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.

帕金森氏病（PD）影响60岁以上人口的1-2％，因此 构成公共卫生的主要问题。当前的治疗策略仅是姑息性的， 必须更好地了解PD的分子机制，以便为了 开发更明确的神经保护疗法。人类遗传研究被证明是 在这项工作和进步中，随着基因组的出现，有价值的资产正在加速 广泛的关联研究（GWAS），其中整个人类基因组被质疑 成千上万的标记。 PI及其神经遗传学的合作者 研究财团（NGRC）目前正在大型PD病例控制中进行GWA 样本;该项目的基因分型将在2009年秋季完成。 在此应用程序中，我们建议使用Next-Next- 生成测序和大脑/CSF蛋白质组学作为关键工具。在AIM 1中，我们将选择一个清单 来自GWAS的候选基因是基于统计理由和证据 PD患者额叶皮质和/或CSF中相应蛋白质的差异表达 与控件。然后，我们将使用阵列中的96名PD患者对每个基因进行整体测序 - 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 SNPS中的SNPS）。然后将在2,000名PD患者中对AIM 2进行基因分型。 来自NGRC的2,000个控件。这将有助于进一步绘制每个候选基因， 并有可能加强真正的易感位点的关联。在AIM 3中，我们将 在1,600例病例和1,600个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，我们将研究基因型与 CSF和PD患者额叶皮层中相应蛋白的总水平/同工型比 和控件（目标4）。结合生物信息学分析，这将有助于识别 每个敏感性基因内的推定功能变体，适用于以后的研究 模型系统。