Association of Glutamate Receptor Metabotropic 5 Gene (Grm5) Polymorphisms With Schizophrenia Susceptibility and Symptoms in a Chinese-Han Population

Association of Glutamate Receptor Metabotropic 5 Gene (Grm5) Polymorphisms With Schizophrenia Susceptibility and Symptoms in a Chinese-Han Population | 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 Association of Glutamate Receptor Metabotropic 5 Gene (Grm5) Polymorphisms With Schizophrenia Susceptibility and Symptoms in a Chinese-Han Population Wenqiang Li, Xi Su, Xiaoge Guo, Qing Liu, Luwen Zhang, Minglong Shao, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-253495/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 Objectives: Metabotropic glutamate receptor subtype 5 (mGluR5) is a potential target for the treatment of schizophrenia (SZ), with the evidence that mGluR5 modulates glutamatergic signaling through the NMDA receptor (NMDAR). Recently it was reported that the GRM5 gene (encoding mGluR5) is associated with SZ in the Scottish population. Methods: Here, case-control association analyses were performed in the Chinese-Han population to investigate if GRM5 gene is implicated in SZ. Twenty-four single nucleotide polymorphisms (SNPs) were analyzed in 528 paranoid SZ and 528 control subjects. Results: The genotypic and allelic frequencies of two SNPs, rs567990 and rs12421343 were significantly different between the case and control group (Genotype P = 0.007 and 0.011; Allele P = 0.003 and 0.021; respectively). The frequency of rs504183 allele was associated with SZ ( P = 0.030). When subjects were stratified by gender, the rs12422021, rs567990, rs12421343, and rs7101540 remained significantly associated with SZ in female patients. Analysis of clinical features of SZ, as measured by the Positive and Negative Syndrome Scale (PANSS) inventory, displayed association of GRM5 to features of the general phenotype of SZ, including traits representing delusions, hallucinations and negative symptoms. Conclusion: In conclusion, our study provides further evidence that GRM5 is associated with SZ, and implies a putative sex difference for the effect of the gene. Cellular & Molecular Neuroscience schizophrenia GRM5 SNPs association analyses PANSS Figures Figure 1 Introduction Schizophrenia (SZ) is a common serious mental disorder, and its symptoms are complex and clinical diagnostic criteria are different, which is mainly characterized by mental, emotional and behavioral disorders and incoordination of mental activities (Keshavan et al. 2020; Schaefer et al. 2020). Researches based on family or twin suggest that schizophrenia has a high heritability of 64-81% and a complex genetic component (Yue et al. 2017). It is often described as a heterogeneous disorder affected by multiple genes, each with a small effect (Goldman et al. 2020). Thus far, genetics studies have suggested numerous putative chromosomal loci for this disorder. Although the pathogenesis of schizophrenia is unclear, studies suggest that the disorder is associated with abnormal neurodevelopment (Matosin and Newell 2013), in which both genetic and environmental factors could influence the structure and function of brain (Lang et al. 2007). Glutamate has been linked to a myriad of processes surrounding cognition, memory, and perception (Thomas et al. 2017). Mounting evidence suggest that glutamatergic dysfunction may be critical in the etiology of schizophrenia (Steele et al. 2012). Glutamate is an excitatory neurotransmitter that is abundant in the brain and plays an important role in various brain functions and brain development (Uno and Coyle 2019; Wickens et al. 2018). Glutamate exerts effects through activating metabotropic glutamate receptors (mGluRs) and ionotropic receptors (iGluRs). The iGluRs include the N-methyl-D-aspartate receptors (NMDAR), a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) and Kainate receptors. Metabotropic glutamate receptors are G protein-coupled receptors and modulate cellular excitability and synaptic transmission (Niswender and Conn 2010). There are different subtypes of mGluRs in presynaptic and postsynaptic membrane that could modulate glutamatergic neurotransmission. The involvement in multiple neuronal processes indicates its importance on the dysfunction of brain (Mukherjee and Manahan-Vaughan 2013). Therefore, it is necessary to conduct in-depth systematic analyses on the relationship between candidate genes of glutamate pathway and schizophrenia. Metabolic glutamate receptor subtype 5 (mGluR5, encoded by gene GRM5 ) plays an irreplaceable role in the glutamate pathway, and convergent lines of evidence suggest that implicated in schizophrenia (Akkus et al. 2017). Studies have shown that mGluR5 critically modulate the function of NMDAR, which is strongly associated with schizophrenia, and mGluR5 abnormalities maybe contribute to pathogenesis of schizophrenia (Zurawek et al. 2018). The involvement of NMDAR in the long-term potentiation (LTP) process involved in memory and cognition, suggesting that mGluR5 may be a potential therapeutic target for the repair of cognitive deficits in schizophrenia (Kosten et al. 2016; Matosin et al. 2017). Abnormal expression or dysfunction of the mGluR5 is associated with schizophrenia (Matosin et al. 2016), and might originate at the genetic level. In a case-control study, the distribution of allele frequencies of the GRM5 gene was found to be significantly different between schizophrenia patients and controls in the Scottish population (Devon et al. 2001). Here, we performed a case-control analysis in the Chinese-Han population to investigate the potential associations between schizophrenia and GRM5 SNPs, providing new evidence for schizophrenia susceptibility gene research. Materials And Methods The Ethical permission was obtained from the Ethical Committee of the Second Affiliated Hospital of Xinxiang Medical University. Written informed consent was obtained from all participants after an adequate explanation of the objectives and procedures about the study. Subjects Unrelated schizophrenic patients were recruited from Han population in northern Henan and 528 paranoid SZ were selected as cases (age from 18-35 years old). According to the diagnostic criteria the DSM-IV, at least two experienced psychiatrists make a consensus diagnosis. Individuals with a history of severe medical complications, organic brain diseases, and other psychiatric disorders were excluded. In the meantime, healthy people who had four biological grandparents of Han Chinese ancestry were recruited from surrounding communities and villages, of which 528 healthy controls matched for sex ratio (1:1 for both groups), age, and ethnicity. The syndromes of 267 first-episode patients were assessed by the Positive and Negative Symptom Scale (PANSS). SNP Selection The functional analysis was performed for all SNPs in the GRM5 gene region using the FASTSNP online tool (Yuan et al. 2006). According to the HapMap database, the SNPs with high ranking risk and minor allele frequency (MAF) ≥ 0.05 in the Chinese-Han population were screened out. Tag SNPs were selected through the same method in previous article (Carlson et al. 2004; Li et al. 2013) (r 2 ≥ 0.80, MAF ≥ 0.05) using HapMap database by Haploview v4.1 (Barrett et al. 2005). All selected SNPs were evaluated, and the SNPs with Illumina design scores below 0.6 were excluded. Genotyping Genomic DNA samples of the participants were isolated from their peripheral blood using the Blood DNA System (Tiangen Biotech, Beijing, China). Genotyping was done using the Illumina GoldenGate assay with a BeadStation 500G System following the Illumina protocol. To evaluate the quality of genotyping, SNP genotyping of 100 samples was performed by DNA sequencing and 96 samples were genotyped in duplicate performed. Statistical analysis Power calculations were performed using the Genetic Power Calculator (Purcell et al. 2003). Genotypes and allele association test, haplotype analysis and Hardy-Weinberg equilibrium (HWE) evaluation were performed using the Haploview v4.1 software. Genotypes and allele were compared between two groups by the Pearson chi-square test. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by SNPStats, a web tool (Sole et al. 2006). Bonferroni corrections for multiple tests were used to exclude type I errors. Comparison of different genotypes in the case group with the clinical symptoms of the patients was performed using the SPSS13.0 statistical software package. The Levene variance homogeneity test was used for ANOVA, and the Krtlskal-Wailis rank sum test was used for SNP with irregular variance. The five factors scores of the PANSS were compared among different genotypes in the same SNP (Yang et al. 2015). The criterion for significance was set at P<0.05 for all tests. Results The alleles and genotype frequencies of twenty-four common SNPs at the GRM5 gene were analyzed in all samples, with a genotyping success rate of 99.83%. The genotype concordance between GoldenGate assay and DNA sequencing was 99.25%. The total sample size (n=1056) had a power of 0.86 to detect a small effect, and a power of 1.00 to detect both medium and large effects on genotype distributions. Among the twenty-four SNPs, twenty-two yielded genotype data, with the genotype and allele frequencies shown in Table 1 . Only rs4753778 and rs982709 were not in HWE. The genotypic and allelic frequencies of two SNPs, rs567990 and rs12421343 were significantly different between the case and control group (Genotype P = 0.007 and 0.011; Allele P = 0.003 and 0.021; respectively). Furthermore, the frequency