Genetic Risk Factors for Parkinson's Disease

描述（由申请人提供）： 帕金森病（PD）影响1-2%的60岁以上的人口，因此构成公共卫生的主要问题。目前的治疗策略只是姑息性的，为了开发更明确的神经保护疗法，更好地了解PD的分子机制是必要的。人类遗传学研究被证明是这一奋进中的宝贵资产，并且随着全基因组关联研究（GWAS）的出现，进展正在加速，在全基因组关联研究（GWAS）中，使用数十万个标记来询问整个人类基因组。PI和他在神经遗传学研究联盟（NGRC）的合作者目前正在一个大型PD病例对照样本中进行GWAS;该项目的基因分型将于2009年秋季完成。 在该应用中，我们建议使用密集的下一代测序和脑/CSF蛋白质组学作为关键工具来验证来自NGRC GWAS的发现。在目标1中，我们将基于统计学理由和PD患者与对照组中额叶皮质和/或CSF中相应蛋白质的差异表达的证据，从GWAS中选择候选基因的列表。然后，我们将使用基于阵列的捕获和下一代焦磷酸测序技术对96名PD患者的每个基因进行完整测序。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和单个箱中的SNP）。然后将在NGRC的2，000名PD患者和2，000名对照中对这些变体进行Aim 2基因分型。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复制这些发现。最后，在剩下的最有希望的基因中，我们将检查PD患者和对照的CSF和额叶皮质中相应蛋白质的基因型和总水平/同种型比率之间的相关性（目的4）。与生物信息学分析相结合，这将有助于确定每个易感基因内的推定功能变体，这些变体将适合于未来在模型系统中的研究。 公共卫生相关性： 帕金森病（PD）影响美国约一百万人，估计每年花费280亿美元。随着人口老龄化，预计这些数字在不久的将来会大幅上升。这项研究旨在确定增加个体患PD风险的基因。通过发现这些基因，我们将更好地了解疾病的根本原因。这将最终导致更好的策略来预防和治疗PD。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) affects approximately one million individuals in the United States at an estimated annual cost of $28 billion. These figures are expected to rise substantially in the near future as the population ages. This study seeks to identify genes that increase an individual's risk of developing PD. By discovering such genes, we will gain a better understanding of the root cause of the disease. This will ultimately lead to better strategies to prevent and treat PD.