Genetics of Parkinsons disease

描述(摘自申请者摘要)：帕金森氏病(PD)是一种神经退行性疾病，在美国有超过100万人患病。起病症状多种多样，通常发生在生命的晚期。绝大多数家族性帕金森病的遗传方式尚不清楚。在病例/对照研究中，一些候选基因建议包括细胞色素P450 2D、载脂蛋白E和白介素2，但这些基因座并没有一致地重复，强调了病例/对照设计的问题。极少数帕金森病患者有常染色体显性遗传。最近，α-突触核蛋白基因突变已被确认为一种非常罕见的常染色体显性早发性帕金森病的原因，但常见的晚发性帕金森病的潜在基因仍不清楚。研究人员已经确定并抽样了215个患有家族性帕金森病的独立、不协调的同胞，并继续收集另外200个家族性帕金森病不一致的同胞，以检验第一个数据集的阳性结果。此外，他们还将收集400对患有散发性帕金森病的不和谐同胞对。这些家系将构成使用同胞不平衡方法进行关联检验的基础，这将绕过病例/对照方法的一些问题。研究人员将在他们自己的连锁筛选中，并通过本提案的项目II中的SAGE分析，测试文献中确定的候选关联基因，以确定帕金森病复杂病因的基因。一旦确定了易感基因，风险因素信息将通过本提案的项目III提供给基因/环境调查。此外，还将开发方法来调整不一致兄弟姐妹关系测试中未受影响兄弟姐妹状态的不确定性，并针对紧密连锁标记的多项测试进行调整。这些研究将有助于确定这种复杂疾病的潜在病因。

Description (from applicant's abstract): Parkinson's disease (PD) is a neurodegenerative disorder affecting over 1,000,000 people in the United States. Onset symptoms are variable and generally occur late in life. The mode of inheritance for the vast majority of familial PD cases is unknown. A number of candidate genes have been suggesting including CYP2D, APOE, and interleukin 2 using case/control studies but these loci have not been consistently replicated, emphasizing the problem with case/control design. A very small percentage of PD cases have autosomal dominant inheritance. Recently mutations in the alpha-synuclein gene have been identified as the cause of a very rare form of autosomal dominant early-onset PD but the genes underlying the common late-onset PD remain unknown. The investigators have ascertained and sampled 215 independent discordant sibships with familial PD and are continuing to collect an additional 200 familial PD-discordant sibships for testing of positive results from the first dataset. In addition, they will collect 400 sets of discordant sibpairs with sporadic PD. These families will form the basis for association testing using sib disequilibrium methods, which will circumvent some of the problems with the case/control approach. The investigators will test for association candidate genes identified in the literature, in their own linkage screens, and through the SAGE analysis in Project II of this proposal in order to identify genes underlying the complex etiology of PD. Risk factor information will be available for gene/ environmental investigations through Project III of this proposal once susceptibility genes are identified. In addition, methods will be developed to adjust for uncertainty in status of unaffected siblings in the discordant sibship tests, and to adjust for multiple tests at tightly linked markers. These studies will help define the underlying etiology of this complex disease.