of rs504183 allele was associated with schizophrenia ( P = 0.030). When we stratified subjects by gender, the genotype and allele frequency of rs12421343 was significantly different between case and control group ( P = 0.003 and 0.004 respectively) in female samples. Additional, rs12422021, rs567990, and rs7101540 allelic frequency was associated with schizophrenia ( P = 0.030, 0.010, 0.040; OR = 0.600, 0.750, 0.630; 95%CI = 0.38-0.96, 0.59-0.95, 0.40-0.97; respectively) ( Supplementary Table 1 ). However, there was no significant difference on genotype and allele frequency between male and control subjects ( P > 0.05, data not shown ). The haplotype structure of our sample and associations between schizophrenia and LD blocks, then pair-wise LD of twenty-two SNPs in the schizophrenia patient and control group was analyzed by the standardized D′ and r 2 values. The SNP’s order and physical locations in the GRM5 gene, the LD structure, and the D′ values for all variants were presented in Fig. 1 Haplotypes GG and AA in the LD block rs567990−rs12421343 showed significant difference between schizophrenia and controls ( P = 0.003, and 0.025, respectively), and so was haplotype AA in the LD block rs7932640−rs7125164 ( P = 0.041). It shows the three significantly associated haplotypes in Table 2. To detect the association between the SNPs of GRM5 gene and symptoms, the PANSS scores of 267 schizophrenia patients were analyzed. As shown in Table 3 , there were significant difference between patients with different rs12422021 genetypes (GG, AA + AG) on total PANSS and positive, excitement, cognitive impairment factor subscores ( P = 0.026, 0.019, 0.016, 0.024; respectively). Furthermore, negative factor subscores were significantly differed among the three genotypes of rs504183 ( P = 0.025, and 0.040; respectively). The significantly associated with positive (rs12421343) and cognitive impairment (rs567990) factor subscores ( P = 0.003, 0.020; respectively). Discussion The aim of this study is to investigate the GRM5 mutations associated with schizophrenia and psychotic symptoms in the Han Chinese population. There were significant differences in genotype and allele frequencies of two SNPs (rs567990 and rs12421343) between the case group and the control group. In addition, the allele frequencies of the rs504183 SNP was significantly associated with schizophrenia in this population. In the GRM5 gene, the haplotypes GG and AA (rs567990-rs12421343) revealed significant associations with schizophrenia, and so did haplotype AA（rs7932640-rs7125164). This indicates that variations in the GRM5 gene may increase susceptibility to schizophrenia in the Chinese Han population. When we divided the patients by gender, we found the association of the genotype and allele frequency of rs12421343 of GRM5 with schizophrenia in female subjects, and the allele frequency of rs12422021, rs567990, and rs7101540, but not in male subjects. Moreover, research have shown that there was a positive correlation between the PAWR gene and female schizophrenia in Taiwanese Han population (Wang et al. 2008), similarly, female specificity was found in the schizophrenia Jewish population associated with rs7341475 in the RELN gene (Liu et al. 2010). Numerous studies have revealed the gender differences in clinical features of schizophrenia, such as age of onset, symptoms, drug response, clinical course and prognosis (Chen et al. 2018; de Boer et al. 2018). Some researchers have demonstrated that there may be differences in etiology between male and female patients (Mendrek and Mancini-Marie 2016; Noguera et al. 2018). Gender differences in schizophrenia are thought to be associated with estrogen levels in patients. It has been demonstrated that estrogen impacts neuronal growth and death at every level, which involved in the mechanism of neurodegenerative in schizophrenia (Goncalves et al. 2019) . Though the interaction between the female-specific association of the GRM5 gene and schizophrenia is unclear, our study support differences in genetic susceptibility between the genders. The clinical characteristics of schizophrenia include positive symptoms (delusions, hallucinations and erratic behavior), negative symptoms (apathy, anhedonia and depression), and cognitive disturbances (poor learning and memory) (Albanna et al. 2014; Zurawek et al. 2018). In this study, two SNPs in GRM5 gene were associated with schizophrenia positive symptoms and one SNP was associated with negative symptoms. This consistently demonstrated the association of GRM5 variants with the pathophysiology of schizophrenia. Jennifer et al. found that positive allosteric modulators (PAMs) for mGluR5 may be effective in treating positive symptoms of schizophrenia (Ayala et al. 2009). Studies have also shown that negative symptoms and cognitive disorders may be the effects of glutamatergic dysfunction (McAllister et al. 2015; Volk et al. 2015). The glutaminergic theory of schizophrenia is supported by the following observations: subchronic administration of ketamine and phenylidine (PCP, the noncompetitive antagonists of the NMDAR) in healthy humans can induce similar clinical manifestations of schizophrenia, including cognitive impairment (Coyle et al. 2012). It should be noted that NMDAR blockade can regulate dopaminergic signal transduction in the marginal pathway of the mesencephalon (Yang et al. 2017). Recent evidence suggests the importance of mGluR5 in regulating the activity and function of NMDAR. Thus, GRM5 is associated with the psychopathology of schizophrenia. mGluR5 is an excitatory post-synaptic receptor which can regulate neuronal excitability, synaptic plasticity and synaptic selection (Hoeffer and Klann 2010). It is enriched in the brain regions involved in cognition, including hippocampus, striatum and cortex (Lopez-Bendito et al. 2002). It is believed that mGluR5 can regulate many cognitive fields and behaviors (Bird et al. 2014; Maksymetz et al. 2017; Matosin et al. 2018; Wu et al. 2020). This study showed that rs567990 and rs12422021 were significantly correlated with cognitive impairment factor subscores. This suggests that GRM5 is associated with cognitive function in schizophrenia. In addition, some susceptible genes of schizophrenia show a dynamic process during the early development of the prefrontal cortex. Therefore, the abnormal expression of these susceptible genes can increase the occurrence of abnormal brain function and cause schizophrenia. The expression of GRM5 gene changes with age (Hernandez et al. 2018). Studies have shown that GRM5 is involved in basic developmental processes such as proliferation, differentiation, and survival of cells (Purgert et al. 2014). Therefore, it reflects the important role of GRM5 in the early development of brain function. GRM5 is the best functional candidate gene involved in psychopathology on chromosome 11 (Devon et al. 2001) . In a case-control study, Devon et al. had found a significant difference in the distribution of allele frequencies of GRM5 gene between schizophrenic patients and controls. The difference was detected in an intron region of the GRM5 gene using microsatellites. Based on recent studies, it has been proved that enhancing the function of GRM5 showed therapeutic effects. This study and previous have demonstrated that GRM5 is a candidate susceptibility gene for schizophrenia. In many previous studies, the subjects were from vast geographic regions and genetically heterogeneous. However, we avoid the effect of group stratification, as all subjects in our study were from Xinxiang or surrounding counties, and genetic structure analysis showed that schizophrenia patients and controls belonged to the same population. Replication studies are required to be carried out in different ethnic groups, particularly in patients with definite schizophrenia phenotypes to confirm the role of GRM5 variants in schizophrenia. Conclusion In summary, our study provides new evidence suggesting that GRM5 is associated with schizophrenia. The genetic variation of GRM5 may increase susceptibility of schizophrenia. Declarations Funding This work was supported in part by the National Natural Science Foundation of China (U1904130 to WQ-L; 82001407 to XS; 81971252 to LX-L; 81903688 to ML-S), Medical science and technology research project of Henan Province (LHGJ20190476 to MS; 2018020371 to XS), Key Scientific Research Project of Henan Higher Education Institutions (20B320016 to MS), The Open Fund of Henan Key lab of Biological Psychiatry (ZDSYS2018003 to MS; ZDSYS2018008 to XS), Science and technology research project of Henan Province (212102310587 to MS; 212102310589 to YF-Y), National Key Research and Development Program of China (2016YFC1307001 to LX-L). Conflict of Interest The authors declare that they have no conflict of interest. Availability of data and material The data is freely available to the public. Code availability Not applicable. Author Contributions All authors contributed to the study conception and design. The literature searches and analyses were managed by Meng Song and Wenqiang Li. Sample selection and data management were conducted by Xiaoge Guo, Qing Liu, Luwen Zhang, Yan Zhang, Minli Ding, Yanli Lu and Yongfeng Yang. The statistical analysis was performed by Wenqiang Li, Xi Su, Xiaoge Guo, Meng Song, Ming Li and Minglong Shao. The first draft of the manuscript was written by Wenqiang Li and Xi Su. All authors contributed to and have approved the final manuscript. Ethics approval The Ethical permission was obtained from the Ethical Committee of the Second Affiliated Hospital of Xinxiang Medical University. Consent to participate Written informed consent was obtained from all participants after an adequate explanation of the objectives and procedures about the study. Consent for publication All participants and authors approved the publication of this manuscript. 