Bidirectional Mendelian randomization explores the causal relationship between arthritis and cerebral cortical volume

Bidirectional Mendelian randomization explores the causal relationship between arthritis and cerebral cortical volume | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Bidirectional Mendelian randomization explores the causal relationship between arthritis and cerebral cortical volume Wantong Xu, Minghe Ouyang, Zhongbiao Jiang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4313710/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Mendelian randomization method was used to explore the causal relationship between the occurrence of arthritis disease and volume changes in specific cerebral cortical regions. Methods By analyzing the GWAS summary data,SNP data related to arthritis and cerebral cortex volume were selected.Using the inverse variance weighted (IVW) method as the preferred method, MR Egger, Simple Mode, Weighted Median, and Weighted Mode were used as auxiliary analysis to conduct a two-sample bidirectional Mendelian randomization analysis. Result IVW analysis showed that Arthrosis was positively correlated with the volume of Left Crus I Cerebellum (OR = 1.18, 95%CI: 1.09 ~ 1.28, P = 9×10 − 5 ).Gout was negatively correlated with the volume of Left Frontal Operculum Cortex (OR = 0.97, 95% CI: 0.95 ~ 0.98, P = 5×10 − 5 ).Gout was positively correlated with Left Precentral Gyrus volume (OR = 1.05, 95%CI: 1.04 ~ 1.07, P = 1.9×10 − 11 ).No positive results were obtained by reverse MR analysis. Conclusion Arthrosis promotes increased volume of the Left Crus I Cerebellum.Gout promotes decreased volume of the Left Frontal Operculum Cortex.Gout promotes increased volume of the Left Precentral Gyrus. Mendelian randomization arthritis cerebral cortical volume Figures Figure 1 Figure 2 Figure 3 1. Introduction Arthritis is an inflammatory condition that affects one or more joints. It can present as swelling, deformity, pain, and stiffness. There are many pathways through which joints are damaged, including degeneration in osteoarthritis (OA), crystal deposition in gout and pseudogout, metabolic abnormalities (hematosis), and autoimmune diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), or congenital cartilage and bone defects [ 1 ] . As cerebral cortical surfaces vary widely in thickness and area, they appear to be largely genetically independent and are independent morphometric features of neurodevelopment, aging, and disease [ 2 ] . Quantitative measurements of brain structural anomalies can provide a neuropathological basis for diseases related to those abnormalities, which is essential to the research of diseases. The blood-brain barrier (BBB) has long been believed to protect the central nervous system (CNS) from circulating inflammatory signals. However, a large body of neurological and psychiatric evidence suggests that peripheral inflammation interacts closely with the central nervous system in chronic inflammatory diseases like arthritis and that this interaction may result in changes in cortical volume [ 3 ] .This interaction can be realized in a number of ways.In some studies, peripheral inflammatory mediators have been demonstrated to enter the CNS through the blood-brain barrier or choroid plexus via infiltration of blood-borne immune cells or inflammatory activation of endothelial cells [ 4 ] . Additionally, CNS-associated myeloid cells, such as microglia, meningeal macrophages, perivascular macrophages, and choroid plexus macrophages, can acquire a spontaneous inflammatory state under certain circumstances [ 5 ] . Therefore, the association of arthritis with cortical volume needs to be further explored. Genetic variations are used as instrumental variables (IVs) in Mendelian randomization (MR), an analysis method of GWAS that establishes associations between instrumental variables and exposures and outcomes in order to infer causal relationships [ 6 ] . Three key assumptions underlie MR analysis: (1) instrumental variables are closely related to exposure.(2) no association is observed between instrumental variables and confounding factors.(3) instrumental variables influence outcomes only through exposure. In contrast to traditional research, MR analysis can reduce the interference of confounding factors on the results through a large sample size [ 7 ] . To explore the causal relationship between arthritis and cerebral cortical volume changes, we used bidirectional Mendelian randomization. We hoped that this study would provide insights into the intrinsic connection between arthritis and cerebral cortical volume changes and could provide further clues for exploring the interaction mechanism between peripheral inflammation and the central nervous system. 2. Materials and Methods 2.1 Data Sources In this study, data on genetic variation related to arthritis was obtained from the FinnGen database ( https://r7.finngen.fi/ ), which covers three types of arthritis: arthrosis, gout, and rheumatoid arthritis. There were 64,930 cases of arthrosis, 7,461 cases of gout, 11,178 cases of rheumatoid arthritis, and 221,323 controls.The genetic data related to cortical volume comes from the Genome Wide Association Study (GWAS), which includes 139 brain regions. 2.2 Instrumental variable First, meaningful SNPs are screened out from the GWAS summary data under the genome-wide significant threshold (P < 5×10 − 8 ).Linkage disequilibrium is removed (R2 < 0.001, genetic distance = 10000kb) to ensure that each SNP is independent of each other [ 8 ] .At the same time, by calculating the F test value, instrumental variables with F < 10 were eliminated (if the F statistic of SNPs is less than 10, it indicates that the SNPs are more likely to have weak instrumental variable bias) [ 9 ] .In addition, the pleiotropic residuals and outliers (MR-PRESSO) test was used to identify potential outliers and level pleiotropy (P < 0.05). Once abnormal SNPs are detected, they should be removed [ 10 ] . 2.3 Statistical analysis In this study, bidirectional MR analysis was conducted on two samples. SNPs associated with arthritis were utilized as instrumental variables for forward MR analysis, and regional cerebral cortical volume was assessed as an outcome.Reverse MR analysis used cerebral cortical volume-related SNPs as instrumental variables, and arthritis was assessed as an outcome. For determining the causal effect of exposure on outcome, inverse variance weighting (IVW) was chosen as the preferred MR analysis method, and additional MR methods were used to confirm the reliability and robustness of the results (MR-Egger, Simple Mode, Weighted Median, and Weighted Mode) [ 11 ] . In sensitivity analysis, we used MR-Egger and IVW tests to detect heterogeneity of results, with P < 0.05 indicating heterogeneity in Cochran's Q test.Potential horizontal pleiotropy was assessed by calculating the intercepts of instrumental variables in the MR-Egger regression, with P < 0.05 indicating the presence of horizontal pleiotropy [ 12 ] .As mentioned previously, we used the MR-PRESSO method to detect and eliminate possible outliers and pleiotropic effects. 3. Result All filtered instrumental variables used for forward and reverse MR analysis are shown in Supplementary Tables 4 and 5. In order to reduce the probability of errors in the experiment, we conducted multiple comparison corrections on the P-value and ultimately selected the result with P < 0.05/139*3 as the positive result. In the forward MR analysis, three sets of positive results were obtained(Table 1 ).IVW analysis showed that Arthrosis was positively correlated with the volume of Left Crus I Cerebellum (OR = 1.18, 95%CI: 1.09 ~ 1.28, P = 9×10 − 5 ).Gout was negatively correlated with the volume of Left Frontal Operculum Cortex (OR = 0.97, 95% CI: 0.95 ~ 0.98, P = 5×10 − 5 ).Gout was positively correlated with Left Precentral Gyrus volume (OR = 1.05, 95%CI: 1.04 ~ 1.07, P = 1.9×10 − 11 ).The results of the five MR analyses were directionally consistent for each set of positive data.And no positive results were obtained in all reverse MR analyses. Table 1 Full positive results of MR estimate for the association between joint disease and cortical volume or its subtypes. Joint diseases (exposure) Cortical volume (outcome) MR method No. SNP F OR(95% CI) P-value Arthrosis Left Crus I Cerebellum IVW(MRE) 34 30.67 1.18 (1.09–1.28) 9.00E-05 MR Egger 34 1.20 (0.87–1.64) 0.28 Weighted median 34 1.17 (1.04–1.31) 9.90E-03 Simple mode 34 1.20 (0.94–1.53) 0.16 Weighted mode 34 1.17 (0.97–1.43) 0.11 Gout Left Frontal Operculum Cortex IVW(MRE) 8 92.42 0.97 (0.95–0.98) 5.00E-05 MR Egger 8 0.98 (0.91–1.05) 0.58 Weighted median 8 0.97 (0.93–1.02) 0.21 Simple mode 8 0.96 (0.90–1.02) 0.27 Weighted mode 8 0.97 (0.94–1.01) 0.25 Gout Left Precentral Gyrus IVW(MRE) 8 92.42 1.05 (1.04–1.07) 1.90E-11 MR Egger 8 1.05 (0.98–1.12) 0.22 Weighted median 8 1.05 (1.01–1.10) 2.70E-02 Simple mode 8 1.06 (0.99–1.13) 0.13 Weighted mode 8 1.05 (1.01–1.10) 0.05 IVW: inverse variance weighted; MRE: multiplicative random effects model; MR Egger: Mendelian randomization-Egger; OR: odds ratio. In the sensitivity analysis, MR-PRESSO and MR-Egger suggested that there was no multiplicity of positive results in the three groups (P > 0.05), and MR-Egger and IVW tests suggested that there was no heterogeneity of positive results in the three groups (P > 0.05). The results are shown in Table 2 . Table 2 Sensitivity analyses for association between joint disease and cortical volume or its subtypes. Joint diseases (exposure) Cortical volume (outcome) No.SNP Pleiotropy Heterogenenity MR-PRESSO Global P-value MR-egger P-value IVW test P-value MR-egger P-value Arthrosis Left Crus I Cerebellum 34 0.4618 0.926920737 0.29848481 0.25778934 Gout Left Frontal Operculum Cortex 8 0.6433 0.719090025 0.99037819 0.98234573 Gout Left Precentral Gyrus 8 0.7769 0.961883801 0.99330544 0.98221574 MR-PRESSO: Mendelian Randomization Pleiotropy RESidual Sum and Outlier; MR-egger: Mendelian randomization-Egger; IVW: inverse variance weighted. 4. Discussion In this study, we used bidirectional MR analysis to screen three specific groups of arthritis for associations with the volume of specific cerebral cortical regions: arthrosis promotes an increase in the volume of the Left Crus I Cerebellum region; Gout promotes a decrease in the volume of the Left Frontal Operculum Cortex region; and Gout promotes an increase in the volume of the Left Precentral Gyrus region. Correspondingly, reverse MR analysis yielded no positive results. To the best of our knowledge, this is the first study to apply Mendelian randomization to explore arthritis with specific cerebral cortical volumes on a large scale. Whether peripheral inflammatory diseases such as arthritis can affect the central nervous system has been a hot topic in immunological and neuroscientific research, and the positive results of our study confirm to some extent the possibility of an association.Given the important role of pro-inflammatory cytokines in the pathogenesis of arthritis, this effect may be largely achieved through pro-inflammatory cytokines.When peripheral inflammation, such as arthritis, occurs in the body, a large number of cytokines are activated. As the main inflammatory mediators, these circulating cytokines not only participate in inducing and maintaining the pathological process of arthritis but also act on the CNS through various pathways [ 13 ] .One of the classic pathways is propagation through neurons. Studies have shown that IL-17, IL-1β, TNF-α, etc. can act on peripheral nociceptive sensory neurons, thereby affecting the release of cytokines in the spinal cord and ultimately inducing central pain sensitization [ 14 ] . In turn, therapeutic neutralization of these cytokines can reduce pain in patients [ 15 ] .The vagus nerve, as a potential second nerve propagation route, has also been observed to be activated by TNF and IL-1β under certain conditions [ 16 ] .In addition to neurotransmission,volume diffusion allows these cytokines to enter the brain through periventricular organs, which lie outside the blood-brain barrier [ 17 ] .Furthermore, circulating cytokines can also directly enter the CNS through the blood-brain barrier. In this case, direct disruption of the blood-brain barrier may occur, with cytokines infiltrating into the brain through the injury [ 18 ] .For instance, Park et al. observed disruption of the blood-brain barrier in a collagen-induced arthritis (CIA) model [ 19 ] .Cytokines have also been reported to be actively transported into the brain through cytokine transporters at the blood-brain barrier [ 20 ] . The multiple pathways of action of peripheral inflammation on the brain ultimately lead to the production of centrally derived pro-inflammatory cytokines by microglia in the brain. These cytokines can slowly diffuse in the brain and are accompanied by the rapid activation of some specific neural pathways [ 21 ] .Cytokines act differently in the brain depending on their receptor distribution and localization. For example, the granule cells of the dental gyrus, the pyramidal cells of the hippocampus, and the anterior pituitary gland are all known to bind to IL-1 receptors [ 22 ] . In view of this, our experimental results may imply the existence of a concentrated distribution of specific cytokine receptors in Left Crus I Cerebellum, Left Frontal Operculum Cortex, and Left Precentral Gyrus. A common form of arthritic pain is knee osteoarthritis (KOA), resulting primarily from degenerative changes in articular cartilage and secondary bone-building development. Millions of people worldwide suffer from chronic pain, stiffness, and gait abnormalities caused by this condition. Motor deficits and emotional and cognitive deficits can result from chronic KOA pain [ 23 ] . Previous neuroimaging studies have shown that osteoarthritis can affect the structure and function of the brain, as well as the plasticity of the cortex.For example, Barroso et al. reported that patients with KOA had lower gray matter (GM) volumes in the precentral cortex than healthy controls (HC) [ 24 ] , and Lewis et al. found that patients with KOA had decreased GM volumes in the bilateral amygdala, the nucleus ambiguus, and the ipsilateral primary somatosensory cortex compared with HC [ 25 ] .In our results, Arthrosis was found to promote increased volume in the Left Crus I Cerebellum area, whereas in another previous study on the effects of KOA on brain function, it was found that KOA could lead to abnormalities in the left cerebellum function of patients, as evidenced by low fALFF measurements in this brain region of the patients compared to HC (fALFF score is the ratio of the power of the low-frequency component to the power of the full-frequency component) [ 26 ] .Our findings are consistent with those of previous studies, which suggest that arthritis may contribute to functional abnormalities in the Left Crus I Cerebellum region by increasing its volume.Based upon the specificity of its function, the Left Crus I Cerebellum is the most prominent and laterally expanded region of the human cerebellum [ 27 ] . In addition to limb motor control and behavioral cognition, this region is also involved in sensorimotor adaptations to pain [ 28 ] . We hypothesized that the emotional experience of chronic pain in arthritis patients may be associated with changes in this brain region. Gout is another common type of inflammatory arthritis. A disorder of uric acid metabolism leads to an elevated blood uric acid concentration, which triggers localized inflammation due to the deposition of uric acid crystals around the joints. Joints affected by this condition are markedly inflamed and painful [ 29 ] .It has been traditionally believed that the central nervous system (CNS) is rarely involved in gout. Nevertheless, recent studies have indicated that hyperuricemia may have some beneficial effects on the CNS when it comes to the development of gout, which is particularly evident in neurodegenerative and psychiatric disorders.For example, it has been shown that hyperuricemia is associated with a lower risk of Alzheimer's disease [ 30 ] . Black CN et al. found that the severity and duration of symptoms of major depression or anxiety disorders were negatively correlated with uric acid levels [ 31 ] .Additionally, it has been reported that gout affects the volume of specific brain regions as well. In a Mendelian randomization study of gout and brain volume, researchers found that genetically predicted gout was significantly associated with gray matter volume in the whole brain, and genetically predicted hyperuricemia was also significantly correlated with gray matter volume in several regions, including the cerebellum, midbrain, pons, and brainstem [ 32 ] . Compared with this previous study, our study provides a more detailed delineation of brain regions, further revealing the correlation between gout and the more subtle brain regions of the Left Frontal Operculum Cortex and Left Precentral Gyrus.Furthermore,Yang et al., in an imaging study using MRI technology to detect cortical volume in gout patients, found that the cortical thickness in the left upper frontal lobe region of gout patients was thinner than that of the healthy control group [ 33 ] . This finding is similar to the genetic prediction in our study that gout can cause a decrease in the volume of the Left Frontal Operculum Cortex. And this strongly supports our experimental results.In fact, both the Left Frontal Operculum Cortex and the Left Precentral Gyrus have extremely complex functions, and when focusing on their functions and pathways related to peripheral inflammation and pain, we found that there are reports that the left frontal-amygdala pathway is involved in endogenous sexual pain inhibition [ 34 ] , while the Left Precentral Gyrus has been reported, along with other subcortical regions, to be involved in modulating pain and inducing pain synchronization [ 35 ] . Based on this, we speculate that gout may induce volume changes in the Left Frontal Operculum Cortex and Left Precentral Gyrus, thereby affecting the pain perception function of gout patients.Given the previously reported potential protective effects of gout and hyperuricemia on some neuropsychiatric diseases, Left Frontal Operculum Cortex and Left Precentral Gyrus may also be potential targets for the effects of uric acid in the CNS. Recent studies suggest that some central nervous system diseases may be genetically linked to arthritis. Researchers have found 15 single nucleotide polymorphisms (SNPs) associated with RA and frontotemporal dementia (FTD) when comparing genome-wide association studies (GWAS) in neurodegenerative diseases and chronic immune-mediated diseases.Notably, most of these SNPs are found on chromosome 6 in the human leukocyte antigen (HLA) region [ 36 ] .Felsky et al. also demonstrated a correlation between polygenic risk for RA and microglia density in the brains of older adults [ 37 ] .The Mendelian randomization study is a genetics-based analysis, and our findings reveal a genetic association between specific arthritis and specific cerebral cortical regions, which may provide ideas for further exploration of the common genetic susceptibility that exists between arthritis and CNS disorders. Our study has the following advantages: A primary advantage of MR analysis is that it has a larger sample size than traditional neuroimaging methods, as well as the ability to effectively avoid interference from reverse causality and potential confounders. Additionally, multiple sensitivity analyses were conducted in this study to ensure robustness. In comparison with previous studies, we have also delineated the cortical regions in a more detailed manner, revealing the relationship between arthritis and certain fine structures in the brain in a more precise manner. Nevertheless, there are some limitations to this study. As a first point, the data used in this study were drawn from Europeans, and the findings may not be generalizable globally. Further, the human brain is capable of performing complex neurobiological functions by interacting synergistically with multiple brain regions. Our findings only indicated a correlation between arthritis and a single brain region, which cannot be interpreted as reflecting the presence of specific brain pathways and networks. Finally, despite the fact that reverse MR did not yield any positive results, this does not necessarily suggest that the CNS is not able to influence peripheral inflammation in an inverse manner. An example would be the vagus nerve, which could influence the onset and progression of arthritis by modulating the production of TNF and other proinflammatory cytokines that contribute to the suppression of immune responses in the CNS [ 38 ] . 5. Conclusion This study is based on the MR analysis method and reveals the causal relationship between arthritis and cortical volume.There is a positive correlation between Arthrosis and Left Crus I Cerebellum volume. Gout has a negative correlation with Left Frontal Operculum Cortex volume. Gout has a positive correlation with the volume of the Left Precentral Gyrus region. Further research is needed on the mechanism and impact of arthritis on the cerebral cortex. Declarations Data Availability declaration arthritis summary statistics derived from https://storage.googleapis.com/finngen-public-data-r8/summary_stats/R8_manifest.tsv and GWAS summary statistics for cortical volume across various areas from https://open.win.ox.ac.uk/ukbiobank/big40/ are both open access. Competing Interest declaration The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article. Author Contributions The study's conception, data analysis and interpretation, and manuscript writing were all done by Wantong Xu and Minghe Ouyang. Zhongbiao Jiang conceived and designed the study and revised the manuscript. The final manuscript was read and approved by the authors. 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Felsky, D., Patrick, E., Schneider, J. A. (2018). Polygenic analysis of inflammatory disease variants and effects on microglia in the aging brain. Mol Neurodegener . ;13(1):38. Published 2018 Jul 24. 