Multilocus Interaction Pattern Of Dopamine Pathway Genes In Schizophrenia Research

Schizophrenia is a common yet severe psychiatric condition that affects about 1%of the population.The disorder always suffers the youth,and brings heavy economical and social burdens to families and societies.After decades of study,schizophrenia is considered as a typical complex disorder. Although the genetic factors account for much of the etiology and the heredity of schizophrenia is over 80%,the candidate gene is still unknown after amounts of association and linkage studies.These studies are mainly complicated by complex genetic background and clinical heterogeneity.Schizophrenia is unlikely to be determined by a single major genetic cause,but rather by the interaction of multiple genes.At the same time,certain genetic factors seem to have more influence on special intermediate traits or endophenotypes than on the disease itself.Therefore,it may be a useful approach to integrate the multiple genetic risk factors with phenomenology in research into the pathogenesis of schizophrenia.In a previous study,we tested the entire dopamine metabolic pathway and found that the combined effect of single-nucleotide polymorphisms(SNPs) in the genes encoding catechol-O-methyltransferase(COMT) and aldehyde dehydrogenase 3B1(ALDH3B1), two enzymes involved in the breakdown of dopamine,conferred a genetic susceptibility to paranoid schizophrenia.However,the diseased-associated SNPs were all intronic, making it difficult to explain the interaction pattern and precise mechanism by which these variants of the COMT and ALDH3B1 genes confer susceptibility to the disorder. We also found that the genes involved in that pathway may increase the susceptibility of some psychiatric symptoms.According to the genetic characteristic of schizophrenia and our previous achievements,we carried out two researches in this thesis:1) to further explore the mechanism under the association of COMT and ALDH3B1 genes with paranoid schizophrenia;2) to explore the molecular etiology of auditory hallucination in schizophrenia. In the first part of this study,we scanned all possible functional SNPs within these two genes by PCR-based genotyping analysis in 540 paranoid schizophrenics and 660 controls from a Han Chinese population.We also determined the effects of schizophrenia-associated SNPs on the development of psychotic symptoms,P300 event-related potential component induced by an auditory odd-ball task,and gene expression examined by quantitative real-time PCR analysis.The major findings of this study were that among the individuals carrying the rs3751082 A allele in the ALDH3B1 gene,the rs4633 T allele in the COMT gene was associated with susceptibility to paranoid schizophrenia(P=0.004),development of hallucinations(P=5.141 E-5), delay of P300 latency in both patients(P=0.006) and controls(P=0.02),and increased expression of the COMT gene in controls(P=0.002).However,the rs4633 T allele did not show any association in the rs3751082 G/G genotype carriers.In the second part of this study,we firstly scanned the 47 SNPs in 27 genes in the dopamine signal pathway among 96 schizophrenics with auditory hallucination,96 schizophrenics without auditory hallucination and 108 controls.And found that the genotypic frequency of rs1700908 in CCKAR gene was distributed significantly differently between schizophrenics with and without hallucinations(Adjust P=0.02).To testify this result,we then make a throughout sequencing of CCKAR gene in another sample.And found that rs1800857-rs2071011 haplotype in CCKAR gene can increase the susceptibility of auditory hallucinations in the schizophrenics(Adjust P=0.003).In the First part of this study,we not only guarantee the repeatability of genetic study, but also support the genetic results by several functions evidence,which can give a systematic view of the association of COMT and ALDH3B1 genes with paranoid schizophrenia.In the second part of the study,we start the work from auditory hallucination,which can control the stratification of samples.We also justified the genetic results by two-stage case-control study,which confirmed the association of CCKAR gene with auditory hallucination and bring new idea for the researches of psychiatric disorders.