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(2006) FASTSNP: an always up-to-date and extendable service for SNP function analysis and prioritization Nucleic Acids Res 34:W635-641 doi:10.1093/nar/gkl236 Yue W, Yu X, Zhang D (2017) Progress in genome-wide association studies of schizophrenia in Han Chinese populations NPJ Schizophr 3:24 doi:10.1038/s41537-017-0029-1 Zurawek D, Salerno-Kochan A, Dziedzicka-Wasylewska M, Nikiforuk A, Kos T, Popik P (2018) Changes in the expression of metabotropic glutamate receptor 5 (mGluR5) in a ketamine-based animal model of schizophrenia Schizophr Res 192:423-430 doi:10.1016/j.schres.2017.04.014 Tables Table 1 Genotype and allele frequencies of twenty-two SNPs in the GRM5 gene in patients with schizophrenia and controls SNP# dbSNP ID Allele(D/d) a Patients Controls p- value c n b HWE( P ) Genotype MAF n b HWE( P ) Genotype MAF DD Dd dd DD Dd dd Genotype Allele 1 rs567990 A/G 528 0.393 130 254 144 0.513 527 0.467 156 269 102 0.449 0.007(0.165) 0.003(0.073) 2 rs12421343 A/G 528 0.275 434 87 7 0.096 528 0.093 456 72 0 0.068 0.011(0.272) 0.021(0.513) 3 rs504183 C/A 528 0.299 224 248 56 0.341 527 0.253 255 231 41 0.297 0.085 0.030(0.728) 4 rs7932640 A/G 528 0.791 196 249 83 0.393 526 0.965 220 240 66 0.354 0.170 0.062 5 rs7101540 A/T 528 0.144 428 98 2 0.097 528 0.985 451 74 3 0.076 0.130 0.088 6 rs7125164 C/A 527 0.844 189 255 83 0.399 527 0.991 173 258 96 0.427 0.430 0.200 7 rs12422021 A/G 527 0.630 453 72 2 0.072 528 0.353 469 56 3 0.059 0.290 0.213 8 rs2306153 G/A 528 0.763 476 51 1 0.050 528 0.963 464 62 2 0.063 0.460 0.220 9 rs679333 C/A 528 0.031 225 256 47 0.331 528 0.120 244 241 43 0.310 0.500 0.284 10 rs16915127 A/G 528 0.654 272 211 45 0.285 528 0.915 257 222 49 0.303 0.650 0.364 11 rs598408 A/G 528 0.258 453 74 1 0.072 528 0.811 445 79 4 0.082 0.360 0.370 12 rs7120151 A/G 528 0.302 241 239 48 0.317 528 0.931 259 221 48 0.300 0.510 0.397 13 rs11018441 C/G 527 0.643 287 201 39 0.265 527 0.095 304 183 40 0.250 0.510 0.425 14 rs5015672 G/A 528 0.138 464 64 0 0.061 528 0.088 455 73 0 0.069 0.410 0.427 15 rs5016282 G/A 528 0.155 315 178 35 0.235 528 0.269 293 207 28 0.249 0.150 0.446 16 rs594561 A/G 528 0.418 200 257 71 0.378 527 0.081 186 270 71 0.391 0.660 0.538 17 rs4753778 A/G 526 0.853 308 190 28 0.234 526 0.049 308 178 40 0.245 0.290 0.540 18 rs3824927 A/C 527 0.628 146 268 113 0.469 528 0.860 155 264 109 0.456 0.830 0.573 19 rs666229 C/A 528 0.147 253 235 40 0.298 528 0.062 246 242 40 0.305 0.900 0.740 20 rs982709 A/G 526 0.843 517 9 0 0.009 523 2.336E-08 516 6 1 0.008 0.450 0.817 21 rs591849 A/T 528 0.077 147 282 99 0.455 528 0.314 153 273 102 0.452 0.860 0.896 22 rs566277 C/A 527 0.804 311 189 27 0.231 527 0.998 312 187 28 0.231 0.980 1.000 a Major/minor allele, major and minor alleles are denoted by D and d, respectively. b Number of samples which are well genotyped. c P -Values in the parenthesis were analyzed with Bonferroni corrections, the significance of bold values is P <0.05. Table 2 Haplotype in the GRM5 gene in patients with schizophrenia and controls Haplotype a Haplotype frequencies b Chi Square P -value c Patients Controls rs567990-rs12421343 GG 582.1 (0.551) 512 (0.486) 9.062 0.003 AG 401.9 (0.381) 442 (0.419) 3.308 0.069 AA 72 (0.068) 100 (0.095) 5.021 0.025 rs7932640-rs7125164 GC 447.9 (0.424) 421.2 (0.399) 1.390 0.238 AA 369.2 (0.350) 414.6 (0.393) 4.171 0.041 GA 235.5 (0.223) 219.8 (0.208) 0.690 0.406 rs3824927-rs566277 AC 482.0 (0.456) 495.2 (0.469) 0.332 0.565 CC 330.1 (0.313) 317.8 (0.301) 0.339 0.560 CG 243.9 (0.231) 243 (0.230) 0.002 0.965 rs666229-rs12422021 AAAG 320.7 (0.304) 308.7 (0.293) 0.326 0.568 GGAG 327.5 (0.311) 298 (0.283) 1.974 0.160 GGCG 251.1 (0.238) 276.7 (0.263) 1.656 0.198 GAAG 92.4 (0.088) 89.3 (0.085) 0.059 0.808 GGCA 62 (0.059) 76 (0.072) 1.520 0.218 rs7101540-rs10830204 TGA 568 (0.538) 557.6 (0.529) 0.165 0.685 TCG 263.7 (0.250) 277.7 (0.263) 0.523 0.469 TGG 144.3 (0.137) 116.7 (0.111) 3.276 0.070 AGG 80 (0.076) 102 (0.097) 2.956 0.086 a Haplotypes were omitted from analysis if the estimated haplotype probabilities were less than 5%. b Frequencies are shown in parenthesis (%). c P -Values in the parenthesis were analyzed with Bonferroni corrections, the significance of bold values is P <0.05. Table 3 Association analyses between PANSS and GRM5 SNPs in patients with SZ dbSNPID Genotype(n) Total PANSS Positive Negative Excitement Depression/anxiety Cognitive impairment rs567990 AA (70) 85.00±26.52 15.93±5.15 25.61±10.01 12.69±5.13 14.89±5.94 15.89±7.34 a AG (132) 85.48±24.72 16.11±3.82 26.78±9.35 12.02±5.28 15.36±6.08 15.21±6.73 GG (65) 77.97±19.43 15.26±4.23 24.14±7.76 11.58±4.40 13.55±4.63 13.20±5.67 rs12421343 AA (2) 68.50±17.68 12.00±8.49 17.50±3.54 13.00±2.83 12.50±0.71 13.50±2.12 AG (42) 80.50±20.87 14.55±4.8 a 25.60±7.09 10.71±4.68 15.33±5.95 14.31±4.66 GG (223) 84.23±24.78 16.14±4.12 25.95±9.57 12.37±5.09 14.71±5.74 15.02±7.06 rs12422021 GG (231) 84.75±24.40 16.15±4.25 26.18±9.30 12.36±5.12 14.91±5.78 15.15±6.84 AA +AG (36) 75.25±18.56a 14.36±4.24a 23.33±7.46 10.19±4.13a 14.03±5.43 13.33±3.94a rs504183 AA (113) 80.15±21.18 15.49±4.29 24.70±8.42 b 11.58±4.585 14.44±5.03 13.81±5.95 AC (127) 87.29±26.80 16.45±4.24 27.36±9.88 c 12.51±5.60 14.91±6.45 16.06±7.47 CC (27) 79.93±20.78 14.63±4.31 23.37±8.09 12.22±3.90 15.74±5.13 13.96±5.03 a P <0.05, compared with GG genotype, LSD tests. b P < 0.05, compared with AC genotype, LSD tests. c P < 0.05, compared with CC genotype, LSD tests. 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Song","email":"","orcid":"https://orcid.org/0000-0001-5002-6979","institution":"Xinxiang Medical College: Xinxiang Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Meng","middleName":"","lastName":"Song","suffix":""}],"badges":[],"createdAt":"2021-02-18 02:22:45","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-253495/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-253495/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":6530397,"identity":"99139551-5f85-4954-9a53-fd9acaca5c65","added_by":"auto","created_at":"2021-03-02 19:02:31","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":2331812,"visible":true,"origin":"","legend":"Haplotype block structure of the GRM5 gene in both SZ patients and HCs. The index association SNP is represented by a diamond. The colors of the remaining SNPs (circles) indicate LD with the index SNP based on pairwise r2 values from our data.","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-253495/v1/69cc3a36dba19b70486cad54.png"},{"id":13673590,"identity":"d6de8691-2cbd-4b5c-9556-bc7d9cfc753f","added_by":"auto","created_at":"2021-09-17 11:18:05","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":870146,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-253495/v1/23c92552-b031-46c5-974c-25feaba48d7b.pdf"},{"id":6530069,"identity":"8946ae90-0d10-41b1-aeb5-9e2778d9fb60","added_by":"auto","created_at":"2021-03-02 18:59:31","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":122880,"visible":true,"origin":"","legend":"","description":"","filename":"TableS1.doc","url":"https://assets-eu.researchsquare.com/files/rs-253495/v1/4149fe0ce2fe35a5865d2e11.doc"}],"financialInterests":"","formattedTitle":"\u003cp\u003eAssociation of Glutamate Receptor Metabotropic 5 Gene (Grm5) Polymorphisms With Schizophrenia Susceptibility and Symptoms in a Chinese-Han Population\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSchizophrenia (SZ) is a common serious mental disorder, and its symptoms are complex and clinical diagnostic criteria are different, which is mainly characterized by mental, emotional and behavioral disorders and incoordination of mental activities (Keshavan et al. 2020; Schaefer et al. 2020). Researches based on family or twin suggest that schizophrenia has a high heritability of 64-81% and a complex genetic component (Yue et al. 2017). It is often described as a heterogeneous disorder affected by multiple genes, each with a small effect (Goldman et al. 2020). Thus far, genetics studies have suggested numerous putative chromosomal loci for this disorder.\u003c/p\u003e\n\u003cp\u003eAlthough the pathogenesis of schizophrenia is unclear, studies suggest that the disorder is associated with abnormal neurodevelopment (Matosin and Newell 2013), in which both genetic and environmental factors could influence the structure and function of brain (Lang et al. 2007). Glutamate has been linked to a myriad of processes surrounding cognition, memory, and perception (Thomas et al. 2017). Mounting evidence suggest that glutamatergic dysfunction may be critical in the etiology of schizophrenia (Steele et al. 2012). Glutamate is an excitatory neurotransmitter that is abundant in the brain and plays an important role in various brain functions and brain development (Uno and Coyle 2019; Wickens et al. 2018). Glutamate exerts effects through activating metabotropic glutamate receptors (mGluRs) and ionotropic receptors (iGluRs). The iGluRs include the N-methyl-D-aspartate receptors (NMDAR), a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) and Kainate receptors. Metabotropic glutamate receptors are G protein-coupled receptors and modulate cellular excitability and synaptic transmission (Niswender and Conn 2010). There are different subtypes of mGluRs in presynaptic and postsynaptic membrane that could modulate glutamatergic neurotransmission. The involvement in multiple neuronal processes indicates its importance on the dysfunction of brain (Mukherjee and Manahan-Vaughan 2013).