Genetic Risk Factors for Parkinson's Disease

帕金森氏病(PD)影响1-2%的60岁以上人口，因此 构成了公共卫生的一个主要问题。目前的治疗策略只是姑息性的和 为了更好地了解帕金森病的分子机制， 开发更明确的神经保护疗法。人类基因研究被证明是一种 随着基因组的出现，这一努力和进展中的宝贵资产正在加速- 广泛的关联研究(GWAS)，其中整个人类基因组被使用 成千上万的记号笔。派和他的神经遗传学合作者 研究联盟(NGRC)目前正在进行一项大规模帕金森病病例对照研究 样本；该项目的基因分型工作将于2009年秋季完成。 在本应用程序中，我们建议使用Dense Next-验证来自NGRC GWAS的研究结果 世代测序和脑/脑脊液蛋白质组学作为关键工具。在目标1中，我们将选择以下列表 根据统计依据和证据，来自GWAs的候选基因 帕金森病患者额叶皮质和/或脑脊液中相应蛋白的差异表达 与控制的对比。然后，我们将使用ARRAY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 未在GWAS中表示或标记的变体(例如，低频编码SNP和 单件箱中的SNPs)。这些变异将在2,000名PD患者的AIM 2中进行基因分型 以及来自NGRC的2000个控制。这将有助于进一步对每个候选基因进行精细定位， 并有可能加强真正的易感基因座之间的联系。在《目标3》中，我们将 在1,600个病例和1,600个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，我们将检查基因型和 帕金森病患者脑脊液和额叶皮质中相应蛋白的总水平/异构体比率 和对照(目标4)。结合生物信息学分析，这将有助于识别 每个易感基因中可能存在的功能变异，将适用于未来的研究 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.