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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

Age Alleles Alzheimer&apos s Disease Alzheimer&apos 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

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项目摘要

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.

抽象的：阿尔茨海默氏病（AD）是老年人最常见的痴呆形式。遗传和环境因素有助于广告风险，但目的地庞大的研究工作，大部分是通用的一部分 AD的病因仍然无法解释。对无关的AD病例和对照组的整个人口研究已经确定几个常见的遗传危险因素以及通过阿尔茨海默氏病测序项目（ADSP）整体正在分析外显（WES）和整个基因组测序（WGS）数据以识别AD风险调节剂。但是，几乎所有这些研究的主要重点都是确定增加风险的变体。旨在识别可能保护AD的变体的研究很少，而且通常功能不足。那，需要其他策略来确定保护或延迟的功能变体广告的开发。阿米什人提供了一个强大而独特的机会来识别保护的变体在控制一些混杂因素的同时，例如教育水平，生活方式和饮食。另外，大型阿米什人的谱系提供了一种富集策略，用于识别自门德利传输以来的稀有变体从父母到后代，耦合到近交环，最大化稀有变体的多个副本的机会存在。该项目的主要目的是确定提供对AD保护的遗传变异。将通过追求三个具体目标来实现这一目标：（1）：基于家庭的Amish广告保护变体数据集。我们将通过检查俄亥俄州和印第安纳州阿米什人家庭的DNA和表型数据随后有800个已知和新确定的认知正常人80岁以上及其一级和第二级亲属。我们将对所有样品和WGS进行SNP基因分型个人（2）：识别AD保护变体。拥有多个80岁以上的人并将分析认知上的正常情况，以分析遗传联系，IBD段共享和关联。单标记基因分析和途径（基于基因集）分析将补充分析；（3）：表演候选保护变体的功能验证。这些实验将包括筛查效果关于基因表达，对Aβ或TAU加工的影响以及对细胞功能的影响。