10.1186/s13024-018-0272-6 . Chavan, S. S., Pavlov, V. A., & Tracey, K. J. (2017). Mechanisms and Therapeutic Relevance of Neuro-immune Communication. Immunity , 46 (6), 927–942. 10.1016/j.immuni.2017.06.008 . Additional Declarations No competing interests reported. Supplementary Files STable1.xlsx STable2.xlsx STable3.xlsx STable4.xlsx STable5.xlsx STable6.xlsx STable7.xlsx STable8.xlsx STable9.xlsx STable10.xlsx STable11.xlsx Supplementaryfigures.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4313710","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":301787637,"identity":"1633cdeb-350c-4c1f-a84c-38308bd86129","order_by":0,"name":"Wantong Xu","email":"","orcid":"","institution":"Second Xiangya Hospital of Central South University","correspondingAuthor":false,"prefix":"","firstName":"Wantong","middleName":"","lastName":"Xu","suffix":""},{"id":301787638,"identity":"6553b02c-dadd-4f31-b525-1d554d014991","order_by":1,"name":"Minghe Ouyang","email":"","orcid":"","institution":"Central South University","correspondingAuthor":false,"prefix":"","firstName":"Minghe","middleName":"","lastName":"Ouyang","suffix":""},{"id":301787639,"identity":"d0fba180-0888-403a-a1c2-c982a7119c29","order_by":2,"name":"Zhongbiao Jiang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDklEQVRIiWNgGAWjYBACxmYwdQCIeUCkDUSYhwQtaYS1QMEBmLLDhLUwtzM/e/jlzx05c/61Bw/8qDgvLz8jgfHB2zYGeXOcDmMzN5bheWZsOeNdwsGeM7cNN9xIYDac28ZguLMBp1/MpCUkDiduuHHG4ABv2+0EA4kENmneNoYEgwO4tLB/k5YwgGg5+LftXALQYey/8WvhMZP8kADUcr7H4DBv24EEhhsJbMwEtJRJMxw4bGxwgy/hsMyZZMMNZx42S845J2G4AYcWw/7j2yR//DksZ3D+7OGPbyrs5OXbkw9+eFNmI4/LFkNgsDCDY0EiAW5zA4iLXT0QyIOU/ACx+HEYOgpGwSgYBaMAAPG7YqWmrZ+aAAAAAElFTkSuQmCC","orcid":"","institution":"Second Xiangya Hospital of Central South University","correspondingAuthor":true,"prefix":"","firstName":"Zhongbiao","middleName":"","lastName":"Jiang","suffix":""}],"badges":[],"createdAt":"2024-04-23 17:44:03","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4313710/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4313710/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":56938853,"identity":"777f93b1-2d9e-4de3-924b-d2f170386368","added_by":"auto","created_at":"2024-05-22 11:43:13","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":301954,"visible":true,"origin":"","legend":"\u003cp\u003eThe working flow chart of this Bidirectional Two-sample Mendelian Randomization Study to explore the causal relationship between arthritis and cortical volume.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4313710/v1/4523c9fd81cfe211646c5218.png"},{"id":56938291,"identity":"5a8b3cba-944a-40db-8ac9-aa3cd0e7e0bc","added_by":"auto","created_at":"2024-05-22 11:35:13","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":14169,"visible":true,"origin":"","legend":"\u003cp\u003eThe forest plot showing MR results which explores the causal effect of arthritis on cortical volume in different regions.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4313710/v1/ce7692c7bce2f7fc7451efc0.png"},{"id":56938290,"identity":"cd6751aa-f17e-475e-b733-2609093d46bd","added_by":"auto","created_at":"2024-05-22 11:35:13","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":527467,"visible":true,"origin":"","legend":"\u003cp\u003eUnderlying mechanisms of changes in cortical volume due to arthritis.\u003c/p\u003e\n\u003cp\u003ePeripheral inflammation such as arthritis leads to a large number of pro-inflammatory cytokines in the body. These cytokines can act on peripheral nociceptive sensory neurons or vagus nerves to affect the central nervous system, and can also enter the brain through the volume diffusion of periventricular organs, or defects at the blood-brain barrier and active transporters. Microglia in the brain are activated and produce central pro-inflammatory cytokines and spread in the brain, accompanied by the activation of specific neural pathways. Specific cytokines act on receptors in specific regions of the brain. Eventually lead to volume changes in specific cerebral cortex.Figure created with BioRender(https://biorender.com).\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4313710/v1/63214257d38f265845842521.png"},{"id":57044963,"identity":"f25e6316-f968-4f4a-9cd1-920dd89a42ec","added_by":"auto","created_at":"2024-05-24 00:01:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1230445,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4313710/v1/16e52d0a-bf39-4721-8b58-7e23e8b2ada2.pdf"},{"id":56938289,"identity":"96d86d3c-7b18-447b-9ef1-c4248d1fc56b","added_by":"auto","created_at":"2024-05-22 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11:35:14","extension":"xlsx","order_by":11,"title":"","display":"","copyAsset":false,"role":"supplement","size":9785,"visible":true,"origin":"","legend":"","description":"","filename":"STable11.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4313710/v1/c915edf4efd6446e3519aef7.xlsx"},{"id":56938855,"identity":"6d829c2e-dded-48f3-a18c-e7dc849d1ba2","added_by":"auto","created_at":"2024-05-22 11:43:13","extension":"docx","order_by":12,"title":"","display":"","copyAsset":false,"role":"supplement","size":16047778,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaryfigures.docx","url":"https://assets-eu.researchsquare.com/files/rs-4313710/v1/21a85391c40e73c84e6d27a0.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Bidirectional Mendelian randomization explores the causal relationship between arthritis and cerebral cortical volume","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eArthritis is an inflammatory condition that affects one or more joints. It can present as swelling, deformity, pain, and stiffness. There are many pathways through which joints are damaged, including degeneration in osteoarthritis (OA), crystal deposition in gout and pseudogout, metabolic abnormalities (hematosis), and autoimmune diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), or congenital cartilage and bone defects\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAs cerebral cortical surfaces vary widely in thickness and area, they appear to be largely genetically independent and are independent morphometric features of neurodevelopment, aging, and disease\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Quantitative measurements of brain structural anomalies can provide a neuropathological basis for diseases related to those abnormalities, which is essential to the research of diseases.\u003c/p\u003e \u003cp\u003eThe blood-brain barrier (BBB) has long been believed to protect the central nervous system (CNS) from circulating inflammatory signals. However, a large body of neurological and psychiatric evidence suggests that peripheral inflammation interacts closely with the central nervous system in chronic inflammatory diseases like arthritis and that this interaction may result in changes in cortical volume\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e.This interaction can be realized in a number of ways.In some studies, peripheral inflammatory mediators have been demonstrated to enter the CNS through the blood-brain barrier or choroid plexus via infiltration of blood-borne immune cells or inflammatory activation of endothelial cells\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Additionally, CNS-associated myeloid cells, such as microglia, meningeal macrophages, perivascular macrophages, and choroid plexus macrophages, can acquire a spontaneous inflammatory state under certain circumstances\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. Therefore, the association of arthritis with cortical volume needs to be further explored.