Genetic Risk Factors for Parkinson's Disease

帕金森病的遗传风险因素

• 批准号: 8195901
• 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/8195901
• 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

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.

帕金森病 (PD) 影响 60 岁以上人口的 1-2%，因此 构成公共卫生的一个重大问题。目前的治疗策略只是姑息治疗 为了更好地理解PD潜在的分子机制是必要的 开发更明确的神经保护疗法。人类遗传学研究被证明是 随着基因组的出现，这一努力的宝贵资产和进展正在加速 广泛关联研究（GWAS），其中使用 数十万个标记。 PI 和他在 NeuroGenetics 的合作者 研究联盟 (NGRC) 目前正在大型 PD 病例对照中开展 GWAS 样本;该项目的基因分型将于 2009 年秋季完成。 在此应用中，我们建议使用密集的下一步验证 NGRC GWAS 的发现 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，我们将选择一个列表 基于统计基础和证据的 GWAS 候选基因 PD患者额叶皮层和/或脑脊液中相应蛋白的差异表达 与控制。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 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 2,000 名 PD 患者进行基因分型 以及来自 NGRC 的 2,000 个控制。这将有助于进一步精细绘制每个候选基因， 并有可能加强真实易感位点的关联。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基因型之间的相关性 PD患者脑脊液和额叶皮质中相应蛋白的总水平/异构体比率 和控制（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异将适合未来的研究 模型系统。