Genetic Risk Factors for Parkinson's Disease

帕金森病（PD）影响1-2%的60岁以上的人口，因此 这是公共卫生的一个主要问题。目前的治疗策略只是治标不治本， 更好地理解帕金森病的分子机制是必要的， 开发更明确的神经保护疗法人类遗传学研究证明， 随着基因组的出现，这一奋进和进展中的宝贵资产正在加速- 广泛关联研究（GWAS），其中使用 成千上万的标记。PI和他的神经遗传学合作者 研究联盟（NGRC）目前正在一个大型PD病例对照中进行GWAS 该项目的基因分型工作将于2009年秋季完成。 在这个应用程序中，我们建议使用密集的下一代网络来验证NGRC GWAS的发现。 代测序和脑/CSF蛋白质组学作为关键工具。在目标1中，我们将选择 GWAS的候选基因基于统计学理由和证据， PD患者额叶皮质和/或CSF中相应蛋白的差异表达 vs.对照然后，我们将使用阵列对96名PD患者的每个基因进行完整测序- 基于捕获和下一代焦磷酸测序技术。这将允许发现 在GWAS中未表示或标记的变体（例如低频编码SNP和 单例箱中的SNP）。然后在Aim 2中对2，000名PD患者的此类变体进行基因分型 还有NGRC的2,000个控制器这将有助于进一步精细定位每个候选基因， 并可能加强真正的易感基因座的关联。在目标3中，我们将 在1,600例病例和1,600例对照的独立样本中重复了这些发现。最后， 在剩下的最有希望的基因中，我们将研究基因型和 PD患者CSF和额叶皮质中相应蛋白的总水平/亚型比率 对照组（目标4）。结合生物信息学分析，这将有助于识别 每个易感基因内的推定功能变体将适合于未来的研究， 模型系统

Parkinson's disease (PD) affects 1-2% of the population over 60 years of age and thus constitutes a major problem in public health. Current treatment strategies are only palliative and a better understanding of the molecular mechanisms underlying PD is necessary in order to develop more definitive neuroprotective therapies. Human genetic studies are proving to be a valuable asset in this endeavor and progress is now accelerating with the advent of genome- wide association studies (GWAS) in which the entire human genome is interrogated using hundreds of thousands of markers. The PI and his collaborators in the NeuroGenetics Research Consortium (NGRC) are currently conducting a GWAS in a large PD case-control sample; genotyping for the project will be complete by the fall of 2009. In this application, we propose to validate findings from the NGRC GWAS using dense next- generation sequencing and brain/CSF proteomics as key tools. In Aim 1, we will select a list of candidate genes from the GWAS based both on statistical grounds and on evidence of differential expression of the corresponding protein in frontal cortex and/or CSF in PD patients vs. controls. We will then sequence each gene in its entirety in 96 PD patients using array- based capture and next-generation pyrosequencing techniques. This will allow discovery of variants that were not represented or tagged in the GWAS (e.g. low-frequency coding SNPs and SNPs in singleton bins). Such variants will then be genotyped in Aim 2 in 2,000 PD patients and 2,000 controls from the NGRC. This will serve to further fine-map each candidate gene, and potentially strengthen the association for bona fide susceptibility loci. In Aim 3, we will then replicated these findings in an independent sample of 1,600 cases and 1,600 controls. Finally, in the most promising genes that remain, we will examine correlation between genotype and total levels/isoform ratios of the corresponding proteins in CSF and frontal cortex of PD patients and controls (Aim 4). Combined with bioinformatics analysis, this will assist in identifying putative functional variants within each susceptibility gene that will be suitable for future study in model systems.