\u003c/p\u003e\n\u003cp\u003eTherefore, it is necessary to conduct in-depth systematic analyses on the relationship between candidate genes of glutamate pathway and schizophrenia. Metabolic glutamate receptor subtype 5 (mGluR5, encoded by gene \u003cem\u003eGRM5\u003c/em\u003e) plays an irreplaceable role in the glutamate pathway, and convergent lines of evidence suggest that implicated in schizophrenia (Akkus et al. 2017). Studies have shown that mGluR5 critically modulate the function of NMDAR, which is strongly associated with schizophrenia, and mGluR5 abnormalities maybe contribute to pathogenesis of schizophrenia (Zurawek et al. 2018). The involvement of NMDAR in the long-term potentiation (LTP) process involved in memory and cognition, suggesting that mGluR5 may be a potential therapeutic target for the repair of cognitive deficits in schizophrenia (Kosten et al. 2016; Matosin et al. 2017). Abnormal expression or dysfunction of the mGluR5 is associated with schizophrenia (Matosin et al. 2016), and might originate at the genetic level. In a case-control study, the distribution of allele frequencies of the \u003cem\u003eGRM5\u003c/em\u003e gene was found to be significantly different between schizophrenia patients and controls in the Scottish population (Devon et al. 2001).\u003c/p\u003e\n\u003cp\u003eHere, we performed a case-control analysis in the Chinese-Han population to investigate the potential associations between schizophrenia and \u003cem\u003eGRM5\u003c/em\u003e SNPs, providing new evidence for schizophrenia susceptibility gene research.\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cp\u003eThe Ethical permission was obtained from the Ethical Committee of the Second Affiliated Hospital of Xinxiang Medical University. Written informed consent was obtained from all participants after an adequate explanation of the objectives and procedures about the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSubjects\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUnrelated schizophrenic patients were recruited from Han population in northern Henan and 528 paranoid SZ were selected as cases (age from 18-35 years old). According to the diagnostic criteria the DSM-IV, at least two experienced psychiatrists make a consensus diagnosis. Individuals with a history of severe medical complications, organic brain diseases, and other psychiatric disorders were excluded. In the meantime, healthy people who had four biological grandparents of Han Chinese ancestry were recruited from surrounding communities and villages, of which 528 healthy controls matched for sex ratio (1:1 for both groups), age, and ethnicity.\u003c/p\u003e\n\u003cp\u003eThe syndromes of 267 first-episode patients were assessed by the Positive and Negative Symptom Scale (PANSS).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSNP Selection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe functional analysis was performed for all SNPs in the \u003cem\u003eGRM5\u003c/em\u003e gene region using the FASTSNP online tool (Yuan et al. 2006). According to the HapMap database, the SNPs with high ranking risk and minor allele frequency (MAF) \u0026ge; 0.05 in the Chinese-Han population were screened out. Tag SNPs were selected through the same method in previous article (Carlson et al. 2004; Li et al. 2013) (r\u003csup\u003e2\u003c/sup\u003e \u0026ge; 0.80, MAF \u0026ge; 0.05) using HapMap database by Haploview v4.1 (Barrett et al. 2005). All selected SNPs were evaluated, and the SNPs with Illumina design scores below 0.6 were excluded.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGenotyping\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGenomic DNA samples of the participants were isolated from their peripheral blood using the Blood DNA System (Tiangen Biotech, Beijing, China). Genotyping was done using the Illumina GoldenGate assay with a BeadStation 500G System following the Illumina protocol. To evaluate the quality of genotyping, SNP genotyping of 100 samples was performed by DNA sequencing and 96 samples were genotyped in duplicate performed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePower calculations were performed using the Genetic Power Calculator (Purcell et al. 2003). Genotypes and allele association test, haplotype analysis and Hardy-Weinberg equilibrium (HWE) evaluation were performed using the Haploview v4.1 software. Genotypes and allele were compared between two groups by the Pearson chi-square test. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by SNPStats, a web tool (Sole et al. 2006). Bonferroni corrections for multiple tests were used to exclude type I errors.\u003c/p\u003e\n\u003cp\u003eComparison of different genotypes in the case group with the clinical symptoms of the patients was performed using the SPSS13.0 statistical software package. The Levene variance homogeneity test was used for ANOVA, and the Krtlskal-Wailis rank sum test was used for SNP with irregular variance. The five factors scores of the PANSS were compared among different genotypes in the same SNP (Yang et al. 2015). The criterion for significance was set at P\u0026lt;0.05 for all tests.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe alleles and genotype frequencies of twenty-four common SNPs at the \u003cem\u003eGRM5\u003c/em\u003e gene were analyzed in all samples, with a genotyping success rate of 99.83%. The genotype concordance between GoldenGate assay and DNA sequencing was 99.25%. The total sample size (n=1056) had a power of 0.86 to detect a small effect, and a power of 1.00 to detect both medium and large effects on genotype distributions. Among the twenty-four SNPs, twenty-two yielded genotype data, with the genotype and allele frequencies shown in \u003cstrong\u003eTable 1\u003c/strong\u003e. Only rs4753778 and rs982709 were not in HWE. The genotypic and allelic frequencies of two SNPs, rs567990 and rs12421343 were significantly different between the case and control group (Genotype \u003cem\u003eP\u003c/em\u003e = 0.007 and 0.011; Allele \u003cem\u003eP \u003c/em\u003e= 0.003 and 0.021; respectively). Furthermore, the frequency of rs504183 allele was associated with schizophrenia (\u003cem\u003eP\u003c/em\u003e = 0.030).\u003c/p\u003e\n\u003cp\u003eWhen we stratified subjects by gender, the genotype and allele frequency of rs12421343 was significantly different between case and control group (\u003cem\u003eP \u003c/em\u003e= 0.003 and 0.004 respectively) in female samples. Additional, rs12422021, rs567990, and rs7101540 allelic frequency was associated with schizophrenia (\u003cem\u003eP \u003c/em\u003e= 0.030, 0.010, 0.040; OR = 0.600, 0.750, 0.630; 95%CI = 0.38-0.96, 0.59-0.95, 0.40-0.97; respectively) (\u003cstrong\u003eSupplementary Table 1\u003c/strong\u003e). However, there was no significant difference on genotype and allele frequency between male and control subjects (\u003cem\u003eP \u003c/em\u003e\u0026gt; 0.05, \u003cstrong\u003edata not shown\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eThe haplotype structure of our sample and associations between schizophrenia and LD blocks, then pair-wise LD of twenty-two SNPs in the schizophrenia patient and control group was analyzed by the standardized D\u0026prime; and r\u003csup\u003e2\u003c/sup\u003e values. The SNP\u0026rsquo;s order and physical locations in the \u003cem\u003eGRM5\u003c/em\u003e gene, the LD structure, and the D\u0026prime; values for all variants were presented in \u003cstrong\u003eFig. 1\u003c/strong\u003e Haplotypes GG and AA in the LD block rs567990\u0026minus;rs12421343 showed significant difference between schizophrenia and controls (\u003cem\u003eP\u003c/em\u003e = 0.003, and 0.025, respectively), and so was haplotype AA in the LD block rs7932640\u0026minus;rs7125164 (\u003cem\u003eP \u003c/em\u003e= 0.041). It shows the three significantly associated haplotypes in \u003cstrong\u003eTable 2.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo detect the association between the SNPs of \u003cem\u003eGRM5\u003c/em\u003e gene and symptoms, the PANSS scores of 267 schizophrenia patients were analyzed. As shown in \u003cstrong\u003eTable 3\u003c/strong\u003e, there were significant difference between patients with different rs12422021 genetypes (GG, AA + AG) on total PANSS and positive, excitement, cognitive impairment factor subscores (\u003cem\u003eP \u003c/em\u003e= 0.026, 0.019, 0.016, 0.024; respectively). Furthermore, negative factor subscores were significantly differed among the three genotypes of rs504183 (\u003cem\u003eP\u003c/em\u003e = 0.025, and 0.040; respectively). The significantly associated with positive (rs12421343) and cognitive impairment (rs567990) factor subscores (\u003cem\u003eP\u003c/em\u003e = 0.003, 0.020; respectively).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe aim of this study is to investigate the \u003cem\u003eGRM5\u003c/em\u003e mutations associated with schizophrenia and psychotic symptoms in the Han Chinese population. There were significant differences in genotype and allele frequencies of two SNPs (rs567990 and rs12421343) between the case group and the control group. In addition, the allele frequencies of the rs504183 SNP was significantly associated with schizophrenia in this population. In the \u003cem\u003eGRM5\u003c/em\u003e gene, the haplotypes GG and AA (rs567990-rs12421343) revealed significant associations with schizophrenia, and so did haplotype AA（rs7932640-rs7125164). This indicates that variations in the \u003cem\u003eGRM5\u003c/em\u003e gene may increase susceptibility to schizophrenia in the Chinese Han population.