Molecular Genetics Studies On Associations Between Stizophrenia And Susceptibility Genes

Schizophrenia is the most serious type of mental disorder that affectsapproximately 1% of the population in the world, with characteristics of split ofthought, affection and behavior, and incompatibility of mental activity andenvironment. In the last century, numerous family, twin, and adoption studies havedemonstrated the role of genetic components in the aetiology of schizophrenia.However, major common risk loci have not been found.Genome-wide genetic linkage studies suggest that schizophrenia is not amonogenic disease, but probably influenced by multiple genes with small or mediumrisks, and by environment factors as well. It is studied as a polygenic disease ingenetics.In the present study, we detected the relationship between three genes-CHL1,DISC1 and BDNF and scizophrenia on the basis of linkage disequilibrium theory.CHL1 (the close homologue of L1), a member of subfamily of CAM, is able topromote neurite elongation and neurite survival in vitro. A lot of evidences fromneuropathology and biochemistry suggest CHL1 as a candidate gene involving in theaetiology of schizophrenia. We performed association study using a set of HanChinese samples of 560 schizophrenics and 576 controls between 4 SNPs in CHL1and schizophrenia. SNP rs2272522 in Exon1 of CHL1 shows a statistically significantdifference in allele frequencies between 576 controls and 560 patients individuals (χ2=31.591, P<0.000001, OR=1.745, 95% CI=1.435–2.121), which is consistent withprevious study in Japanese. Therefore, the association between rs2272522 andschizophrenia suggests that CHL1 is likely involved in the etiology of schizophrenia.DISC1 (Disrupted-in-Schizophrenia-1) has first been identified as a candidate genefor schizophrenia through study of a Scottish family with a balanced (1;11) (q42.1;q14.3) translocation. DISC1 is demonstrated a role in neuronal migration, cytoskeletalfunction and neuronal signaling. Based on a sample of 560 schizophrenia patients and576 controls of Han Chinese, we genotyped three markers-rs2492367, rs821616 andrs2295959 within DISC1 gene. No SNP showed significant difference in allelefrequencies between total 576 control and 560 patients individuals. But SNPrs2295959 gave a weak different allele frequencies between cases and controls infemale samples (χ2 = 6.188, P = 0.0135, OR = 0.728, 95% CI = 0.567–0.935) whilenot in male samples. Our findings supported the possibility that there are sex-specificgenetic components involved in the pathology of schizophrenia. As the most abundantof the neurotrophins in human brain, BDNF (Brain-derived neurotrophic factor) playsthe key role in the development of brain, especially in differentiation of serotonergicneurons and dopaminergic neurons. Hyperactivity of dopaminergic transmission andabnormal serotonergic transmission are two hypothesizes of the etiology ofschizophrenia. We chose three SNPs in BDNF gene for association study and failed tofind any significant differences in genotype or allele distribution in either totalsamples or groups were divided according to gender.It is the first time to perform the association studies between these genes andschizophrenia in Han Chinese. The three studies are very innovative. Our resultsprovide important evidence for the pathogenesis of schizophrenia.