Candidate Genes and Complex Interactions in PD

帕金森病（PD）仅在美国就影响了超过一百万人。PD是一种复杂的疾病，遗传和环境因素都有助于易感性。剖析复杂疾病的病因，如PD，需要整合许多不同的实验室和统计方法。该项目旨在继续资助寻找导致特发性PD的基因。认识到帕金森病的复杂病因和发现复杂疾病中涉及的基因的困难，我们采用了“基因组融合”的方法。我们依靠遗传连锁研究，表达研究和基于家族的关联分析的证据的融合，产生PD易感基因的强有力的候选者。通过这一提议，我们将继续根据基因组趋同的原则检查候选基因。我们将通过分析复杂的遗传和环境相互作用，以及开发减少大家庭样本异质性的方法来加强这些努力。该提案的具体目的是：1）检测与PD相关的生物学候选基因;以及项目II基因表达的基因组趋同和连锁分析所建议的候选基因; 2）检测PD候选基因之间的基因-基因相互作用; 3）检测候选基因与PD潜在环境危险因素之间的基因-环境相互作用。这种全面的分析方法，在项目II和协会进行的表达分析的指导下， 本提案项目IV中的基因定位将使我们能够系统地评估和鉴定在PD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.