Protective Genetic Variants for Alzheimer Disease in the Amish

摘要： 阿尔茨海默病(AD)是老年人中最常见的痴呆形式。无论是遗传还是 环境因素导致阿尔茨海默病的风险，然而，尽管做出了巨大的研究努力，很大一部分基因 阿尔茨海默病的病因尚不清楚。对无关AD病例和对照的全人群研究发现 几种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风险调节因素。 然而，几乎所有这些研究的主要焦点都集中在识别增加风险的变异上； 旨在识别可能预防阿尔茨海默病的变异的研究很少，而且通常力度不够。因此， 需要额外的策略来确定保护或延缓 AD的发展。亚米希人提供了一个强大而独特的机会来识别变种，以保护 同时控制一些混杂因素，如教育水平、生活方式和饮食。此外， 大的亚米希人家系提供了一种丰富的策略来识别自孟德尔人传播以来的罕见变异 从父母到后代，再加上近亲交配循环，最大限度地增加了稀有变异的多个副本的机会 是存在的。该项目的主要目标是识别可预防阿尔茨海默病的基因变异。该项目 将通过追求三个具体目标来实现这一目标：(1)：生成基于家庭的阿米什AD保护器 变量数据集。我们将收集俄亥俄州和印第安纳州阿米什家庭的DNA和表型数据 在800名已知的和新发现的认知正常的人中，年龄在80岁以上，以及他们的一级和二级 亲戚。我们将对所有样本进行SNP基因分型，并对200名认知正常的WGS子集进行SNP基因分型 个体；(2)：AD保护性变异体的鉴定。与多个年满80岁的人的兄弟姐妹关系 并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通径(基于基因集)分析；(3)：执行 候选保护性变异体的功能验证。这些实验将包括筛选效果 对基因表达的影响，对Aβ或tau加工的影响，以及对细胞功能的影响。

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.