Linkage And Association Analyses Of Schizophrenia In The Han Chinese

The thesis contains two main pieces of work. In the first one, we performeda two-stage linkage analysis of 25 Chinese schizophrenia pedigrees fromShanghai focusing on 10 target chromosomes which have already been the subjectof considerable research: Chromosome 1, 2, 5, 6, 8, 10, 13, 15, 18 and 22.In another piece of work, we studied the association between the SNPs withinCAPON and schizophrenia in the Han Chinese population using case-controlmethods.We initially genotyped 237 individuals in 25 pedigrees with 186 markers.Five candidate regions were then chosen for fine mapping and 49 additionalmarkers were genotyped. In region 1q21-23, a maximum multipoint HLOD(HLOD=2.38, α=0.36) was observed between D1S484 and D1S2705, under thedominant model. In region 5q35, dominant HLOD of 2.36 (α=0.50), 2.04(α=0.48), and 2.31 (α=0.50) were found at marker D5S2030, D5S408 and D5S2006,respectively. Consistent multipoint results also supported linkage to thisregion under the same dominant model, with a highest HLOD of 2.47 (α=0.33).Furthermore, single-point HLODs (HLOD=1.95 with α=0.46 at D22S274, andHLOD=1.91 with α=0.41 at D22S1157) were found in region 22q13, under thedominant model. Evidence from these three chromosomal regions satisfied thecriteria for suggestive linkage.Recently, some genetic variants within CAPON, in 1q21-23, have beenreported as exhibiting significant linkage disequilibrium (LD) toschizophrenia in Canadian familial-schizophrenia pedigrees. Here, weexamined nine single-nucleotide polymorphisms (SNPs), which span anapproximately 236Kb region of CAPON, in 664 schizophrenia cases and 941controls in the Chinese Han population. We detected a significant differencein allele distributions of SNP rs348624 (P=0.000017). Moreover, the overallfrequency of haplotypes constructed from three SNPs including rs348624 showedsignificant difference between cases and controls (P=2.5×10-5). Our findingsindicate that CAPON gene may be a candidate susceptibility gene forschizophrenia in Chinese Han population, and also provide further support forthe potential importance of NMDAR-mediated glutamatergic transmission in theetiology of schizophrenia.