\u003c/p\u003e \u003cp\u003eGenetic variations are used as instrumental variables (IVs) in Mendelian randomization (MR), an analysis method of GWAS that establishes associations between instrumental variables and exposures and outcomes in order to infer causal relationships\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Three key assumptions underlie MR analysis: (1) instrumental variables are closely related to exposure.(2) no association is observed between instrumental variables and confounding factors.(3) instrumental variables influence outcomes only through exposure. In contrast to traditional research, MR analysis can reduce the interference of confounding factors on the results through a large sample size\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTo explore the causal relationship between arthritis and cerebral cortical volume changes, we used bidirectional Mendelian randomization. We hoped that this study would provide insights into the intrinsic connection between arthritis and cerebral cortical volume changes and could provide further clues for exploring the interaction mechanism between peripheral inflammation and the central nervous system.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Data Sources\u003c/h2\u003e \u003cp\u003eIn this study, data on genetic variation related to arthritis was obtained from the FinnGen database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://r7.finngen.fi/\u003c/span\u003e\u003cspan address=\"https://r7.finngen.fi/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), which covers three types of arthritis: arthrosis, gout, and rheumatoid arthritis. There were 64,930 cases of arthrosis, 7,461 cases of gout, 11,178 cases of rheumatoid arthritis, and 221,323 controls.The genetic data related to cortical volume comes from the Genome Wide Association Study (GWAS), which includes 139 brain regions.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Instrumental variable\u003c/h2\u003e \u003cp\u003eFirst, meaningful SNPs are screened out from the GWAS summary data under the genome-wide significant threshold (P\u0026thinsp;\u0026lt;\u0026thinsp;5\u0026times;10\u003csup\u003e\u0026minus;\u0026thinsp;8\u003c/sup\u003e).Linkage disequilibrium is removed (R2\u0026thinsp;\u0026lt;\u0026thinsp;0.001, genetic distance\u0026thinsp;=\u0026thinsp;10000kb) to ensure that each SNP is independent of each other\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e.At the same time, by calculating the F test value, instrumental variables with F\u0026thinsp;\u0026lt;\u0026thinsp;10 were eliminated (if the F statistic of SNPs is less than 10, it indicates that the SNPs are more likely to have weak instrumental variable bias)\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e.In addition, the pleiotropic residuals and outliers (MR-PRESSO) test was used to identify potential outliers and level pleiotropy (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Once abnormal SNPs are detected, they should be removed\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Statistical analysis\u003c/h2\u003e \u003cp\u003eIn this study, bidirectional MR analysis was conducted on two samples. SNPs associated with arthritis were utilized as instrumental variables for forward MR analysis, and regional cerebral cortical volume was assessed as an outcome.Reverse MR analysis used cerebral cortical volume-related SNPs as instrumental variables, and arthritis was assessed as an outcome.\u003c/p\u003e \u003cp\u003eFor determining the causal effect of exposure on outcome, inverse variance weighting (IVW) was chosen as the preferred MR analysis method, and additional MR methods were used to confirm the reliability and robustness of the results (MR-Egger, Simple Mode, Weighted Median, and Weighted Mode)\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn sensitivity analysis, we used MR-Egger and IVW tests to detect heterogeneity of results, with P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 indicating heterogeneity in Cochran's Q test.Potential horizontal pleiotropy was assessed by calculating the intercepts of instrumental variables in the MR-Egger regression, with P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 indicating the presence of horizontal pleiotropy\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e.As mentioned previously, we used the MR-PRESSO method to detect and eliminate possible outliers and pleiotropic effects.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Result","content":"\u003cp\u003eAll filtered instrumental variables used for forward and reverse MR analysis are shown in Supplementary Tables\u0026nbsp;4 and 5. In order to reduce the probability of errors in the experiment, we conducted multiple comparison corrections on the P-value and ultimately selected the result with P\u0026thinsp;\u0026lt;\u0026thinsp;0.05/139*3 as the positive result.\u003c/p\u003e \u003cp\u003eIn the forward MR analysis, three sets of positive results were obtained(Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).IVW analysis showed that Arthrosis was positively correlated with the volume of Left Crus I Cerebellum (OR\u0026thinsp;=\u0026thinsp;1.18, 95%CI: 1.09\u0026thinsp;~\u0026thinsp;1.28, P\u0026thinsp;=\u0026thinsp;9\u0026times;10\u003csup\u003e\u0026minus;\u0026thinsp;5\u003c/sup\u003e).Gout was negatively correlated with the volume of Left Frontal Operculum Cortex (OR\u0026thinsp;=\u0026thinsp;0.97, 95% CI: 0.95\u0026thinsp;~\u0026thinsp;0.98, P\u0026thinsp;=\u0026thinsp;5\u0026times;10\u003csup\u003e\u0026minus;\u0026thinsp;5\u003c/sup\u003e).Gout was positively correlated with Left Precentral Gyrus volume (OR\u0026thinsp;=\u0026thinsp;1.05, 95%CI: 1.04\u0026thinsp;~\u0026thinsp;1.07, P\u0026thinsp;=\u0026thinsp;1.9\u0026times;10\u003csup\u003e\u0026minus;\u0026thinsp;11\u003c/sup\u003e).The results of the five MR analyses were directionally consistent for each set of positive data.And no positive results were obtained in all reverse MR analyses.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eFull positive results of MR estimate for the association between joint disease and cortical volume or its subtypes.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJoint diseases (exposure)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCortical volume (outcome)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMR method\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo. SNP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eOR(95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArthrosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLeft Crus I Cerebellum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW(MRE)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e30.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.18 (1.09\u0026ndash;1.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9.00E-05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMR Egger\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.20 (0.87\u0026ndash;1.64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWeighted median\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.17 (1.04\u0026ndash;1.