【作者】 韩柏慧；

【导师】 于雅琴；

【作者基本信息】 吉林大学 ， 流行病与卫生统计学， 2007， 硕士

【摘要】 精神分裂症是所有精神疾病中最常见、最严重的一种,其病因尚未阐明。遗传流行病学研究证实,精神分裂症与遗传因素有密切关系,系谱分析、双生子法和寄养子法等群体遗传学研究提示精神分裂症有明显的遗传背景,但不符合经典的孟德尔单基因遗传规律,属于多基因遗传病或人类复杂疾病。精神分裂症的基因组扫描和候选基因研究,虽然获得了不少阳性结果,但重复性较差。至今尚未发现导致精神分裂症的主要的、特异性的易感基因。本研究工作是在本研究室前期工作的基础上进一步以中国北方汉族精神分裂症患者核心家系为研究对象,利用PCR–RFLP方法检测PIP3-E基因上4个SNPs标记和APOD基因上的一个SNP标记,应用SPSS12.0软件进行数据管理与分析。检测与分析结果表明,所检测的5个SNPs位点与精神分裂症无关联,但发现PIP3-E基因上的rs2236257位点等位基因频率与关系妄想、自责自罪妄想以及思维连贯性障碍相关联(P<0.05)。本研究检测与分析结果虽然未发现与精神分裂症相关联的阳性位点。但尚不能排除APOD基因和PIP3-E基因与精神分裂症的相关联的可能性,需进一步加大核心家系样本量加以确证。本研究为进一步开展精神分裂症遗传学研究奠定了基础。更多还原

【Abstract】 Schizophrenia is a kind of common mental disorder, which pathogenesis remains undefined. 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. To map and clone schizophrenia-related genes in humans, is not only helpful to interpret the mechanisms of its molecular genetics, but also establishes the foundation of clinical gene diagnosing and curing diseases in gene’s level and drug designing. Therefore, the researches on candidate gene of schizophrenia have always been an important part of aetiology research of schizophrenia. The development of molecular genetic and genetic epidemiology has made it possible to carry on such kind of research, and we have got some achievements. Association analysis which based on trios and makered by SNPs, opens up the possibility of studying the genetic basis of complex disease,such as oncomas,cardiovascular and cerebrovascular diseases,neuro and psychiosis,and it establishes the foundation of preventing,diagnosing and curing diseases on gene’s level.APOD and PIP3-E gene have been suggested as a promising candidate for the vulnerability to schizophrenia in view of both its function and location in the genome, thus its polymorhpism probably has association with schizophrenia. In order to detect our hypothesis, five SNPs were genotyped in this study, they were rs2280250(APOD), rs17278409(PIP3-E), rs11155952(PIP3-E), rs17085177(PIP3-E) and rs9371781 (PIP3-E). The study used a family-based analysis in which the family trios,consisting of father, mother and affected offspring. They were all Chinese Han decent in North China. Polymerase chain reaction and restriction fragment length polymorphism (PCR–RFLP)were adopted to examine individual genotype. Statistical software SPSS was used to handle the data on genotype. Goodness of fitχ2 test was used to detect whether the SNPs distribution in the sample population is in Hardy-Weinberg equilibrium. Multifunctional genetic statistical software were used to detect whether the tested SNPs locus was associated with schizophrenia by two family-based association analysis, the haplotype relative risk (HRR) and the transmission disequilibrium test (TDT). Then we determined whether APOD gene and PIP3-E gene was associated with schizophrenia.The analytic results showed that age of schizophrenia was between 14 and 48 yeares old, the mean of age was 25.14±6.568 years old. Most schizophrenia (153) are 20 ~ 29 years old. There were no difference between the male and female schizophrenia with age. There was significant difference between the male and female schizohrenia at the positive clinical symptoms of experience of being revealed, delusion of love, other delusion, illogic of thinking and bizarre behavior ( P < 0.05 ). The incidence rate of the five positive clinical symptoms were higher in female schizophrenia than in male schizophrenia. And there was significant difference between the male and female schizohrenia in the negative clinical symptoms of illogic of thinking and bizarre behavior. Premorbid personality of most schizophrenia was introvert and there was sex differences.The goodness-of-fit test showed that the genotype frequency distributions of these 5 SNPs were not deviated from the Hardy-Weinberg equilibrium. Neither HRR nor TDT showed a genetic association between the 5 SNPs and schizophrenia. Schizophrenia has been characterized heterogeneously in clinical presentation. The clinical heterogeneity may be related to genetic heterogeneity. To validate this hypothesis, we divided the patients into two groups based on the clinical symptoms. With theχ2 test, we can conclude that whether there were some significant differences of the frequencies distribution of allele and genotype in two groups.The results showed that there were correlations between rs2236257 allelic frequencies and some clinical symptoms of schizophrenia, such as delusion of observation, delusion of negation, and incoherence of thinking (P<0.05), and there were correlations between its genotypic frequencies and some clinical symptoms of schizophrenia, such as delusion of observation and delusion of negation (P<0.05).On the whole, The findings of this study suggested that APOD gene and PIP3-E gene family may not play an important role(at least in chinese han population) in schizophrenia development. However,locus rs2236257 is associated with some of the symptoms of schizophrenia. Therefore,its modest effect should not be excluded while the mechanisms need further study.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