Association Study Of SLC6A2,SLC6A3,DRD2 Polymorphisms With Schizophrenia And Major Depressive Disorder In The Chinese Han Population

Mental diseases,as complex diseases with brain dysfunction,are caused by both internal genetic factors and external environmental factors.The abnormal performances of people with mental disorders include emotion,cognitive,willpower and activities.Schizophrenia and major depression disorder(MDD)are two common mental diseases with a high incidence,high degree of genetic,high suicide rate and heavy burden of disease.Although the pathogenesis of mental disorder is not clear,the genetic factors,according to the accumulation of research,is the core factor for the development of mental illness.Family,twin and adoption studies suggest that schizophrenia and major depressive disorder with a high degree of genetic,and the closer relationship between the individual with higher genetic rate.The heritability of schizophrenia is as high as 80%,for MDD is 40%.Some susceptibility genes of mental disease,including schizophrenia and MDD,have been found by genetic association studies and genome-wide association(GWAS).Although there are some inconsistencies among some studies,but remain some polymorphism sites have been replicated in different studies.Neurotransmitter hypotheses received most widespread attention among the hypotheses of mental diseases.Many neurotransmitter hypotheses have been partly proved by the accumulation of scientific research,but these also reflect that any a single neurotransmitter hypothesis cannot interpret the spirit of the mental diseases.Dopamine and norepinephrine hypotheses are two important hypotheses of mental disorders and many studies have shown that the genes in dopamine and norepinephrine pathways have a certain influence to mental diseases.And tyrosine serving as the precursor of the dopamine and norepinephrine is also involved in the pathogenesis of mental illness.We chose three genes involved in dopamine and norepinephrine pathways,namely norepinephrine transporter gene SLC6A2,the dopamine transporter gene SLC6A3 and dopamine receptor gene DRD2 and selected 7 single nucleotide polymorphisms(SNPs)from these three genes to explore their correlation with the schizophrenia and severe depression,respectively.In the association analyses of schizophrenia,we genotyped the 7 SNPs of SLC6A2,SLC6A3 and DRD2 in 1034 schizophrenia patients and 1034 healthy controls from Chinese Han origin.The frequencies of genotype and allele of each SNP were conducted by SHEsis.To further verify the results,R package “genetics” was adapted to assess the association between these SNPs and schizophrenia in codominant,dominant,recessive,overdominant and log-additive models,respectively.Moreover,we performed gene-gene interaction analysis and stratified analyses by gender.The results showed that no significant difference in the frequency of allele or genotype was detected between cases and controls.Still,the negative result remained in the extra stratified analysis of gender and gene-gene interaction analysis.But,rs1362621 and rs2242446 were in strong LD(D’=0.971)and rs1362621-rs2242446-rs5564 consisted a positive haplotype(C-A-T:P=0.0095;C-T-T: P=0.021;Global P=0.019).In MDD research,a SNP genotyping case-control study was carried out in a group of Han Chinese population including 568 patients with major depressive disorder and 846 healthy individuals.And the process of statistical analyses was similar with schizophrenia research.In the results,rs2550956 showed significant differences in allelic(P=0.033)and genotypic frequencies(P=0.039)between cases and controls before correction.Haplotypes rs1362621-rs2242446-rs5564(Global P=0.036)and rs3863145-rs2550956(C-T)(P=0.029)demonstrated significant association with MDD.MDR model displayed a 3-loci interaction among rs2242446,rs5564 and rs7131056 for MDD(P=0.0153).According to our results,SLC6A2,SLC6A3 and DRD2 gene polymorphisms(rs1362621,rs2242446,rs5564,rs3863145,rs2550956 and rs7131056)may be correlated with major depressive disorder and schizophrenia,and the correlation is mainly displayed by the interaction of SNP-SNP and gene-gene.The present research suggested that the three genes SLC6A2,SLC6A3 and DRD2 may play a role for schizophrenia as well as MDD and the interaction of norepinephrine and dopamine pathways may influence the development of mental illness.For better understand the pathogenesis of mental disorders,it is worth to pay more attention to the interaction of SNP-SNP,gene-gene and different pathways.