Association Studies Of SNAP25、CMYA5、ZNF804A、CDH7 With Schizophrenia And Major Depressive Disorder

Recent applications of genome-wide association studies(GWASs) and Next Generation Sequencing(NGS) have discovered rare copy number variants and common single-nucleotide polymorphisms(SNPs) that are associated with the risk of psychiatric disorders. In this study, on the basis of recent GWASs, we selected 4 candidate genes(SNAP25, CMYA5, ZNF804 A, CDH7), genotyped tag SNPs within each gene and performed association with these genes and schizophrenia or major depressive disorder(MDD) in the Han Chinese pop ulation.SNAP25(synaptosomal-associated protein of 25 k Da) is a member of the SNARE(soluble N-ethylmaleimide-sensitive factor attachment receptor) protein complex, which plays essential roles in the modulation of different voltage- gated calcium channels and neurotransmitter release. We performed a large-scale case-control study to test the association between SNAP25 and two major mental disorders, schizophrenia and MDD, in the Han Chinese population. Seven SNPs were genotyped in 1,235 schizophrenia patients, 1,045 MDD patients and 1,235 normal controls of Han Chinese origin. Two SNPs, rs3787283 and rs3746544, were found to be associated with both schizophrenia(rs3746544, adjusted P=0.00257) and MDD(rs3746544, adjusted P=0.0485; rs3787283, adjusted P=0.00387) in this study. The haplotype consisted of rs3787283 and rs3746544 was also significantly associated with both schizophrenia and MDD(schizophrenia: adjusted P=0.0126; MDD: adjusted P=0.000580). Post hoc analysis revealed that the allelic effect of rs3746544 shared the same risk direction between schizophrenia and MDD. Additionally, we carried out a meta-analysis of the current data and published association results and further confirmed the association between rs3746544 and schizophrenia(Pmeta=0.002, ORmet a=1.213). Our results indicated that SNPs in SNAP25 represented a common risk factor of both schizophrenia and MDD in the Han Chinese population.A recent GWAS of the European population implicated the CMYA5 gene in schizophrenia. Previous functional studies showed that the CMYA5 protein can interact with DTNBP1 and PKA, providing further support for a role of CMYA5 in the pathogenesis of schizophrenia. However, this association requires further validation in independent populations. We genotyped 16 SNPs within the CMYA5 gene and performed case-control studies rs6883197 and rs259127 were significantly associated with schizophrenia, and rs12514461, rs259127, and rs7343 were associated with MDD. Additionally, one risk haplotype of rs16877109–rs3828611(G-G) was associated with both schizophrenia(P=0.0000784, after correction) and MDD(P=0.00230, after correction). O ur findings supported that specific alleles and haplotype in the CMYA5 confer genetic risk to schizophrenia and MDD in the Han Chinese population.ZNF804A has been widely investigated as a promising risk gene for schizophrenia and the most important finding should be the association of rs1344706 in European populations. To identify new potential common risk variants within ZNF804 A of schizophrenia and MDD, we performed a case-control association study using 13 polymorphisms that span approximately the whole ZNF804 A gene. We also conducted a systematic meta-analysis of rs1344706 with schizophrenia in Chinese population. Finally, we identified rs17508595(p=0.0475) and rs12476147(p=0.00391) to be associated with schizophrenia in the Han Chinese population. Rs17617913 showed nominal significant association with MDD(p=0.024, before corrected). The haplotype analysis indicated significant association existed between ZNF804 A and both schizophrenia and MDD in our samples. Meta-analysis of rs1344706 was further confirmed suggesting that rs1344706 may not be a risk SNP for schizophrenia in Han Chinese(p=0.078). Our study indicated that the rs17508595 and rs12476147 beyond rs1344706 in ZNF804 A played an important role in schizophrenia in the Han Chinese population.Cadherin-7(CDH7) gene encodes a calcium dependent cell-cell adhesion glycoprotein. Gene loci of cadherins family have been supposed to be involved in the pathogenesis of psychiatric disorders. Recent GWASs also demonstrated that CDH7 was significant associated with bipolar disorder(BPD). Due to the fact that the same genetic risk factor can be shared by different kinds of psychiatric disorders, we examined whether CDH7 is also associated with MDD in this study with a large Han Chinese sample set. We carried out a 2-stage case–control study to examine the association between CDH7 and MDD in the Han Chinese population. Ten tag SNPs were genotyped using Taqman technology in 1,045 MDD patients and 1,520 healthy controls. Significant SNPs(P<0.05) were additionally genotyped in another independent sample set with 576 MDD cases and 576 healthy controls. Among ten genotyped SNPs, rs1444067 and rs12605720 were found to be significantly associated with MDD(rs1444067: Pallele=0.00571, OR=0.830, 95% CI=0.728~0.947; rs12605720: Pallele=0.00321, OR=1.245, 95%CI=1.076~1.441). We successfully replicated the association in independent sample sets(rs1444067: P allele=0.00518; rs12605720: Pallele=0.0227). Finally we combined these results by a meta-analysis(rs1444067: Pallele=0.000174, OR=0.817; rs12605720: Pallele =0.000199, OR=1.255). Our results support CDH7 to be a risk factor of MDD in the Han Chinese population. However, further studies with more markers and independent samples were suggested for further validation.In summary, we conducted case-control study with larger sample size and investigated several candidate genes for schizophrenia or MDD in Han Chinese population. The results indicated CMYA5 and attention deficit hyperactivity disorder(ADHD) risk allele SNAP25 confer risk of major depressive disorder and schizophrenia, which further verified the hot topic of genetic overlap between different psychiatric disorders. For ZNF804 A and CDH7 multiple new risk loci were observed to be associated with schizophrenia or MDD in the Han Chinese population. Our study also confirmed the evidence that the vulnerability to schizophrenia is influenced by a polygenic component, environmental factors, and their interactions, which provided a foundation for the following research of psychiatric genetics.