【作者】 郭伟；

【导师】 于雅琴；

【作者基本信息】 吉林大学 ， 流行病与卫生统计学， 2006， 硕士

【摘要】 精神分裂症是一种复杂的由多种因素所致的精神障碍,可见于各种社会文化和阶层中,全世界患病率约为1%。精神分裂症和其他常见的慢性疾病如糖尿病、高血压等一样,具有遗传基础,表现为显著的家族聚集倾向,是人类面临的最为严重的疾病之一,给家庭和社会造成长期沉重的负担。随着分子遗传学研究的深入,对精神分裂症的致病基因定位,有关精神分裂症的病因、临床诊断、治疗方面的相关研究倍受关注,已经成为医学界乃至全社会面临的中心课题。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,它不符合经典的孟德尔单基因遗传规律,可能是由几个中度效应基因遗传或多个轻度微效基因遗传的多基因遗传病或人类复杂疾病。这种微效基因,正常个体携带的越多,其患病的可能性也越大,故有人称此类基因为易感基因。目前大多数人采用定位克隆法和候选基因法来识别精神分裂症的易感基因,进而为阐明精神分裂症的遗传学机制提供依据。本研究通过检索与精神分裂症存在连锁关系的染色体上某个基因或已经报道有病理指标的相关基因为候选基因,以中国北方汉族精神分裂症患者和他们的健康父母双亲组成的核心家系为研究对象,研究1号染色体区域上的KCNJ10和MEF2D两个基因上的各一个SNP位点,用聚合酶链式反应–限制性片段长度多态性(PCR–RFLP)方法检测个体基因型,用SPSS统计学软件管理基因分型数据,应用基于家系的连锁不平衡分析方法(TDT及HRR)和多功能统计学软件(SPSS)分析数据,确定KCNJ10和MEF2D基因与精神分裂症的关系。结果显示,各位点与精神分裂症无关联,但在临床症状分析中KCNJ10基因(rs1186679)和MEF2D基因(rs1171558)的两个位点与精神分裂症的某些阳性症状即不同临床表型有显著的关联性,提示KCNJ10基因上的rs1186679位点和MEF2D基因上的rs1171558位点与精神分裂症的临床表型的发生密切相关。更多还原

【Abstract】 Schizophrenia is a complex mental disorder, which can be observed indifferent kinds of culture and society stratum, with a lifetime prevalence of1% in the general population worldwide, governed by several factors. As achronic disorder like diabetes and hypertension, a genetic contribution to thetransmission of schizophrenia has been established, which displayeddistinguished family aggregation tendency. It is the most severe disorder,which human beings have to be faced with. It brought long-term and heavyeconomic burden to the society and families. With the development ofmolecular genetics, the same to other chronic disorders, fiding intermediatebetween genetic predisposition and the clinical phenotype of schizophrenia.Has become a hot topic all over the world. Genetic epidemiological study hasindicated that the mechanism of schizophrenia is mainly related to geneticcomponents. It is not a simple Mendelian disease but belongs tonon-Mendelian inheritance. It looks like a disease of multifactorial inheritanceor a human complex disease caused by several midrange-effector or polygenic.The more a person takes along with such minor gene (allelomorph), the morelikely he or she will suffer this disease, so people named them predisposinggenes. Nowadays, in order to interpret the biological mechanisms ofschizophrenia, most researchers take the method of positional cloning andcandidate gene to identify predisposing genes of schizophrenia,In this study, we search for the gene on chromosome, which has linkagerelationship with schizophrenia, or the gene, which has been reported as apatho-index, and use it as candidate gene. To investigate the geneticassociation of the two SNPs on KCNJ10 gene and MEF2D gene, whichlocates on human chromosome 1,with schizophrenia among Chinese Hanfamily trios, consisting of fathers, mothers, and affected offsprings withschizophrenia. Polymerase chain reaction and restriction fragment lengthpolymorphism (PCR–RFLP)were adopted to examine individual genotype.Statistical software SPSS were used to handle the data on genotype.In this study, rs1186679 on KCNJ10 gene and rs 1171558 on MEF2Dgene were selected and tested in 200 trios. The result is the following:1. Goodness of fit χ2 test showed that the distribution of the genotypesfor the two SNPs was all in Hardy-Weinberg equilibrium (P>0.05). HRR andTDT analysis indicated that all of them had no association with schizophrenia.2. Clinical subset analysis proved that schizophrenia has beencharacterized by heterogeneity both in clinical presentation.3. The analysis between each SNP and the symptoms of schizophreniashowed that allele frequency and genotype frequency of rs1171558 at MEF2Dlocus was associated with the positive symptoms of schizophrenia, such asgenuine auditory hallucination, delusion of grandeur, and incoherence ofthinking. The anylysis between SNPs and symptoms of paranoidschizophrenia showed that the allele frequency and genotype frequency ofrs1171558 was associated with both genuine auditory hallucination anddelusion of persecution.There was no association between allele frequencyand the positive symptoms of schizophrenia on rs1186679 at KCNJ10 locus,whose genotype frequency was associated with genuine auditory hallucination.This indicated that the polymorphism of KCNJ1 gene and MEF2D gene arehighly associated with the development of clinical phenotypes ofschizophrenia.According to the results presented above, KCNJ10(rs1186679) geneand MEF2D ( rs1171558 ) gene are not main etiological factor inschizophrenia, but they are associated with some positive symptoms ofschizophrenia, so we can’t rule out its minor effect. We need to enlarge thesample size and using polygene analysis and multi-site association analysis,and take on the newest technology to detect the mechanism of the happeningof schizophrenia.更多还原