\u003c/p\u003e\n\u003cp\u003eWhen we divided the patients by gender, we found the association of the genotype and allele frequency of rs12421343 of \u003cem\u003eGRM5\u003c/em\u003e with schizophrenia in female subjects, and the allele frequency of rs12422021, rs567990, and rs7101540, but not in male subjects. Moreover, research have shown that there was a positive correlation between the \u003cem\u003ePAWR\u003c/em\u003e gene and female schizophrenia in Taiwanese Han population (Wang et al. 2008), similarly, female specificity was found in the schizophrenia Jewish population associated with rs7341475 in the \u003cem\u003eRELN\u003c/em\u003e gene (Liu et al. 2010). Numerous studies have revealed the gender differences in clinical features of schizophrenia, such as age of onset, symptoms, drug response, clinical course and prognosis (Chen et al. 2018; de Boer et al. 2018). Some researchers have demonstrated that there may be differences in etiology between male and female patients (Mendrek and Mancini-Marie 2016; Noguera et al. 2018). Gender differences in schizophrenia are thought to be associated with estrogen levels in patients. It has been demonstrated that estrogen impacts neuronal growth and death at every level, which involved in the mechanism of neurodegenerative in schizophrenia (Goncalves et al. 2019)\u003csub\u003e.\u003c/sub\u003e Though the interaction between the female-specific association of the \u003cem\u003eGRM5\u003c/em\u003e gene and schizophrenia is unclear, our study support differences in genetic susceptibility between the genders.\u003c/p\u003e\n\u003cp\u003eThe clinical characteristics of schizophrenia include positive symptoms (delusions, hallucinations and erratic behavior), negative symptoms (apathy, anhedonia and depression), and cognitive disturbances (poor learning and memory) (Albanna et al. 2014; Zurawek et al. 2018). In this study, two SNPs in \u003cem\u003eGRM5\u003c/em\u003e gene were associated with schizophrenia positive symptoms and one SNP was associated with negative symptoms. This consistently demonstrated the association of \u003cem\u003eGRM5\u003c/em\u003e variants with the pathophysiology of schizophrenia. Jennifer et al. found that positive allosteric modulators (PAMs) for mGluR5 may be effective in treating positive symptoms of schizophrenia (Ayala et al. 2009). Studies have also shown that negative symptoms and cognitive disorders may be the effects of glutamatergic dysfunction (McAllister et al. 2015; Volk et al. 2015). The glutaminergic theory of schizophrenia is supported by the following observations: subchronic administration of ketamine and phenylidine (PCP, the noncompetitive antagonists of the NMDAR) in healthy humans can induce similar clinical manifestations of schizophrenia, including cognitive impairment (Coyle et al. 2012). It should be noted that NMDAR blockade can regulate dopaminergic signal transduction in the marginal pathway of the mesencephalon (Yang et al. 2017). Recent evidence suggests the importance of mGluR5 in regulating the activity and function of NMDAR. Thus, \u003cem\u003eGRM5\u003c/em\u003e is associated with the psychopathology of schizophrenia.\u003c/p\u003e\n\u003cp\u003emGluR5 is an excitatory post-synaptic receptor which can regulate neuronal excitability, synaptic plasticity and synaptic selection (Hoeffer and Klann 2010). It is enriched in the brain regions involved in cognition, including hippocampus, striatum and cortex (Lopez-Bendito et al. 2002). It is believed that mGluR5 can regulate many cognitive fields and behaviors (Bird et al. 2014; Maksymetz et al. 2017; Matosin et al. 2018; Wu et al. 2020). This study showed that rs567990 and rs12422021 were significantly correlated with cognitive impairment factor subscores. This suggests that \u003cem\u003eGRM5\u003c/em\u003e is associated with cognitive function in schizophrenia.\u003c/p\u003e\n\u003cp\u003eIn addition, some susceptible genes of schizophrenia show a dynamic process during the early development of the prefrontal cortex. Therefore, the abnormal expression of these susceptible genes can increase the occurrence of abnormal brain function and cause schizophrenia. The expression of \u003cem\u003eGRM5\u003c/em\u003e gene changes with age (Hernandez et al. 2018). Studies have shown that \u003cem\u003eGRM5\u003c/em\u003e is involved in basic developmental processes such as proliferation, differentiation, and survival of cells (Purgert et al. 2014). Therefore, it reflects the important role of \u003cem\u003eGRM5\u003c/em\u003e in the early development of brain function.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eGRM5\u003c/em\u003e is the best functional candidate gene involved in psychopathology on chromosome 11 (Devon et al. 2001)\u003csub\u003e. \u003c/sub\u003eIn a case-control study, Devon et al. had found a significant difference in the distribution of allele frequencies of \u003cem\u003eGRM5\u003c/em\u003e gene between schizophrenic patients and controls. The difference was detected in an intron region of the \u003cem\u003eGRM5\u003c/em\u003e gene using microsatellites. Based on recent studies, it has been proved that enhancing the function of \u003cem\u003eGRM5\u003c/em\u003e showed therapeutic effects. This study and previous have demonstrated that \u003cem\u003eGRM5\u003c/em\u003e is a candidate susceptibility gene for schizophrenia.\u003c/p\u003e\n\u003cp\u003eIn many previous studies, the subjects were from vast geographic regions and genetically heterogeneous. However, we avoid the effect of group stratification, as all subjects in our study were from Xinxiang or surrounding counties, and genetic structure analysis showed that schizophrenia patients and controls belonged to the same population. Replication studies are required to be carried out in different ethnic groups, particularly in patients with definite schizophrenia phenotypes to confirm the role of \u003cem\u003eGRM5\u003c/em\u003e variants in schizophrenia.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, our study provides new evidence suggesting that \u003cem\u003eGRM5\u003c/em\u003e is associated with schizophrenia. The genetic variation of \u003cem\u003eGRM5\u003c/em\u003e may increase susceptibility of schizophrenia.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding \u003c/strong\u003eThis work was supported in part by the National Natural Science Foundation of China (U1904130 to WQ-L; 82001407 to XS; 81971252 to LX-L; 81903688 to ML-S), Medical science and technology research project of Henan Province (LHGJ20190476 to MS; 2018020371 to XS), Key Scientific Research Project of Henan Higher Education Institutions (20B320016 to MS), The Open Fund of Henan Key lab of Biological Psychiatry (ZDSYS2018003 to MS; ZDSYS2018008 to XS), Science and technology research project of Henan Province (212102310587 to MS; 212102310589 to YF-Y), National Key Research and Development Program of China (2016YFC1307001 to LX-L).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest \u003c/strong\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e The data is freely available to the public.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode availability\u003c/strong\u003e Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions \u003c/strong\u003eAll authors contributed to the study conception and design. The literature searches and analyses were managed by Meng Song and Wenqiang Li. Sample selection and data management were conducted by Xiaoge Guo, Qing Liu, Luwen Zhang, Yan Zhang, Minli Ding, Yanli Lu and Yongfeng Yang. The statistical analysis was performed by Wenqiang Li, Xi Su, Xiaoge Guo, Meng Song, Ming Li and Minglong Shao. The first draft of the manuscript was written by Wenqiang Li and Xi Su. All authors contributed to and have approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e The Ethical permission was obtained from the Ethical Committee of the Second Affiliated Hospital of Xinxiang Medical University.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e Written informed consent was obtained from all participants after an adequate explanation of the objectives and procedures about the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e All participants and authors approved the publication of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments \u003c/strong\u003eWe thank the patient, their families, and the healthy volunteers for their participation, and the physicians who collect clinical data and blood samples in the Second Affiliated Hospital of Xinxiang Medical University.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAkkus F, Treyer V, Ametamey SM, Johayem A, Buck A, Hasler G (2017) Metabotropic glutamate receptor 5 neuroimaging in schizophrenia Schizophr Res 183:95-101 doi:10.1016/j.schres.2016.11.008\u003c/li\u003e\n\u003cli\u003eAlbanna A et al. 