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9.90E-03\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSimple mode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.20 (0.94\u0026ndash;1.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWeighted mode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.17 (0.97\u0026ndash;1.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGout\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLeft Frontal Operculum Cortex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW(MRE)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e92.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.97 (0.95\u0026ndash;0.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.00E-05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMR Egger\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.98 (0.91\u0026ndash;1.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWeighted median\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.97 (0.93\u0026ndash;1.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSimple mode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.96 (0.90\u0026ndash;1.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWeighted mode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.97 (0.94\u0026ndash;1.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGout\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLeft Precentral Gyrus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW(MRE)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e92.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.05 (1.04\u0026ndash;1.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.90E-11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMR Egger\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.05 (0.98\u0026ndash;1.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWeighted median\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.05 (1.01\u0026ndash;1.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.70E-02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSimple mode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.06 (0.99\u0026ndash;1.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWeighted mode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.05 (1.01\u0026ndash;1.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eIVW: inverse variance weighted; MRE: multiplicative random effects model; MR Egger: Mendelian randomization-Egger; OR: odds ratio.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn the sensitivity analysis, MR-PRESSO and MR-Egger suggested that there was no multiplicity of positive results in the three groups (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05), and MR-Egger and IVW tests suggested that there was no heterogeneity of positive results in the three groups (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). The results are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSensitivity analyses for association between joint disease and cortical volume or its subtypes.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eJoint diseases (exposure)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCortical volume (outcome)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNo.SNP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003ePleiotropy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eHeterogenenity\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMR-PRESSO Global P-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMR-egger P-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIVW test P-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMR-egger P-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArthrosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLeft Crus I Cerebellum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.4618\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.926920737\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.29848481\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.25778934\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGout\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLeft Frontal Operculum Cortex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.6433\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.719090025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.99037819\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.98234573\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGout\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLeft Precentral Gyrus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.7769\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.961883801\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.99330544\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.98221574\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eMR-PRESSO: Mendelian Randomization Pleiotropy RESidual Sum and Outlier; MR-egger: Mendelian randomization-Egger; IVW: inverse variance weighted.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eIn this study, we used bidirectional MR analysis to screen three specific groups of arthritis for associations with the volume of specific cerebral cortical regions: arthrosis promotes an increase in the volume of the Left Crus I Cerebellum region; Gout promotes a decrease in the volume of the Left Frontal Operculum Cortex region; and Gout promotes an increase in the volume of the Left Precentral Gyrus region. Correspondingly, reverse MR analysis yielded no positive results. To the best of our knowledge, this is the first study to apply Mendelian randomization to explore arthritis with specific cerebral cortical volumes on a large scale.\u003c/p\u003e \u003cp\u003eWhether peripheral inflammatory diseases such as arthritis can affect the central nervous system has been a hot topic in immunological and neuroscientific research, and the positive results of our study confirm to some extent the possibility of an association.Given the important role of pro-inflammatory cytokines in the pathogenesis of arthritis, this effect may be largely achieved through pro-inflammatory cytokines.When peripheral inflammation, such as arthritis, occurs in the body, a large number of cytokines are activated. As the main inflammatory mediators, these circulating cytokines not only participate in inducing and maintaining the pathological process of arthritis but also act on the CNS through various pathways\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e.One of the classic pathways is propagation through neurons. Studies have shown that IL-17, IL-1β, TNF-α, etc. can act on peripheral nociceptive sensory neurons, thereby affecting the release of cytokines in the spinal cord and ultimately inducing central pain sensitization\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. In turn, therapeutic neutralization of these cytokines can reduce pain in patients\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e.The vagus nerve, as a potential second nerve propagation route, has also been observed to be activated by TNF and IL-1β under certain conditions\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e.In addition to neurotransmission,volume diffusion allows these cytokines to enter the brain through periventricular organs, which lie outside the blood-brain barrier\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e.Furthermore, circulating