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: 9439190
• 负责人: Jonathan L Haines
• 金额: $ 753.77万
• 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/9439190
• 关键词: Age; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Amish; Amyloid beta-Protein; Architecture; 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; 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; 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 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; secondary analysis; 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.

抽象的： 阿尔茨海默病（AD）是老年人中最常见的痴呆症。无论是遗传还是 环境因素会导致 AD 风险，尽管进行了大量的研究工作，但很大一部分遗传因素 AD 的病因仍无法解释。对不相关的 AD 病例和对照进行的全人群研究已确定 几个常见的遗传风险因素并通过阿尔茨海默病测序项目 (ADSP) 整体 正在分析外显子组 (WES) 和全基因组测序 (WGS) 数据，以确定 AD 风险调节剂。 然而，几乎所有这些研究的主要焦点都是识别增加风险的变异。 旨在识别可预防 AD 的变异的研究很少，而且通常力度不够。因此， 需要额外的策略来识别功能变体，以防止或延迟 AD的发展。阿米什人提供了一个强大而独特的机会来识别变种，以防止 AD 同时控制一些混杂因素，如教育水平、生活方式和饮食。此外， 庞大的阿米什血统提供了一种丰富策略，用于识别自孟德尔传播以来的罕见变异 从父母到后代，再加上近亲繁殖循环，最大限度地提高了稀有变异的多个拷贝的机会 存在。该项目的主要目标是识别可预防 AD 的遗传变异。项目 将通过追求三个具体目标来实现这一目标：(1)：生成以家庭为基础的阿米什 AD 保护者 变体数据集。我们将通过检查从俄亥俄州和印第安纳州的阿米什家庭收集 DNA 和表型数据 并对 800 名已知和新发现的 80 岁以上认知正常且一级和二级认知正常的个体进行了追踪 亲属。我们将对所有样本进行 SNP 基因分型，并对 200 个认知正常的子集进行全基因组测序 (WGS) 个人； (2)：AD保护性变体的识别。与多名 80 岁以上人士有同胞关系 将分析认知正常的遗传连锁、IBD 片段共享和关联。单标记 分析将辅以基因分析和途径（基于基因集）分析； (3)：执行 候选保护性变体的功能验证。这些实验将包括筛选效果 对基因表达、对 Aβ 或 tau 加工的影响以及对细胞功能的影响。