论文摘要
精神分裂症是一种以基本个性改变,思维、情感和行为的分裂、精神活动与环境不协调为主要特征的精神疾患,属于人类复杂疾病。该病的发生涉及遗传和环境因素的共同作用。国内外的学者在精神分裂症易感基因的筛查和定位研究中已获得了一定有价值的结果,但是由于精神分裂症是复杂的多基因遗传性疾病,其易感基因的数量、各基因的致病风险度以及致病机制仍未被阐明。确定精神分裂症的病因,在基因水平上预防和治疗疾病是当前医学研究中的重大课题。本研究以296个中国汉族精神分裂症患者及其健康父母双亲组成的核心家系以及400例无血缘关系的精神分裂症患者和419例健康者为研究对象,利用生物信息学方法和分子遗传学技术在22q11-12构建单核苷酸多态性（SNPs）连锁不平衡图,通过检测该染色体区域候选基因上的SNPs,筛检与精神分裂症相关联的基因位点。在5个候选基因（PRODH、UFD1L、CLDN5、APOL1和APOL3）上选择6个SNPs遗传标记,利用PCR-RFLP方法确定个体基因型。应用基于家系的连锁不平衡分析方法（TDT及HHRR）和基于群体的case-control相关分析方法以及多功能遗传统计学软件（SPSS11.5和UNPHASED2.404）分析数据。结果显示,UFD1L基因和CLDN5基因均与中国汉族人群精神分裂症发病密切相关,UFD1L基因的SNP2 C/G等位基因和CLDN5基因的SNP4 C/G等位基因与精神分裂症易感基因既连锁又关联。含SNP2（C）的单倍型和含SNP4（C）的单倍型可能携带精神分裂症抗性位点。含SNP4（G）的单倍型可能携带精神分裂症易感位点。各SNPs与精神分裂症的临床症状相关性分析结果显示,SNP3、SNP4和SNP6位点分别与精神分裂症的某些阳性症状相关联,SNP4位点与精神分裂症的阴性症状思维贫乏相关联。SNPs与精神分裂症性别相关性分析显示,SNP2位点与女性精神分裂症发病密切相关,而SNP4与男性精神分裂症发病密切相关,表明精神分裂症在男女之间存在着遗传异质性。这些结果提示,UFD1L和CLDN5基因可能是精神分裂症相关基因。22q11-12区域可能存在多个决定精神分裂症易感性和抗性的突变位点。这些位点可能存在于同一个基因上,即等位基因异质性;也可能存在于不同基因上,即位点异质性。此项研究工作是后基因组时期功能基因组学研究的前沿课题。本实验结果将有助于阐明精神分裂症的分子遗传学机制,为在基因水平上建立诊断方法,开发新型药物奠定重要的实验基础。
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