【作者】 樊金波；

【导师】 贺林；

【作者基本信息】 中国科学院研究生院（上海生命科学研究院） ， 神经生物学， 2003， 博士

【摘要】 一个多世纪以来通过对家系，孪生子和寄养子的研究已经证明了遗传因素在精神分裂症致病机理中的重要作用，然而其致病基因位点一直未能找到。本文阐述了传递不平衡分析的原理及其优缺点，我们认为基于侯选基因的传递不平衡分析将对阐明精神分裂症致病机理中的遗传因素起到重要作用。 儿茶酚胺-O-甲基转移酶基因(COMT)和NOTCH4基因从其染色体定位及其编码的蛋白质生物功能角度上考虑都是精神分裂症的侯选基因。我们对COMT和NOTCH4基因上多个单核苷酸多态性标记(SNP)或微卫星遗传标记进行的传递不平衡分析未发现由父母传递给患病子代的等位基因(Allele)或单体型(Haplotype)频率之间存在显著性差异。进一步用大样本量的病例-对照样本进行的关联分析也没有发现在检测的遗传标记等位基因和基因型分布频率在精神分裂症患者群体和正常对照群体中存在显著性差异。我们的研究结果否定了(至少在中国汉族人群中)COMT基因和NOTCH4基因在精神分裂症致病机理中起主要作用的假说。我们还对5—羟色胺转运蛋白基因(5-HTT)和脯氨酸脱氢酶基因(PRODH)进行了初步的传递不平衡分析，研究结果否定了(至少在中国汉族人群中)所检测的三个遗传标记与精神分裂症可能的致病基因位点之间处于连锁不平衡的假说。 今后精神分裂症分子遗传学的研究应着重于大规模SNP遗传标记基础上的连锁不平衡分析方法并综合考虑基因之间的相互作用以及基因与环境变量之间的相互作用才有可能最终阐明遗传因素在精神分裂症致病机理中的作用。更多还原

【Abstract】 Numerous family, twin, and adoption studies have demonstrated the role of genetic components in the aetiology of schizophrenia. However, major common risk loci have not been found. In this work, I, together with colleagues, have compared the properties of the Transmission/disequilibrium test (TDT) with linkage and association approaches in any details, from which we propose that TDT analysis using candidate gene strategy is a powerful method in identification of susceptibility alleles for complex diseases such as schizophrenia.COMT and N0TCH4 gene have been suggested as a promising candidate for the vulnerability to schizophrenia in view of both its function and location in the genome. To further investigate their roles in schizophrenia susceptibility, several polymorphic markers in COMT and N0TCH4 gene were analyzed using the TDT in Chinese family trios. No preferential transmission of any allele or haplotype was detected for any of the polymorphisms studied. Subsequent association study did not demonstrate significant differences of genotype and allele frequency of studied polymorphisms between schizophrenics and controls in a large a case-control sample from China. These data suggest that COMT and N0TCH4 gene are unlikely to play a major role in the aetiology of schizophrenia in Han Chinese population. Our results also suggest that two VNTR polymorphisms of the 5-HTT gene and a single nucleotide polymorphism of PRODH gene are unlikely in linkage disequilibrium with a schizophrenia susceptibility gene in Han Chinese population.Future directions in schizophrenia genetics research include family-based linkage disequilibrium mapping based on large-scale genotyping of SNP markers and investigations of the epigenetic regulation of genes and the interaction between genes and environment variable may be necessary for complete understanding the genetic components to the aetiology of schizophrenia.更多还原