Molecular Genetics Study Of Candidate Genes For Drug Na(?)ve Schizophrenia

Schizophrenia is a common and serious mental disorder, whose pathogenesis remains undefined. Family, twins and adoptive studies have precisely indicated a genetic component may be involved in schizophrenia. Studies of schizophrenia on genome scanning and candidate gene have acquired many positive results, but most of these results produce poor replication. So far, the major and specific susceptibility genes leading to schizophrenia remains unidentified. ObjectiveTo investigate a genetic association between drug-na?ve schizophrenia and polymorphisms of 3 genes, including DBH,BDNF and TNF-α, 8 SNPs in these 3 genes were detected. The DBH gene encodes Dopamine Beta-Hydroxylase. TNF-αmay modulate normal brain development in central nervous system. The TNF-αmay participated in the pathogenesis of drug-na?ve schizophernia by means of modulating cerebral cortex neuronal number and density. BDNF is involved in the neural development. The present study tried to reveal the predisposing genes and molecular genetic mechanism of drug na?ve schizophrenia. MethodsThe study of the polymorphisms of possible genes for drug na?ve schizophrenia is carried out through the case-control study. In the case-control study, patients with drug na?ve schizophrenia were recruited in Beijing Huilongguan hospital and the control subjects were well matched in sex, age and ethinicity. All subjects are Chinese Han origin and all patients with drug na?ve schizophrenia were diagnosed using the DSM-IV.All the subjects signed informed consent for the genetic analysis and peripheral blood samples were then taken from them. Genomic DNA used for PCR amplification was extracted from the whole blood sample using a DNA extraction kit ( Promega, USA). 19bp Ins/Del in the DBH gene was genotyped using PCR-AFLP technology. We genotyped 7 polymorphic SNPs using PCR-RFLP technology, including rs6265, rs12273539, rs10835210 and rs2030324 in the BDNF gene,rs1800629, -C863A and–T1031C in the TNF-αgene. DBH 19bp Ins/Del and 7 SNPs in the three genes were genotyped with case-control samples.The Hardy–Weinberg equilibrium for genotypic distributions was tested using the chi-square (χ2) goodness-of-fit test. The description of data, case-control analysis was performed with the SPSS15.0 soft. The haplotype analysis was performed with the online SHEsis soft. Results(1)Hardy-Weinberg equilibrium test The chi-square (χ2) goodness-of-fit test showed that the genotypic distributions of these 8 SNPs were in Hardy-Weinberg equilibrium in the parent group (P>0.05) and the control group (P > 0.05).(2) Single SNP analysis of Case-ControlAnalysis of the drug-na?ve schizophrenic and health subjects showed disease association for DBH 19bp Ins/Del,-C863A and -T1031C in all patients(P<0.05).Analysis of the female drug-na?ve schizophrenic and female health subjects showed disease association for rs12273539 and DBH 19bp Ins/Del in female patients(P<0.05).Analysis of the male drug-na?ve schizophrenic and male health subjects showed disease association for DBH 19bp Ins/Del,-C863A and -T1031C in male drug na?ve patients(P<0.05).(3)Haplotype analysis of Case-ControlThere was no haplotypic association for the rs10835210-rs2030324 haplotype system in the BDNF gene. However, Objective that SHEsis soft anlazyed showed preferential transmission for the rs6265(G)- rs12273539 (T),rs12273539(T)-rs10835210(C),rs12273539(T) -rs10835210(C)- rs2030324(C)and rs6265(G)- rs12273539(T)-rs10835210(C)-rs2030324(C) in the BDNF gene, and for the rs1800629(G)- -C863A(C),-C863A(C)--T1031C (T),rs1800629(G)--C863A(C)--T1031C(T) and rs1800629(A)- -C863A(A)--T1031C(T) haplotypes in the TNF-αgene.In the female samples, there were 5 haplotypes showing preferential transmission, including the rs6265(G)-rs12273539(T)-rs10835210(A),rs6265(A)-rs12273539(C) -rs1085210(A),rs12273539 (T)-rs10835210(C)-rs2030324(C),rs6265(G)-rs12273539(T)-rs1083521(C)-rs2030324(C)and rs62 65(A)-rs12273539(C)-rs10835210(A)-rs2030324(C) haplotypes in the BDNF gene.In the male samples, there were 5 haplotypes showing prefeential transmission, including the rs1800629(G)--C863A(C),-C863A(C)--T1031C(T)and rs1800629(G)--C863A(C)--T1031C(T) haplotypes.These findings suggested that the BDNF and TNF-αgenes are likely to confer susceptibility to drug na?ve schizophrenia. ConclusionsAccording to the present results, it can be concluded that (1) the genetic polymorphisms of the DBH,BDNF and TNF-αgenes are likely to confer susceptibility to drug na?ve schizophrenia; (2) DBH and BDNF genetic variation may be associated with female patients with drug-naive schizophrenia; (3)DBH and TNF-αgenes are susceptibility of male drug-na?ve schizophrenia likely.