Candidate Genes and Complex Interactions in PD

帕金森病(PD)仅在美国就影响了100多万人。帕金森病是一种复杂的疾病，遗传和环境因素都与易感性有关。剖析复杂疾病的病因，如帕金森病，需要整合许多不同的实验室和统计方法。该项目寻求继续资助寻找导致特发性帕金森病的基因。认识到帕金森病的复杂病因和发现复杂疾病涉及的基因的困难，我们采用了“基因组融合”的方法。我们依赖于来自遗传连锁研究、表达研究和基于家族的关联分析的证据的融合，以产生PD易感基因的强有力的候选基因。通过这一提议，我们将继续基于基因组收敛的原则来研究候选基因。我们将加强这些努力，包括分析复杂的遗传和环境相互作用，以及开发方法，以减少我们的大家庭样本的异质性。这项建议的具体目的是：1)测试与帕金森病相关的生物候选基因；以及项目II中基因表达的基因组聚合和连锁分析所推荐的候选基因；2)帕金森病候选基因之间的基因-基因相互作用测试；以及3)帕金森病候选基因与潜在环境风险因素之间的基因-环境相互作用测试。这一综合分析方法，以项目II和协会中进行的表达式分析为指导 在本提案的项目IV中绘制图谱，将使我们能够系统地评估和识别在帕金森病中发挥作用的基因。

Parkinson disease (PD) affects over one million people in the United States alone. PD is a complex disorder, with both genetic and environmental factors contributing to susceptibility. Dissecting the etiology of complex diseases, such as PD, requires the integration of many different laboratory and statistical approaches. This project seeks to continue funding to search for genes contributing to idiopathic PD. Recognizing the complex etiology of PD and the difficulties in uncovering genes involved in complex diseases, we have adopted the approach of "genomic convergence". We have relied on the convergence of evidence from genetic linkage studies, expression studies and family-based association analysis to yield strong candidates for PD susceptibility genes. Through this proposal, we will continue to examine candidate genes based on the principle of genomic convergence. We will enhance these efforts by including analysis of complex genetic and environmental interactions, as well as developing methods to reduce heterogeneity in our large family sample. The specific aims of this proposal are: 1) Test biological candidate genes for association with PD; and candidates suggested by the genomic convergence of gene expression from project II and linkage analysis 2) Test for gene-gene interaction between candidate genes in PD; and 3) Test for gene-environment interaction between candidate genes and potential environmental risk factors for PD. This comprehensive analytic approach, guided by the expression analysis conducted in Project II and association mapping in Project IV of this proposal, will allow us to systematically evaluate and identify genes playing a role in PD.