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: 8264601
• 负责人: JEFFERY Marvin VANCE
• 金额: $ 68.01万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8264601
• 关键词: Age; Amish; Candidate Disease Gene; Cell Culture Techniques; Cells; Chromosomes; Chromosomes, Human, Pair 9; Cluster Analysis; Complex; Data; Data Set; Disease; Environmental Exposure; Fission Yeast; Frequencies; Gene Cluster; Gene Expression Profile; Gene Frequency; Gene Silencing; Genes; Genetic; Goals; Growth; Individual; Mitochondria; Modeling; Mutation; Nuclear; Nucleic Acid Regulatory Sequences; Odds Ratio; Organism; 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.

帕金森氏病（PD）的遗传研究已成为推动这一巨大进步的主要工具