cytokines can also directly enter the CNS through the blood-brain barrier. In this case, direct disruption of the blood-brain barrier may occur, with cytokines infiltrating into the brain through the injury\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e.For instance, Park et al. observed disruption of the blood-brain barrier in a collagen-induced arthritis (CIA) model\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e.Cytokines have also been reported to be actively transported into the brain through cytokine transporters at the blood-brain barrier\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe multiple pathways of action of peripheral inflammation on the brain ultimately lead to the production of centrally derived pro-inflammatory cytokines by microglia in the brain. These cytokines can slowly diffuse in the brain and are accompanied by the rapid activation of some specific neural pathways\u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e.Cytokines act differently in the brain depending on their receptor distribution and localization. For example, the granule cells of the dental gyrus, the pyramidal cells of the hippocampus, and the anterior pituitary gland are all known to bind to IL-1 receptors\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn view of this, our experimental results may imply the existence of a concentrated distribution of specific cytokine receptors in Left Crus I Cerebellum, Left Frontal Operculum Cortex, and Left Precentral Gyrus.\u003c/p\u003e \u003cp\u003eA common form of arthritic pain is knee osteoarthritis (KOA), resulting primarily from degenerative changes in articular cartilage and secondary bone-building development. Millions of people worldwide suffer from chronic pain, stiffness, and gait abnormalities caused by this condition. Motor deficits and emotional and cognitive deficits can result from chronic KOA pain\u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. Previous neuroimaging studies have shown that osteoarthritis can affect the structure and function of the brain, as well as the plasticity of the cortex.For example, Barroso et al. reported that patients with KOA had lower gray matter (GM) volumes in the precentral cortex than healthy controls (HC)\u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e, and Lewis et al. found that patients with KOA had decreased GM volumes in the bilateral amygdala, the nucleus ambiguus, and the ipsilateral primary somatosensory cortex compared with HC\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e.In our results, Arthrosis was found to promote increased volume in the Left Crus I Cerebellum area, whereas in another previous study on the effects of KOA on brain function, it was found that KOA could lead to abnormalities in the left cerebellum function of patients, as evidenced by low fALFF measurements in this brain region of the patients compared to HC (fALFF score is the ratio of the power of the low-frequency component to the power of the full-frequency component)\u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e.Our findings are consistent with those of previous studies, which suggest that arthritis may contribute to functional abnormalities in the Left Crus I Cerebellum region by increasing its volume.Based upon the specificity of its function, the Left Crus I Cerebellum is the most prominent and laterally expanded region of the human cerebellum\u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e. In addition to limb motor control and behavioral cognition, this region is also involved in sensorimotor adaptations to pain\u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e. We hypothesized that the emotional experience of chronic pain in arthritis patients may be associated with changes in this brain region.\u003c/p\u003e \u003cp\u003eGout is another common type of inflammatory arthritis. A disorder of uric acid metabolism leads to an elevated blood uric acid concentration, which triggers localized inflammation due to the deposition of uric acid crystals around the joints. Joints affected by this condition are markedly inflamed and painful\u003csup\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e.It has been traditionally believed that the central nervous system (CNS) is rarely involved in gout. Nevertheless, recent studies have indicated that hyperuricemia may have some beneficial effects on the CNS when it comes to the development of gout, which is particularly evident in neurodegenerative and psychiatric disorders.For example, it has been shown that hyperuricemia is associated with a lower risk of Alzheimer's disease\u003csup\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e. Black CN et al. found that the severity and duration of symptoms of major depression or anxiety disorders were negatively correlated with uric acid levels\u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e.Additionally, it has been reported that gout affects the volume of specific brain regions as well. In a Mendelian randomization study of gout and brain volume, researchers found that genetically predicted gout was significantly associated with gray matter volume in the whole brain, and genetically predicted hyperuricemia was also significantly correlated with gray matter volume in several regions, including the cerebellum, midbrain, pons, and brainstem\u003csup\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e. Compared with this previous study, our study provides a more detailed delineation of brain regions, further revealing the correlation between gout and the more subtle brain regions of the Left Frontal Operculum Cortex and Left Precentral Gyrus.Furthermore,Yang et al., in an imaging study using MRI technology to detect cortical volume in gout patients, found that the cortical thickness in the left upper frontal lobe region of gout patients was thinner than that of the healthy control group\u003csup\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e. This finding is similar to the genetic prediction in our study that gout can cause a decrease in the volume of the Left Frontal Operculum Cortex. And this strongly supports our experimental results.In fact, both the Left Frontal Operculum Cortex and the Left Precentral Gyrus have extremely complex functions, and when focusing on their functions and pathways related to peripheral inflammation and pain, we found that there are reports that the left frontal-amygdala pathway is involved in endogenous sexual pain inhibition\u003csup\u003e[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e, while the Left Precentral Gyrus has been reported, along with other subcortical regions, to be involved in modulating pain and inducing pain synchronization\u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e. Based on this, we speculate that gout may induce volume changes in the Left Frontal Operculum Cortex and Left Precentral Gyrus, thereby affecting the pain perception function of gout patients.Given the previously reported potential protective effects of gout and hyperuricemia on some neuropsychiatric diseases, Left Frontal Operculum Cortex and Left Precentral Gyrus may also be potential targets for the effects of uric acid in the CNS.