【作者】 罗培芬；

【导师】 沈岩； 许琪；

【作者基本信息】 中国协和医科大学 ， 临床医学， 2008， 博士

【摘要】 精神分裂症是一种严重的精神疾病,全世界的群体发病率约为1%。研究表明遗传因素在其中起了十分重要的作用。药理学研究发现许多抗精神病药通过拮抗多巴胺D2受体发挥药理作用,提示DRD2基因与精神分裂症关联性。然而,多年大量研究结果提示DRD2基因上的与疾病相关的多态性位点很难在不同地理人群中被重复。该问题除了以遗传和表型异质性来解释外,也不能排除研究的样本量不够大、人群层化及一些其他混杂因素的干扰。针对此问题,本研究仍围绕DRD2基因上的多态性位点,在前期工作的基础上展开。根据前期工作在小样本中所筛出杂合度较高的位点,继续在本研究所收集的大样本中国北方汉族人群(512名偏执型精神分裂症患者和480例正常对照)中,采用“病例-对照”关联分析,探讨这些SNPs(共10个)与精神分裂症的相关性。此外,还根据临床表型对病例组进一步分层。本研究希望通过增加样本量提高检验效力,并且希望通过表型分层,提高样本内部的同质性,增加阳性结果的可信度。本研究结果发现:①单位点分析:无论是否进行了表型分层,这些SNPs与精神分裂症均无关,而且性别因素并不会影响它们与疾病的关联性。②多位点(单倍型)分析:阳性单倍型中大部分都包含rs2511521(C)-rs6275(C),而且部分与精神分裂症相关的单倍型在男性病例和对照组中的频率有显著差异(p＜0.001)。表型分层后,发现多数单倍型与阳性症状相关从本工作中得到的结论:第一,在中国北方汉族人群中,我们所选取的SNPs均不与精神分裂症相关,该病的易感位点可能存在于阳性单倍型中。第二,性别因素影响疾病易感性。第三,单倍型分析结果高度提示疾病易感位点可能位于第4内含子和第7外显子之间。更多还原

【Abstract】 Background:Schizophrenia is a complex multifactorial disorder with a worldwide lifetime prevalence of 1%.Particular attention has been focused on dopamine type D2 receptors(DRD2) due to the fact that they are the primary targets for some neuroleptic drugs.Polymorphisms of DRD2 have repeatedly been associated with schizophrenia; however,ethnic disparity seems to be a confounding factor in disease association.Objective:1) To examine the association between the high heterozogosity SNPs of DRD2 gene screened from the previous work and schizophrenia in a larger sample from the Northern Chinese population.2) To explore the association of SNP(s) with certain phenotypes scaled by PANSS grading system.3) To specify the haplotypes within DRD2 that influences risk for schizophrenia.Methods:We investigated the association of 10 polymorphisms,including -141C ins/del(rs1799732),Ser311Cys(rs1801028),His313His(rs6277),Pro319Pro(rs6275) in the DRD2 with schizophrenia using a case-control study,in 512 patients with DSM-IV diagnosis of paranoid schizophrenia and 480 unrelated mentally healthy controls.For quantitative trait analysis,we further stratified the patients by their phenotypes according to PANSS scale.Results:1) In allelic and genotypic studies,no association of 10 polymorphisms with schizophrenia or any of its symptoms was found.2) In haplotypic study,haplotypes containing rs2511521(C)-rs6275(C) were associated with the disease,specifically in males(p＜0.001).3) The quantitative trait analysis revealed that haplotypes in DRD2 are associated with most of the positive syndromes of schizophrenia.Conclusion:Our findings suggest that the haplotypes in DRD2 gene may associate with schizophrenia,and gender factor may take part in the pathogenesis of schizophrenia.A causal variant(s) in DRD2 remains to be elucidated by further fine mapping of the gene, with particular attention given to the area surrounding the fourth intron through seventh exons.更多还原