Supplement-ES10751 (Molecular Epidemiology of PD)

描述(由申请人提供) 拟议研究的长期目标是阐明帕金森氏病(PD)的病因并确定预防方法。具体地说，研究人员将在800名帕金森病患者、1222名兄弟姐妹和800名无关对照(总共2822名受试者)中进行一系列基因关联研究。第一个目标是通过对相同的帕金森病患者与未受影响的兄弟姐妹和无关对照进行独立比较，研究人口混合的影响和研究设计对遗传相关性的影响。第二个目标是通过基于关联的全基因组(“自上而下”)和候选基因(“自下而上”)研究来识别帕金森病的易感基因。具体地说，研究人员将使用至少1,494个单核苷酸多态标记在他们的受试者中进行全基因组扫描以寻找关联。他们将寻求通过对病例和对照的独立样本(通过合作提供)进行类似的全基因组扫描来复制相关性。研究人员还将研究至少24个候选基因与帕金森病的关联。这将包括与泛素蛋白酶体途径相关的基因，以及与神经毒素的细胞分区和可能的神经保护相关的基因。他们将考虑等位基因和单倍型变异。调查人员将独立地将病例与未受影响的兄弟姐妹和无关的对照进行比较。第三个目标将通过递归划分和条件Logistic回归模型来探索帕金森病中可能的基因-基因和基因-环境相互作用。研究人员此前曾观察到帕金森病患者中逐个基因和性别的交互作用，并将建立更复杂的模型，以包括多种基因类型和环境暴露。本申请是作为“帕金森病分子流行病学”(ES10751)拨款的竞争性补充申请提交的，并将这些活动与第二项拨款“帕金森病的流行病学和遗传学”(NS33978)的活动联系起来。拟议的目标是对调查人员正在进行的工作的极大扩充和扩展。拟议的研究将为帕金森病的预期毒理学研究提供一个宝贵的遗传框架。

DESCRIPTION (provided by applicant) The long-term objectives of the proposed studies are to clarify the etiology of Parkinson's Disease (PD) and to identify means to prevent it. Specifically, the investigators will conduct a series of genetic association studies in 800 PD, 1,222 siblings, and 800 unrelated controls (2,822 subjects total). The first aim will be to study the impact of population admixture and study design on genetic associations, through the independent comparison of the same PD cases with unaffected siblings and unrelated controls. The second aim will be to identify susceptibility genes for PD through association based genome wide ("top down") and candidate gene ("bottom up") studies. Specifically, the investigators will conduct a genome wide scan for association in their subjects using at least 1,494 single nucleotide polymorphism markers. They will seek to replicate associations through a similar genome wide scan in an independent sample of cases and controls (provided through collaboration). The investigators will also study the association of at least 24 candidate genes with PD. This will include genes related to the ubiquitin proteasomal pathway and genes related to cellular compartmentalization of neurotoxins and possibly neuroprotection. They will consider allele and haplotype variants. The investigators will compare cases independently to unaffected siblings and to unrelated controls. The third aim will explore possible gene-gene and gene-environment interactions in PD through recursive partitioning and conditional logistic regression models. The investigators have previously observed gene by gene by gender interactions in PD, and will build more complex models to include multiple genotypes and environmental exposures. This application is submitted as a competing supplement application to the "Molecular Epidemiology of Parkinson's Disease" (ES10751) grant and bridges these activities with those of the second grant "Epidemiology and Genetics of Parkinson's Disease" (NS33978). The proposed aims represent a significant amplification and expansion of the investigators' ongoing work. The proposed studies will provide an invaluable genetic framework for anticipated toxicogenomic studies of PD.