Protective Genetic Variants for Alzheimer Disease in the Amish

阿米什人阿尔茨海默病的保护性遗传变异

• 批准号: 9898659
• 负责人: Jonathan L Haines
• 金额: $ 28.73万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898659
• 关键词: Age; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Amish; Amyloid beta-Protein; Biological; Biology; Case-Control Studies; Cell physiology; Chromosomes; Cognitive; Collection; Communities; Consanguinity; Coupled; DNA; Data; Data Linkages; Data Set; Dementia; Development; Diet; Educational Background; Emotional; Environmental Risk Factor; Etiology; Family; Financial Hardship; Founder Generation; Gene Expression; General Population; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic Transcription; Genetic Variation; Genomics; Genotype; Goals; In Vitro; Inbreeding; Indiana; Individual; Life Style; Maintenance; Metabolism; Ohio; Onset of illness; Parents; Pathway interactions; Phase; Play; Population; Process; Property; Proteins; Quality Control; Research; Research Design; Risk; Role; SNP genotyping; Sampling; Screening procedure; Series; Signal Transduction; Survival Analysis; Testing; Variant; Vertebral column; Work; base; candidate validation; case control; cognitive testing; exome; experimental study; follow-up; genetic architecture; genetic association; genetic linkage analysis; genetic pedigree; genetic risk factor; genetic variant; genome sequencing; genomic data; novel; offspring; overexpression; phenotypic data; protein expression; rare variant; reference genome; risk variant; screening; success; tau Proteins; transmission process; whole genome

ABSTRACT: Alzheimer disease (AD) is the most common form of dementia in older individuals. Both genetic and environmental factors contribute to AD risk, yet despite huge research efforts, a significant portion of the genetic etiology of AD remains unexplained. Population-wide studies of unrelated AD cases and controls have identified several common genetic risk factors and through the Alzheimer’s Disease Sequencing Project (ADSP) whole exome (WES) and whole genome sequencing (WGS) data are being analyzed to identify AD risk modulators. However, the primary focus of almost all of these studies has been on identifying variants that increase risk; studies designed to identify variants that may protect from AD are few and usually underpowered. Thus, additional strategies are required to identify functional variants that protect against or delay the development of AD. The Amish provide a powerful and unique opportunity to identify variants protecting against AD whilst controlling for some confounding factors such as level of education, lifestyle and diet. In addition, the large Amish pedigrees offer an enrichment strategy for identifying rare variants since Mendelian transmissions from parents to offspring, coupled to inbreeding loops, maximize the chance that multiple copies of rare variants exist. The primary goal of this project is to identify genetic variations offering protection against AD. The project will achieve this goal by pursuing three specific aims: (1): Generation of a family-based Amish AD Protective Variant dataset. We will collect DNA and phenotype data from Amish families in Ohio and Indiana by examining and following 800 known and newly identified cognitively normal individuals age 80+ and their 1st and 2nd degree relatives. We will perform SNP genotyping on all samples and WGS on a subset of 200 cognitively normal individuals; (2): Identification of AD protective variants. Sibships with multiple individuals who are age 80+ and cognitively normal will be analyzed for genetic linkage, IBD segment sharing, and association. Single-marker analyses will be supplemented by gene-wise analysis and pathway (gene set-based) analysis; (3): Perform functional validation of candidate protective variants. These experiments will include screening for effects on gene expression, impact on Aβ or tau processing, and effects on cellular function.

文摘: