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。遗传和 环境因素有助于AD风险，然而，尽管进行了大量的研究工作，但遗传因素的很大一部分仍然存在。 AD的病因学仍然无法解释。对不相关的AD病例和对照的人群范围研究已经确定， 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）的整体 外显子组（WES）和全基因组测序（WGS）数据正在被分析以鉴定AD风险调节剂。 然而，几乎所有这些研究的主要重点都是确定增加风险的变异; 旨在识别可能保护AD的变体的研究很少，并且通常动力不足。因此，在本发明中， 需要额外的策略来识别功能变体，这些功能变体可以防止或延迟 AD的发展。阿米什人提供了一个强大而独特的机会，以确定变种保护免受 AD，同时控制一些混杂因素，如教育水平，生活方式和饮食。此外该 大的阿米什人家系提供了一种富集策略，用于识别孟德尔遗传以来的罕见变异 从父母到后代，再加上近亲繁殖的循环，最大限度地增加了罕见变异的多个拷贝的机会， 存在.该项目的主要目标是确定提供预防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）：建立一个以家庭为基础的阿米什人 变量数据集。我们将收集来自俄亥俄州和印第安纳州的阿米什家庭的DNA和表型数据， 以及800名年龄在80岁以上的已知和新发现的认知正常个体及其一级和二级 亲戚我们将对所有样本进行SNP基因分型，并对200名认知正常的人进行WGS 个体;（2）：AD保护性变体的鉴定。与80岁以上的多个人的兄弟姐妹关系 并且认知正常的患者将分析遗传连锁、IBD区段共享和关联。单标记 分析将通过基因分析和途径（基于基因集）分析进行补充;（3）： 候选保护性变体的功能验证。这些实验将包括筛选影响 对基因表达的影响、对Aβ或tau蛋白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.