Refining the Use of Polygenic Risk Scores for Alzheimer's Disease in Diverse and Founder Populations

项目总结/摘要 阿尔茨海默病（AD）是美国第六大死亡原因，影响约580万人 美国人目前与其他主要死因不同，AD导致的死亡人数大幅增加 自2000年以来由于人口老龄化，AD和其他慢性疾病对医疗保健的负担 系统将在未来几年继续增加。AD的风险是多因素的，包括遗传和 环境组成部分。双胞胎研究表明，晚发性AD的遗传率高达70% 而是可以取决于种群和种群所居住的环境。正因为如此， 合理的调查使用遗传风险，以确定目前未受影响的个人谁是高风险 的AD。评估个人层面风险的一种重要方法是使用多基因风险评分（PRSs）。 PRS通过结合多种，通常是数百或数千种， 风险和保护位点。一般来说，PRS只是给定权重的总和，通常来源于基因组- 广泛关联研究汇总统计，对于给定的单核苷酸多态性（SNP）乘以 SNP的拷贝数。PRS已被用于为其他疾病的干预、筛查和生活规划提供信息。 慢性病尽管取得了这些成功，但减贫战略方法仍有一些局限性，包括缺乏对 非欧洲和高度相关的人群，如创始人人群。使用国家研究所的数据 老年痴呆症测序项目（ADSP）和阿米什人老龄化与记忆协作组织 项目（CAAMP），这项工作将研究在不同的创始人人群中使用PRS的可能性 旨在开发一种基于路径的遗传风险评分，用于分析不同人群中AD的遗传风险。我 已经在ADSP数据中确定了58，925个具有全基因组测序数据的个体，其中包括8，856个 非洲血统的个体，4,000名亚洲血统的个体，9,835名西班牙裔个体。此数据源 这是一个独特的机会，可以在大量不同的人群中分析测序数据。CAAMP数据 包括2,100多名关系密切的阿米什人阿米什人，一个创始人人口，是后裔的 十八世纪移民到美国的瑞士再洗礼派移民。他们生活在相对 文化上孤立的生活方式，因此，大多是遗传和环境同质相比， 一般欧洲血统队列。阿米什人被进一步认为是丰富的变异，这是罕见的，在 一般美国人群，允许检测可能无法捕获的影响。每个数据 在以减贫战略方针解决当前问题方面，资源提供了独特的好处。我的核心假设是 标准的减贫战略方法必须根据目标人口的血统加以调整， 整体样本的相关性。该提案将改进临床和研究环境中PRS的使用 对于非欧洲和创始人人群。更好地了解这些影响将有助于减轻负担 随着减贫战略越来越多地被用于告知相对风险，健康差距也越来越大。

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is the sixth leading cause of death in the United States, affecting about 5.8 million Americans currently. Unlike other leading causes of death, deaths attributable to AD have increased immensely since 2000. As a result of population aging, the burden of AD and other chronic diseases on the healthcare system will continue to increase in coming years. Risk for AD is multifactorial, including genetic and environmental components. Twin studies have revealed that the heritability for late-onset AD is as high as 70% but can depend on the population and the environment in which a population resides. Because of this, it is reasonable to investigate the use of genetic risk to identify currently unaffected individuals who are at high risk of AD. One prominent means of evaluating person-level risk is through the use of polygenic risk scores (PRSs). A PRS captures the genetic risk of AD by incorporating the effects of multiple, often hundreds or thousands, of risk and protective loci. Generally, a PRS is simply the sum of the given weight, typically derived from genome- wide association study summary statistics, for a given single nucleotide polymorphism (SNP) multiplied by the number of copies of the SNP. PRSs have been used to inform intervention, screening, and life planning for other chronic diseases. Despite these successes, the PRS approach has several limitations, including lack of use in non-European and highly related populations, such as founder populations. Using data from the National Institute on Aging’s Alzheimer’s Disease Sequencing Project (ADSP) and the Collaborative Amish Aging & Memory Project (CAAMP), this work will examine the possibility of using PRSs across diverse and founder populations and aim to develop a pathway-based genetic risk score for analyzing genetic risk of AD across populations. I have identified 58,925 individuals with whole genome sequencing data in the ADSP data, including 8,856 individuals with African ancestry, 4,000 Asian ancestry individuals, 9,835 Hispanic individuals. This data source represents a unique opportunity to analyze sequencing data in a large and diverse population. The CAAMP data includes over 2,100 closely related Amish individuals. The Amish, a founder population, are descendants of Swiss Anabaptist immigrants who immigrated to the United States in the eighteenth century. They live a relatively culturally isolated lifestyle and thus, are mostly genetically and environmentally homogeneous compared to a general European ancestry cohort. The Amish are further thought to be enriched for variation that is rare in the general US population, allowing for detection of effects that may not otherwise be captured. Each of these data sources provides a unique benefit in addressing current issues with PRS approaches. My central hypothesis is that standard PRS methods must be adapted depending on both the ancestry of the target population and relatedness of the overall sample. The proposal will refine the use of PRSs in both clinical and research settings for non-European and founder populations. A better understanding of these effects will help to ease the burden of health disparities as PRSs are increasingly used to inform relative risk.