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(2015) Association Study of N-Methyl-D-Aspartate Receptor Subunit 2B (GRIN2B) Polymorphisms and Schizophrenia Symptoms in the Han Chinese Population PLoS One 10:e0125925 doi:10.1371/journal.pone.0125925\u003c/li\u003e\n\u003cli\u003eYuan HY et al. (2006) FASTSNP: an always up-to-date and extendable service for SNP function analysis and prioritization Nucleic Acids Res 34:W635-641 doi:10.1093/nar/gkl236\u003c/li\u003e\n\u003cli\u003eYue W, Yu X, Zhang D (2017) Progress in genome-wide association studies of schizophrenia in Han Chinese populations NPJ Schizophr 3:24 doi:10.1038/s41537-017-0029-1\u003c/li\u003e\n\u003cli\u003eZurawek D, Salerno-Kochan A, Dziedzicka-Wasylewska M, Nikiforuk A, Kos T, Popik P (2018) Changes in the expression of metabotropic glutamate receptor 5 (mGluR5) in a ketamine-based animal model of schizophrenia Schizophr Res 192:423-430 doi:10.1016/j.schres.2017.04.014\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1 \u003c/strong\u003eGenotype and allele frequencies of twenty-two SNPs in the \u003cem\u003eGRM5\u003c/em\u003e gene in patients with schizophrenia and controls\u003c/p\u003e\n\u003ctable border=\"1\"\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 38px;\"\u003e\n\u003ctd style=\"height: 38px;\"\u003e\n\u003cp\u003eSNP#\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 38px;\"\u003e\n\u003cp\u003edbSNP ID\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 38px;\"\u003e\n\u003cp\u003eAllele(D/d)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 38px;\" colspan=\"6\"\u003e\n\u003cp\u003ePatients\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 38px;\" colspan=\"6\"\u003e\n\u003cp\u003eControls\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 76px;\" colspan=\"2\" rowspan=\"2\"\u003e\n\u003cp\u003e\u003cem\u003ep-\u003c/em\u003evalue\u003cem\u003e\u003csup\u003ec\u003c/sup\u003e\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 38px;\"\u003e\n\u003ctd style=\"height: 38px;\"\u003e\n\u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 38px;\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 38px;\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 38px;\"\u003e\n\u003cp\u003en\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 38px;\"\u003e\n\u003cp\u003eHWE(\u003cem\u003eP\u003c/em\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 38px;\" colspan=\"3\"\u003e\n\u003cp\u003eGenotype\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 38px;\"\u003e\n\u003cp\u003eMAF\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 38px;\"\u003e\n\u003cp\u003en\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 38px;\"\u003e\n\u003cp\u003eHWE(\u003cem\u003eP\u003c/em\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 38px;\" colspan=\"3\"\u003e\n\u003cp\u003eGenotype\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 38px;\"\u003e\n\u003cp\u003eMAF\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003eDD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003eDd\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003edd\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003eDD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003eDd\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003edd\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003eGenotype\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003eAllele\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35.4403px;\"\u003e\n\u003ctd style=\"height: 35.4403px;\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35.4403px;\"\u003e\n\u003cp\u003ers567990\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35.4403px;\"\u003e\n\u003cp\u003eA/G\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35.4403px;\"\u003e\n\u003cp\u003e528\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35.4403px;\"\u003e\n\u003cp\u003e0.393\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35.4403px;\"\u003e\n\u003cp\u003e130\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35.4403px;\"\u003e\n\u003cp\u003e254\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35.4403px;\"\u003e\n\u003cp\u003e144\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35.4403px;\"\u003e\n\u003cp\u003e0.513\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35.4403px;\"\u003e\n\u003cp\u003e527\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35.4403px;\"\u003e\n\u003cp\u003e0.467\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35.4403px;\"\u003e\n\u003cp\u003e156\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35.4403px;\"\u003e\n\u003cp\u003e269\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35.4403px;\"\u003e\n\u003cp\u003e102\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35.4403px;\"\u003e\n\u003cp\u003e0.449\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35.4403px;\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.007(0.165)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35.4403px;\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.003(0.073)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 49px;\"\u003e\n\u003ctd style=\"height: 49px;\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 49px;\"\u003e\n\u003cp\u003ers12421343\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 49px;\"\u003e\n\u003cp\u003eA/G\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 49px;\"\u003e\n\u003cp\u003e528\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 49px;\"\u003e\n\u003cp\u003e0.275\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 49px;\"\u003e\n\u003cp\u003e434\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 49px;\"\u003e\n\u003cp\u003e87\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 49px;\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 49px;\"\u003e\n\u003cp\u003e0.096\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 49px;\"\u003e\n\u003cp\u003e528\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 49px;\"\u003e\n\u003cp\u003e0.093\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 49px;\"\u003e\n\u003cp\u003e456\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 49px;\"\u003e\n\u003cp\u003e72\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 49px;\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 49px;\"\u003e\n\u003cp\u003e0.068\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 49px;\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.011(0.272)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 49px;\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.021(0.513)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003ers504183\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003eC/A\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e528\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e0.299\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e224\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e248\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e56\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e0.341\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e527\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e0.253\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e255\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e231\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e41\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e0.297\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.085\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.030(0.728)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003ers7932640\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003eA/G\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e528\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e0.791\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e196\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e249\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e83\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e0.393\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e526\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 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49px;\"\u003e\n\u003cp\u003e0.009\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 49px;\"\u003e\n\u003cp\u003e523\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 49px;\"\u003e\n\u003cp\u003e2.336E-08\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 49px;\"\u003e\n\u003cp\u003e516\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 49px;\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 49px;\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 49px;\"\u003e\n\u003cp\u003e0.008\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 49px;\"\u003e\n\u003cp\u003e0.450\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 49px;\"\u003e\n\u003cp\u003e0.817\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e21\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003ers591849\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003eA/T\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e528\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e0.077\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e147\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e282\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e99\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e0.455\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e528\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e0.314\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e153\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e273\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e102\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e0.452\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e0.860\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e0.896\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003ers566277\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003eC/A\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e527\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e0.804\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e311\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e189\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e27\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e0.231\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e527\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e0.998\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e312\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e187\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e0.231\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e0.980\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e Major/minor allele, major and minor alleles are denoted by D and d, respectively.