Genetic Risk Factors for Parkinson's Disease

帕金森病的遗传风险因素

• 批准号: 7797927
• 负责人: CYRUS P ZABETIAN
• 金额: --
• 依托单位: VA PUGET SOUND HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7797927
• 关键词: Address; Affect; Age; Age-Years; Bioinformatics; Biological Assay; Biological Models; Brain; Candidate Disease Gene; Cessation of life; Code; DNA Resequencing; Data; Data Set; Databases; Disease; Enrollment; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Europe; Event; Frequencies; Future; Genes; Genetic; Genomics; Genotype; Goals; Human Genetics; Human Genome; Individual; Lead; Light; Maps; Methods; Modality; Molecular; Neurodegenerative Disorders; Neuronal Injury; Onset of illness; Parkinson Disease; Patients; Pattern; Plant Roots; Population; Predisposition; Protein Isoforms; Proteins; Proteomics; Public Health; Research; Risk; Sampling; Staging; Susceptibility Gene; Techniques; Technology; Testing; Time; United States; Validation; Variant; Work; base; brain tissue; candidate selection; case control; cost; database of Genotypes and Phenotypes; design; falls; frontal lobe; gene environment interaction; genetic pedigree; genetic risk factor; genome wide association study; interest; neurogenetics; next generation; palliative; prevent; public health relevance; tool; treatment strategy

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.

描述（由申请人提供）： 帕金森病（PD）影响1-2%的60岁以上人口，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，有必要更好地了解 PD 的分子机制。事实证明，人类遗传学研究是这一努力的宝贵财富，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中，使用数十万个标记来询问整个人类基因组。该 PI 及其在神经遗传学研究联盟 (NGRC) 的合作者目前正在对大型 PD 病例对照样本进行 GWAS；该项目的基因分型将于 2009 年秋季完成。在本申请中，我们建议使用密集下一代测序和脑/CSF 蛋白质组学作为关键工具来验证 NGRC GWAS 的研究结果。在目标 1 中，我们将根据统计依据以及 PD 患者与对照者额叶皮层和/或脑脊液中相应蛋白质差异表达的证据，从 GWAS 中选择候选基因列表。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 GWAS 中未表示或标记的变异（例如低频编码 SNP 和单例箱中的 SNP）。然后，这些变异将在 Aim 2 中对来自 NGRC 的 2,000 名 PD 患者和 2,000 名对照进行基因分型。这将有助于进一步精细绘制每个候选基因，并有可能加强与真正易感基因座的关联。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 患者和对照的脑脊液和额叶皮层中相应蛋白质的基因型和总水平/异构体比率之间的相关性（目标 4）。与生物信息学分析相结合，这将有助于识别每个易感性基因内的假定功能变异，这些变异适用于模型系统的未来研究。 公共卫生相关性： 帕金森病 (PD) 在美国影响约 100 万人，估计每年造成 280 亿美元的损失。随着人口老龄化，这些数字预计在不久的将来将大幅上升。本研究旨在找出增加个体患帕金森病风险的基因。通过发现这些基因，我们将更好地了解疾病的根本原因。这最终将导致更好的预防和治疗帕金森病的策略。