Grm7, Grm3, Cmya5 Gene With Schizophrenia Correlation Studies

Schizophrenia is a common yet severe psychiatric condition that affects about1%of the population. The disorder always suffers the youth, and brings heavy economical and social burdens to families and societies.Schizophrenia is considered as a typical complex disorder and the heritability is over80%. However, after decades of study, the molecular etiology of schizophrenia remains unknown. Most of results of linkage and association studies could not be replicated in different samples, because of the complex genetic background and clinical heterogeneity. Endophenotypes is a kind of intermediate traits which seems to be more determined by certain genetic factors. Therefore, it may be a useful approach to proclaim the pathogenesis underlie schizophrenia. Based on the results and problems previously reported, we tried to explore the candidate genes for schizophrenia as the following strategy:First, to investigate the susceptible genes based on the common pathogenesis hypothesis for schizophrenia. Second, to combine data-mining of GWA datasets and bioinformatic prioritization to select promising candidate genes and followed by verification of a large number of independent datasets. According to the genetic characteristic of schizophrenia we carried out two researches in this thesis as following:1. Association analysis of the metabotropic glutamate receptor7(GRM7) and metabotropic glutamate receptor3(GRM3) with schizophrenia.In recent years, evidence has been accumulating indicating a major role of glutamate hypothesis in the pathogenesis of schizophrenia. Of particular importance in this regard are the metabotropic glutamate receptors, agonist of which could improve the psychotic symptoms as the effect of Olanzapine.1.1In this section, we carried out a detail association analysis of variants in GRM7with schizophrenia, including single nucleotide polymorphisms (SNPs) and Copy number variations (CNVs).1.1.1We conducted a two step study for the analysis of SNPs in GRM7. In the first step, the functional regions of GRM7were scanned using PCR-sequencing genotyping method and a total of46SNPs were observed among84cases and84controls. SNPs with MAF>0.05were selected for the next step study. In the second step, a total of14common SNPs with MAF＞0.05were analyzed among549cases and562controls. None of the14SNPs’s allelic and genotypic frequency differences were observed. However, the overall frequency of haplotypes constructed from5SNPs,6SNPs and7SNPs showed significant differences between cases and controls. Results were as following:1) rs3749380-rs9868134-rs2291867-rs712773-rs1704763(P=0.0169)2) rs3749380-rs9868134-rs2291867-rs712773-rs162802(P=0.0145)3)rs3749380-rs9868134-rs2291867-rs712773-rs17047632-rs162802(P=0.0497)4)rs3749380-rs9868134-rs2291867-rs712773-rsl7047632-rs3792452-rs162802(P=0.0127)Focusing on the tag SNPs between blocks (7SNPs), we studied its effects on putative cognitive endophenotypes. We found that rs17047632showed a significant effect of genotype for measures of experience (P=0.0004, adjusted P=0.00364) and a nominal difference for measure of mind involving remembering.1.1.2We conducted a association analysis of CNVs in the hotspot region of GRM7with schizophrenia in180cases and33controls. No CNVs was found both in cases and controls.1.2We carried out a association analysis of tag SNPs overlapping GRM3with schizophrenia in465cases and477controls. We found that rs274622(allelic P=0.07) in promoter region and rs701332(genotypic P=0.06) in intronl showed trend association with schizophrenia. Haplotype including these two SNPs and rs701332showed trend association with schizophrenia either. Another haplotype constructed with rs724226, rs10266758, rs13230321was strongly associated with schizophrenia (P=0.0004).2. Association analysis of the cardiomyopathy associated5(CMYA5) with schizophrenia.CMYA5was found to be associated with schizophrenia in a GWAS data-mining study and was verified in22independent European Caucasian samples and1African American samples. To verification this findings, we conducted a replication study of CMYA5with schizophrenia in2701cases and2803controls origin from Han Chinese. We found a functional SNP in exon2showed significant association with schizophrenia. A decreased frequency of the G allele (P=0.008) and G/G genotype (P=0.02) in schizophrenia were found.In the first part of this thesis, we carried out a association studies with schizophrenia based on glutamate hypothesis (GRM7and GRM3). We found several haplotypes associated with schizophrenia, which indicated that there may several variants involved disease. In the second part, we confirmed that CMYA5was associated with schizophrenia in Han Chinese, which was verified in23independent samples. However, the mechanism underlie that was not known.