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003e Number of samples which are well genotyped.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ec\u003c/sup\u003e \u003cem\u003eP\u003c/em\u003e-Values in the parenthesis were analyzed with Bonferroni corrections, the significance of bold values is \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2 \u003c/strong\u003eHaplotype in the \u003cem\u003eGRM5\u003c/em\u003e gene in patients with schizophrenia and controls\u003c/p\u003e\n\u003ctable border=\"1\" width=\"0\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" width=\"163\"\u003e\n\u003cp\u003eHaplotype\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"289\"\u003e\n\u003cp\u003eHaplotype frequencies\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"63\"\u003e\n\u003cp\u003eChi Square\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"69\"\u003e\n\u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003ePatients\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003eControls\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"163\"\u003e\n\u003cp\u003ers567990-rs12421343\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"63\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"69\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"163\"\u003e\n\u003cp\u003eGG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e582.1 (0.551)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e512 (0.486)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"63\"\u003e\n\u003cp\u003e9.062\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"69\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.003\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"163\"\u003e\n\u003cp\u003eAG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e401.9 (0.381)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e442 (0.419)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"63\"\u003e\n\u003cp\u003e3.308\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"69\"\u003e\n\u003cp\u003e0.069\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"163\"\u003e\n\u003cp\u003eAA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e72 (0.068)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e100 (0.095)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"63\"\u003e\n\u003cp\u003e5.021\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"69\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.025\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"163\"\u003e\n\u003cp\u003ers7932640-rs7125164\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"63\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"69\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"163\"\u003e\n\u003cp\u003eGC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e447.9 (0.424)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e421.2 (0.399)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"63\"\u003e\n\u003cp\u003e1.390\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"69\"\u003e\n\u003cp\u003e0.238\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"163\"\u003e\n\u003cp\u003eAA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e369.2 (0.350)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e414.6 (0.393)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"63\"\u003e\n\u003cp\u003e\u0026nbsp; 4.171\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"69\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.041\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"163\"\u003e\n\u003cp\u003eGA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e235.5 (0.223)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e219.8 (0.208)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"63\"\u003e\n\u003cp\u003e0.690\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"69\"\u003e\n\u003cp\u003e0.406\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"163\"\u003e\n\u003cp\u003ers3824927-rs566277\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"63\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"69\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"163\"\u003e\n\u003cp\u003eAC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e482.0 (0.456)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e495.2 (0.469)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"63\"\u003e\n\u003cp\u003e0.332\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"69\"\u003e\n\u003cp\u003e0.565\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"163\"\u003e\n\u003cp\u003eCC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e330.1 (0.313)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e317.8 (0.301)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"63\"\u003e\n\u003cp\u003e0.339\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"69\"\u003e\n\u003cp\u003e0.560\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"163\"\u003e\n\u003cp\u003eCG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e243.9 (0.231)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e243 (0.230)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"63\"\u003e\n\u003cp\u003e0.002\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"69\"\u003e\n\u003cp\u003e0.965\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"163\"\u003e\n\u003cp\u003ers666229-rs12422021\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"63\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"69\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"163\"\u003e\n\u003cp\u003eAAAG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e320.7 (0.304)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e308.7 (0.293)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"63\"\u003e\n\u003cp\u003e0.326\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"69\"\u003e\n\u003cp\u003e0.568\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"163\"\u003e\n\u003cp\u003eGGAG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e327.5 (0.311)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e298 (0.283)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"63\"\u003e\n\u003cp\u003e1.974\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"69\"\u003e\n\u003cp\u003e0.160\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"163\"\u003e\n\u003cp\u003eGGCG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e251.1 (0.238)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e276.7 (0.263)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"63\"\u003e\n\u003cp\u003e1.656\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"69\"\u003e\n\u003cp\u003e0.198\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"163\"\u003e\n\u003cp\u003eGAAG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e92.4 (0.088)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e89.3 (0.085)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"63\"\u003e\n\u003cp\u003e0.059\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"69\"\u003e\n\u003cp\u003e0.808\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"163\"\u003e\n\u003cp\u003eGGCA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e62 (0.059)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e76 (0.072)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"63\"\u003e\n\u003cp\u003e1.520\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"69\"\u003e\n\u003cp\u003e0.218\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"163\"\u003e\n\u003cp\u003ers7101540-rs10830204\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"63\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"69\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"163\"\u003e\n\u003cp\u003eTGA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e568 (0.538)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e557.6 (0.529)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"63\"\u003e\n\u003cp\u003e0.165\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"69\"\u003e\n\u003cp\u003e0.685\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"163\"\u003e\n\u003cp\u003eTCG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e263.7 (0.250)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e277.7 (0.263)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"63\"\u003e\n\u003cp\u003e0.523\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"69\"\u003e\n\u003cp\u003e0.469\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"163\"\u003e\n\u003cp\u003eTGG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e144.3 (0.137)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e116.7 (0.111)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"63\"\u003e\n\u003cp\u003e3.276\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"69\"\u003e\n\u003cp\u003e0.070\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"163\"\u003e\n\u003cp\u003eAGG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e80 (0.076)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e102 (0.097)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"63\"\u003e\n\u003cp\u003e2.956\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"69\"\u003e\n\u003cp\u003e0.086\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003ea \u003c/sup\u003eHaplotypes were omitted from analysis if the estimated haplotype probabilities were less than 5%.