Analysis Of Common Variants In ZEB2,QPCT And SLCO6A1 Genes For Association With Schizophrenia,bipolar Disorder And Major Depressive Disorder In The Han Chinese Population

Schizophrenia,bipolar disorder（BPD）and major depressive disorder（MDD）are three major psychiatric disorders.A previous genome-wide association study（GWAS）in Caucasians reported13 new risk loci for schizophrenia.Out of these thirteen susceptibility loci,we selected three genes（ZEB2,QPCT,and SLCO6A1）to ascertain whether they also confer risk loci for schizophrenia in the Han Chinese population.We also wondered whether these selected genes are involved in cross-disorder epidemiology of schizophrenia,BPD and MDD in the Han Chinese population.We genotyped tag SNPs,which were selected at different r² thresholds within each gene,and these previously reported susceptibility SNPs of schizophrenia in each gene region,using the Sequenom MassARRAY platform.After genotyping,we performed association analysis for selected genes with schizophrenia,BPD and MDD in the Han Chinese Population.The ZEB2 gene encodes the Zinc Finger E-box binding protein.As a key regulator of epithelial mesenchymal differentiation,ZEB2 plays an important role in the pathogenesis of cancer,and its high-level expression has been observed in glioma patients.Different mutations in this gene have been identified in patients with Mowat-Wilson syndrome.The GWAS of schizophrenia in Caucasians has shown a significant association of rs12991836 which is located near the ZEB2 gene.Thus,we conducted a case control study to further investigate whether this genomic region is also a susceptibility locus for schizophrenia in the Han Chinese population.In total,1,248schizophrenia cases（mean age±S.D.,36.44±9.0 years）,1,344 BPD cases（mean age±S.D.,34.84±11.44 years）,1,056 MDD cases（mean age±S.D.,34.41±12.09 years）and 1,248 healthy control samples（mean age±S.D.,30.62±11.35 years）were recruited.We genotyped 12 SNPs using the Sequenom MassARRAY platform in this study.We found that rs6755392 showed a significant association with schizophrenia(rs6755392:adjusted P_allele=0.016;adjusted P_genotype=0.052;OR（95%CI）=1.201（1.073¹.344）).Additionally,two haplotypes（TCTG,TCTA）were also found to be significantly associated with schizophrenia.This is the first study claiming the association of the genetic risks of rs6755392 in the ZEB2 gene with schizophrenia.The QPCT gene encodes Glutaminyl cyclase（QC）,an enzyme that is involved in the post translational modification by converting N-terminal glutamate of protein to pyroglutamate,which is resistant to protease degradation,more hydrophobic and prone to aggregation and neurotoxic.To further investigate the role of this gene in the pathogenesis of schizophrenia in the Han Chinese population,we conducted the analysis in 1,248 schizophrenia cases（Mean age±S.D.,36.44±9.0years）and 1,248 healthy controls samples（Mean age±S.D.,30.62±11.35 years）.We genotyped six SNPs in this study,including one positive SNP reported in a previous research,using the Sequenom MassARRAY platform.We found that rs2373000 was significantly associated with schizophrenia before multiple tests correction(rs2373000:P _allele=0.016,Chi²=5.784,OR[95%CI]=0.861[0.762⁰.972],P _genotype=0.018,Chi²=8.001).After the correction,rs2373000(rs2373000:P _allele corrected=0.063,P _genotype corrected=0.069)showed marginal association with schizophrenia.Additionally,one pathogenic haplotype（TGT）containing rs2373000 was also significantly associated with schizophrenia.Our results provided evidence that the genetic risk of QPCT gene for schizophrenia also exists in the Han Chinese population.The SLCO6A1 belongs to superfamily of genes,which is known as solute carrier family of OATPs（SLCO）.The SLCO6A1 gene encodes OATP6A1 protein in the Homo sapiens.The GWAS conducted in the Caucasian population has demonstrated a significant association of rs6878284,which is located in SLCO6A1 gene,with schizophrenia.To further investigate whether this gene is a risk locus for schizophrenia and also exhibits cross-disorder epidemiology across schizophrenia,BPD and MDD in the Han Chinese population,we designed the case control study.In total,1,248 unrelated schizophrenia cases（mean age±S.D.,36.44±9.0 years）,1,344 BPD cases（mean age±S.D.,34.84±11.44 years）,1,056 unrelated MDD cases（mean age±S.D.,34.41±12.09 years）and 1,248 normal controls（mean age±S.D.,30.62±11.35 years）were analyzed in this research.We genotyped five SNPs by the Sequenom MassARRAY platform.We found no association of rs6878284 with schizophrenia[P_allele=0.969&P _genotype=0.997 after correction].Furthermore,we found statistically significant association of rs7734060 genotype with MDD after correction[rs7734060:P_allele=0.114&P_genotype=0.036 after correction]in the Han Chinese population.This is the first study found rs7734060 to be a risk locus for MDD in the Han Chinese Population.Furthermore,we carried out pathways analysis of these genes and the corresponding proteins.An indirect protein-protein interaction was found between proteins encoded by ZEB2and QPCT genes.In summary,we reported rs6755392 in ZEB2,rs2373000 in QPCT,to be significantly associated with schizophrenia in the Han Chinese Population;we also found rs7734060 in SLCO6A1 to be associated with MDD in the Han Chinese population.However,heterogeneity were found to be existed between the Han Chinese and Caucasian populations.As we also noticed an indirect protein-protein interaction between proteins encoded by ZEB2 and QPCT genes,the correlated pathway can be highlighted in the genetic etiology of schizophrenia.These studies provide new insights of psychiatric genetics researches in the Han Chinese population.