1 9 6.22E-04 417902 0.241664 Down CDK14 9 0.001263 851908 0.22599 Down STMN2 9 0.002254 721108 0.232841 Down KCNB2 9 0.001206 802372 0.198416 Down CIP2A 7 2.24E-04 241298 0.239978 Down SYN3 4 1.46E-04 145294 0.227633 Down DMXL2 4 0.002655 1926438 0.251713 Down SLC17A6 3 0 0 0.211747 Down STXBP5L 3 0 0 0.208761 Down PLCB1 3 2.10E-05 18594 0.221502 Down ATP1B1 3 6.26E-06 15332 0.199217 Down ROBO2 3 3.54E-05 31552 0.234057 Down SYT4 2 0 0 0.208725 Down HTR5A 2 7.00E-08 84 0.180232 Down MAP1A 2 2.46E-04 133368 0.213477 Down GABRB3 2 0 0 0.198505 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Down FGF14 2 0 0 0.20453 Down CHGB 2 2.14E-04 426162 0.248651 Down RPH3A 2 0 0 0.20852 Down FGF12 2 0 0 0.214725 Down SV2C 2 0 0 0.202739 Down MCF2 2 0 0 0.20201 Down DLGAP2 2 0 0 0.197047 Down MPO 1 0 0 0.191186 Down RSPH4A 1 0 0 0.131345 Down KYAT3 1 0 0 0.172822 Down FASTKD3 1 0 0 0.181747 Down SEMA3A 1 0 0 0.205433 Down SRI 1 0 0 0.205676 Down GABRB2 1 0 0 0.189945 Down LRRTM2 1 0 0 0.180705 Down FARSB 1 0 0 0.180338 Down RAB3C 1 0 0 0.197653 Down NMNAT2 1 0 0 0.267057 Down HHIP 1 0 0 0.183467 Down CSMD3 1 0 0 0.211563 Down TRIM9 1 0 0 0.207334 Down SYTL2 1 0 0 0.197653 Down STMN4 1 0 0 0.219383 Down GLMN 1 0 0 0.242745 Down GSTA4 1 0 0 0.202437 Down RAB3B 1 0 0 0.197653 Down TRPC3 1 0 0 0.216524 Down SMN1 1 0 0 0.208707 Down SV2B 1 0 0 0.202714 Down PDP1 1 0 0 0.189701 Down VSNL1 1 0 0 0.207334 Down KAT14 1 0 0 0.21849 Down CFAP221 1 0 0 0.131345 Down GAS2 1 0 0 0.213982 Down RIMS2 1 0 0 0.197653 Down VARS2 1 0 0 0.180338 Down ZIM2 1 0 0 0.172822 Table 5 MiRNA - hub gene and TF – hub gene topology table Regulation Hub Genes Degree MicroRNA Regulation Hub Genes Degree TF Up HSP90AA1 538 hsa-mir-545-3p Up LSM2 57 PLAG1 Up FN1 439 hsa-mir-296-3p Up SMAD7 14 NFIC Up YAP1 412 hsa-mir-183-5p Up FN1 14 CREB1 Up STIP1 309 hsa-miR-23a-5p Up ZAP70 14 USF2 Up TTN 297 hsa-miR-3909 Up HSP90AA1 13 SREBF1 Up SMAD7 296 hsa-miR-3616-5p Up RRAS 12 RELA Up DNAJB1 196 hsa-mir-1976 Up DHX16 11 SRY Up ITGB5 159 hsa-miR-598-3p Up TTN 11 PDX1 Up KIT 150 hsa-miR-6736-5p Up HSPA1A 10 YY1 Up HSPA1A 140 hsa-mir-22-5p Up YAP1 9 STAT3 Up DHX16 130 hsa-miR-769-3p Up KIT 8 TFAP2A Up LSM2 102 hsa-mir-4739 Up STIP1 7 ARID3A Up RRAS 86 hsa-mir-1245b-3p Up DNAJB1 7 HINFP Up PECAM1 77 hsa-miR-148a-3p Up ITGB5 3 ELK1 Up ZAP70 9 hsa-miR-631 Up PECAM1 2 FOXC1 Down DDX39B 370 hsa-miR-548f-5p Down DDX39B 56 MEF2A Down TCERG1 334 hsa-miR-429 Down EIF5A2 10 MAX Down EIF5A2 273 hsa-mir-4521 Down CDK7 9 CEBPB Down SKP1 234 hsa-miR-4735-5p Down GTF2H4 9 POU2F2 Down PLRG1 216 hsa-miR-489-3p Down SUV39H1 9 NFYA Down MED23 185 hsa-miR-301b-3p Down TCERG1 9 FOXA1 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Down GTF2H3 183 hsa-miR-302e Down TAF9 8 NFKB1 Down SUV39H1 154 hsa-miR-4632-5p Down LRRK2 8 TEAD1 Down LRRK2 122 hsa-mir-582-3p Down SNAP25 6 SP1 Down SEC61A2 121 hsa-miR-1180-3p Down PLK4 6 HOXA5 Down TAF9 88 hsa-miR-30e-3p Down GTF2H3 6 ESR1 Down SNAP25 77 hsa-miR-153-3p Down MED23 5 EN1 Down CDK7 57 hsa-miR-1264 Down PLRG1 4 SRF Down GTF2H4 43 hsa-miR-15b-3p Down SKP1 4 FOXL1 Down H2BC15 20 hsa-miR-21-5p Down SEC61A2 4 GATA3 Fig. 1. Volcano plot of differentially expressed genes. Genes with a significant change of more than two-fold were selected. Green dot represented up regulated significant genes and red dot represented down regulated significant genes. (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Fig. 2. Heat map of differentially expressed genes. Legend on the top left indicate log fold change of genes. (A1 – A39 = AD samples; B1 – B8 = Normal control samples) Fig. 3. PPI network of DEGs. Up regulated genes are marked in t green; down regulated genes are marked in red. Fig. 4. Modules selected from the PPI network. (A) The most significant module was obtained from PPI network with 37 nodes and 179 edges for up regulated genes (B) The most significant module was obtained from PPI network with 37 nodes and 179 edges for down regulated genes. Up regulated genes are marked in parrot green; down regulated genes are marked in red. (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Fig. 5. Hub gene - miRNA regulatory network. The light gray color diamond nodes represent the key miRNAs; up regulated genes are marked in green; down regulated genes are marked in red. Fig. 6. Hub gene - TF regulatory network. The brown color triangle nodes represent the key TFs; up regulated genes are marked in dark green; down regulated genes are marked in dark red. (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint Fig. 7. ROC curve analyses of hub genes. A) HSP90AA1 B) FN1 C) KIT D) YAP1 E) LSM2 F) SKP1 G) EIF5A2 H) TAF9 I) DDX39B J) CDK7 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprintthis version posted December 6, 2024. ; https://doi.org/10.1101/2024.12.03.626535doi: bioRxiv preprint