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003e Frequencies are shown in parenthesis (%).\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ec\u003c/sup\u003e \u003cem\u003eP\u003c/em\u003e-Values in the parenthesis were analyzed with Bonferroni corrections, the significance of bold values is \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3 \u003c/strong\u003eAssociation analyses between PANSS and \u003cem\u003eGRM5\u003c/em\u003e SNPs in patients with SZ\u003c/p\u003e\n\u003ctable border=\"1\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003edbSNPID\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003eGenotype(n)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003eTotal PANSS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003ePositive\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003eNegative\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003eExcitement\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003eDepression/anxiety\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003eCognitive impairment\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003ers567990\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003eAA (70)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e85.00\u0026plusmn;26.52\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e15.93\u0026plusmn;5.15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e25.61\u0026plusmn;10.01\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e12.69\u0026plusmn;5.13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e14.89\u0026plusmn;5.94\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e15.89\u0026plusmn;7.34\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003eAG (132)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e85.48\u0026plusmn;24.72\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e16.11\u0026plusmn;3.82\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e26.78\u0026plusmn;9.35\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e12.02\u0026plusmn;5.28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e15.36\u0026plusmn;6.08\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e15.21\u0026plusmn;6.73\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003eGG (65)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e77.97\u0026plusmn;19.43\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e15.26\u0026plusmn;4.23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e24.14\u0026plusmn;7.76\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e11.58\u0026plusmn;4.40\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e13.55\u0026plusmn;4.63\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e13.20\u0026plusmn;5.67\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003ers12421343\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003eAA (2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e68.50\u0026plusmn;17.68\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e12.00\u0026plusmn;8.49\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e17.50\u0026plusmn;3.54\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e13.00\u0026plusmn;2.83\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e12.50\u0026plusmn;0.71\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e13.50\u0026plusmn;2.12\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003eAG (42)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e80.50\u0026plusmn;20.87\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e14.55\u0026plusmn;4.8\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e25.60\u0026plusmn;7.09\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e10.71\u0026plusmn;4.68\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e15.33\u0026plusmn;5.95\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e14.31\u0026plusmn;4.66\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003eGG (223)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e84.23\u0026plusmn;24.78\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e16.14\u0026plusmn;4.12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e25.95\u0026plusmn;9.57\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e12.37\u0026plusmn;5.09\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e14.71\u0026plusmn;5.74\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e15.02\u0026plusmn;7.06\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003ers12422021\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003eGG (231)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e84.75\u0026plusmn;24.40\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e16.15\u0026plusmn;4.25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e26.18\u0026plusmn;9.30\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e12.36\u0026plusmn;5.12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e14.91\u0026plusmn;5.78\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e15.15\u0026plusmn;6.84\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003eAA +AG (36)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e75.25\u0026plusmn;18.56a\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e14.36\u0026plusmn;4.24a\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e23.33\u0026plusmn;7.46\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e10.19\u0026plusmn;4.13a\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e14.03\u0026plusmn;5.43\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e13.33\u0026plusmn;3.94a\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003ers504183\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003eAA 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(27)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e79.93\u0026plusmn;20.78\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e14.63\u0026plusmn;4.31\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e23.37\u0026plusmn;8.09\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e12.22\u0026plusmn;3.90\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e15.74\u0026plusmn;5.13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e13.96\u0026plusmn;5.03\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e \u003cem\u003eP\u003c/em\u003e \u0026lt;0.05, compared with GG genotype, LSD tests.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb \u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05, compared with AC genotype, LSD tests.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ec \u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e\u0026lt; 0.05, compared with CC genotype, LSD tests.\u003c/p\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":"schizophrenia, GRM5, SNPs, association analyses, PANSS","lastPublishedDoi":"10.21203/rs.3.rs-253495/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-253495/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjectives: \u003c/strong\u003eMetabotropic glutamate receptor subtype 5 (mGluR5) is a potential target for the treatment of schizophrenia (SZ), with the evidence that mGluR5 modulates glutamatergic signaling through the NMDA receptor (NMDAR). Recently it was reported that the \u003cem\u003eGRM5\u003c/em\u003e gene (encoding mGluR5) is associated with SZ in the Scottish population. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eHere, case-control association analyses were performed in the Chinese-Han population to investigate if \u003cem\u003eGRM5\u003c/em\u003e gene is implicated in SZ. Twenty-four single nucleotide polymorphisms (SNPs) were analyzed in 528 paranoid SZ and 528 control subjects.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThe genotypic and allelic frequencies of two SNPs, rs567990 and rs12421343 were significantly different between the case and control group (Genotype \u003cem\u003eP\u003c/em\u003e = 0.007 and 0.011; Allele \u003cem\u003eP \u003c/em\u003e= 0.003 and 0.021; respectively). The frequency of rs504183 allele was associated with SZ (\u003cem\u003eP\u003c/em\u003e = 0.030). When subjects were stratified by gender, the rs12422021, rs567990, rs12421343, and rs7101540 remained significantly associated with SZ in female patients. Analysis of clinical features of SZ, as measured by the Positive and Negative Syndrome Scale (PANSS) inventory, displayed association of \u003cem\u003eGRM5\u003c/em\u003e to features of the general phenotype of SZ, including traits representing delusions, hallucinations and negative symptoms. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eIn conclusion, our study provides further evidence that \u003cem\u003eGRM5\u003c/em\u003e is associated with SZ, and implies a putative sex difference for the effect of the gene.\u003c/p\u003e","manuscriptTitle":"Association of Glutamate Receptor Metabotropic 5 Gene (Grm5) Polymorphisms With Schizophrenia Susceptibility and Symptoms in a Chinese-Han Population","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-03-02 18:59:29","doi":"10.21203/rs.3.rs-253495/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":"6073baeb-ae69-4721-b3fb-735a82d26a31","owner":[],"postedDate":"March 2nd, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":2721102,"name":"Cellular \u0026 Molecular Neuroscience"}],"tags":[],"updatedAt":"2021-04-09T23:04:36+00:00","versionOfRecord":[],"versionCreatedAt":"2021-03-02 18:59:29","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-253495","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-253495","identity":"rs-253495","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}