\u003c/p\u003e \u003cp\u003eRecent studies suggest that some central nervous system diseases may be genetically linked to arthritis. Researchers have found 15 single nucleotide polymorphisms (SNPs) associated with RA and frontotemporal dementia (FTD) when comparing genome-wide association studies (GWAS) in neurodegenerative diseases and chronic immune-mediated diseases.Notably, most of these SNPs are found on chromosome 6 in the human leukocyte antigen (HLA) region\u003csup\u003e[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e.Felsky et al. also demonstrated a correlation between polygenic risk for RA and microglia density in the brains of older adults\u003csup\u003e[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e.The Mendelian randomization study is a genetics-based analysis, and our findings reveal a genetic association between specific arthritis and specific cerebral cortical regions, which may provide ideas for further exploration of the common genetic susceptibility that exists between arthritis and CNS disorders.\u003c/p\u003e \u003cp\u003eOur study has the following advantages: A primary advantage of MR analysis is that it has a larger sample size than traditional neuroimaging methods, as well as the ability to effectively avoid interference from reverse causality and potential confounders. Additionally, multiple sensitivity analyses were conducted in this study to ensure robustness. In comparison with previous studies, we have also delineated the cortical regions in a more detailed manner, revealing the relationship between arthritis and certain fine structures in the brain in a more precise manner.\u003c/p\u003e \u003cp\u003eNevertheless, there are some limitations to this study. As a first point, the data used in this study were drawn from Europeans, and the findings may not be generalizable globally. Further, the human brain is capable of performing complex neurobiological functions by interacting synergistically with multiple brain regions. Our findings only indicated a correlation between arthritis and a single brain region, which cannot be interpreted as reflecting the presence of specific brain pathways and networks. Finally, despite the fact that reverse MR did not yield any positive results, this does not necessarily suggest that the CNS is not able to influence peripheral inflammation in an inverse manner. An example would be the vagus nerve, which could influence the onset and progression of arthritis by modulating the production of TNF and other proinflammatory cytokines that contribute to the suppression of immune responses in the CNS\u003csup\u003e[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eThis study is based on the MR analysis method and reveals the causal relationship between arthritis and cortical volume.There is a positive correlation between Arthrosis and Left Crus I Cerebellum volume. Gout has a negative correlation with Left Frontal Operculum Cortex volume. Gout has a positive correlation with the volume of the Left Precentral Gyrus region. Further research is needed on the mechanism and impact of arthritis on the cerebral cortex.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eData Availability declaration\u003c/p\u003e\n\u003cp\u003earthritis summary statistics derived from https://storage.googleapis.com/finngen-public-data-r8/summary_stats/R8_manifest.tsv and GWAS summary statistics for cortical volume across various areas from https://open.win.ox.ac.uk/ukbiobank/big40/ are both open access.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCompeting Interest declaration\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAuthor Contributions\u003c/p\u003e\n\u003cp\u003eThe study\u0026apos;s conception, data analysis and interpretation, and manuscript writing were all done by Wantong Xu and\u0026nbsp;Minghe Ouyang.\u0026nbsp;Zhongbiao Jiang\u0026nbsp;conceived and designed the study and revised the manuscript. The final manuscript was read and approved by the authors.\u003c/p\u003e\n\u003cp\u003eAcknowledgments\u003c/p\u003e\n\u003cp\u003eThe consortium\u0026apos;s release of cortical volume phenotypes of the GWAS summary statistics were appreciated by the authors. The authors also wish to thank the authors of the GWAS summary statistics for arthritis from FinnGen.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis study was funded by the Natural Science Foundation of Hunan Province \u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHarth, M., \u0026amp; Nielson, W. R. (2019). 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Mechanisms and Therapeutic Relevance of Neuro-immune Communication. \u003cem\u003eImmunity\u003c/em\u003e, \u003cem\u003e46\u003c/em\u003e(6), 927\u0026ndash;942. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.immuni.2017.06.008\u003c/span\u003e\u003cspan address=\"10.1016/j.immuni.2017.06.008\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Mendelian randomization arthritis cerebral cortical volume","lastPublishedDoi":"10.21203/rs.3.rs-4313710/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4313710/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eMendelian randomization method was used to explore the causal relationship between the occurrence of arthritis disease and volume changes in specific cerebral cortical regions.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eBy analyzing the GWAS summary data,SNP data related to arthritis and cerebral cortex volume were selected.Using the inverse variance weighted (IVW) method as the preferred method, MR Egger, Simple Mode, Weighted Median, and Weighted Mode were used as auxiliary analysis to conduct a two-sample bidirectional Mendelian randomization analysis.\u003c/p\u003e\u003ch2\u003eResult\u003c/h2\u003e \u003cp\u003eIVW analysis showed that Arthrosis was positively correlated with the volume of Left Crus I Cerebellum (OR\u0026thinsp;=\u0026thinsp;1.18, 95%CI: 1.09\u0026thinsp;~\u0026thinsp;1.28, P\u0026thinsp;=\u0026thinsp;9\u0026times;10\u003csup\u003e\u0026minus;\u0026thinsp;5\u003c/sup\u003e).Gout was negatively correlated with the volume of Left Frontal Operculum Cortex (OR\u0026thinsp;=\u0026thinsp;0.97, 95% CI: 0.95\u0026thinsp;~\u0026thinsp;0.98, P\u0026thinsp;=\u0026thinsp;5\u0026times;10\u003csup\u003e\u0026minus;\u0026thinsp;5\u003c/sup\u003e).Gout was positively correlated with Left Precentral Gyrus volume (OR\u0026thinsp;=\u0026thinsp;1.05, 95%CI: 1.04\u0026thinsp;~\u0026thinsp;1.07, P\u0026thinsp;=\u0026thinsp;1.9\u0026times;10\u003csup\u003e\u0026minus;\u0026thinsp;11\u003c/sup\u003e).No positive results were obtained by reverse MR analysis.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eArthrosis promotes increased volume of the Left Crus I Cerebellum.Gout promotes decreased volume of the Left Frontal Operculum Cortex.Gout promotes increased volume of the Left Precentral Gyrus.\u003c/p\u003e","manuscriptTitle":"Bidirectional Mendelian randomization explores the causal relationship between arthritis and cerebral cortical volume","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-22 11:35:07","doi":"10.21203/rs.3.rs-4313710/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"00f0792b-719d-45a6-a85a-8a937c89ff15","owner":[],"postedDate":"May 22nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-05-23T23:53:28+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-22 11:35:07","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4313710","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4313710","identity":"rs-4313710","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}