Identification of Rare Variants in PD through Whole Exome Sequencing

通过全外显子组测序鉴定 PD 罕见变异

• 批准号: 8540540
• 负责人: JEFFERY Marvin VANCE
• 金额: $ 7.65万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8540540
• 关键词: Age; Amish; Candidate Disease Gene; Chromosomes; Chromosomes, Human, Pair 9; Cluster Analysis; Complex; Data; Data Set; Disease; Environmental Exposure; Frequencies; Gene Cluster; Gene Frequency; Genes; Genetic; Goals; Growth; Individual; Mitochondria; Modeling; Mutation; Nuclear; Nucleic Acid Regulatory Sequences; Odds Ratio; Parkinson Disease; Pathway interactions; Patients; Population; Recording of previous events; Research; Risk; Sample Size; Sampling; Techniques; Testing; Universities; Variant; Work; Yeasts; Zebrafish; biological systems; cost; disorder control; exome; gene discovery; gene function; genetic linkage analysis; genetic pedigree; genome sequencing; genome wide association study; genome-wide; improved; induced pluripotent stem cell; interest; meetings; next generation; tool

Project I - Genetic studies in Parkinson Disease (PD) have been a major tool fueling the tremendous growth in research. However, there is increasing realization that common variations (MAF > 5%) alone are not responsible for the genetic contribution to risk for developing PD and many other complex disorders. One of the alternative hypothesis for this missing genetic contribution are rare variants. Over the past year we initiated one of the first whole exome sequencing (WES) projects for Parkinson disease to search for rare variants contributing to PD. This project continues this work, incorporates our recent work on pathways into our analyses, and will provide information on the pathways and function of the genes discovered. Specific Aim 1 identifies an initial set of rare variants and additional SNPs in a discovery set of 500 Parkinson Disease patients and 500 controls for testing in our replication dataset in Specific Aim 3a. Specific Aim 2 utilizes a large Amish pedigree to look for rare variants using WES, targeted capture and potentially whole genome sequencing. The Amish present a group of individuals with both a relatively uniform environmental exposure history and increased genetic homogeneity. Linkage analysis reveals a strong locus on chromosome 9 In several branches of the pedigree, and additional loci on other chromosomes. This is thus a good model for PD in the outbred population. In Specific Aim 3 we will test the top 200 genes and/or variants from our discovery dataset in an additional 500 cases and 500 controls . To accomplish this efficiently we will create a targeted capture for next generation sequencing . Analyses of this verification datasets will include multiple subsets of the data including by variant, variants within a gene "cluster", pathway analyses, gene networks of interest such as mitochondrial nuclear genes and AAO differences. In order to improve information on pathways and also evaluate the identified genes and there relationship to other known PD genes, we will examine differentially expression using silencing and other interventional techniques for the candidate genes in three different biological systems through Core D: yeast, zebrafish and induced pluripotent stem cells derived from PD patients and controls.

项目 I - 帕金森病 (PD) 的遗传学研究已成为推动巨大进展的主要工具 研究的增长。然而，人们越来越认识到，仅常见的变化（MAF > 5%）就可以解决问题。 与遗传对帕金森病和许多其他复杂疾病风险的影响无关。 对于这种缺失的遗传贡献的替代假设之一是罕见变异。过去一年 我们启动了第一个针对帕金森病的全外显子组测序 (WES) 项目，以寻找 导致 PD 的罕见变异。该项目继续这项工作，纳入了我们最近在路径方面的工作 进入我们的分析，并将提供有关所发现基因的途径和功能的信息。 具体目标 1 在 500 个发现集中识别出一组初始的罕见变异和其他 SNP 帕金森病患者和 500 名对照者在特定目标 3a 的复制数据集中进行测试。 Specific Aim 2 利用庞大的阿米什血统，使用 WES、定向捕获和 潜在的全基因组测序。阿米什人代表了一群具有相对 统一的环境暴露史和增加的遗传同质性。连锁分析揭示了 9号染色体上的强基因座 在谱系的几个分支中，以及其他基因座上的附加基因座 染色体。因此，这是近交群体中 PD 的良好模型。在具体目标 3 中我们将测试 我们的发现数据集中另外 500 个病例和 500 个对照中的前 200 个基因和/或变异。 为了有效地实现这一目标，我们将为下一代测序创建目标捕获。分析 该验证数据集将包括数据的多个子集，包括基因内的变体 “簇”、途径分析、感兴趣的基因网络，例如线粒体核基因和 AAO 差异。为了改善有关途径的信息并评估已识别的基因， 与其他已知的 PD 基因的关系，我们将使用沉默和其他方法检查差异表达 通过Core D对三个不同生物系统中的候选基因进行介入技术： 来自 PD 患者和对照的酵母、斑马鱼和诱导多能干细胞。