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

项目摘要/摘要 阿尔茨海默病(AD)是美国第六大致死原因，影响了约580万人 目前是美国人。与其他主要死亡原因不同，可归因于AD的死亡人数大幅增加 从2000年开始。由于人口老龄化，AD和其他慢性病对医疗保健造成的负担 系统将在未来几年继续增加。阿尔茨海默病的风险是多因素的，包括遗传和 环境成分。双胞胎研究表明，晚发性AD的遗传率高达70% 但可能取决于人口和人口居住的环境。正因为如此，它是 合理地调查使用遗传风险来识别目前未受影响的高危个体 公元一代的。评估个人水平风险的一个重要手段是使用多基因风险评分(PRSS)。 通过结合多个，通常是数百或数千个， 风险和保护性基因座。一般说来，一个prs仅仅是给定权重的总和，通常来自基因组- 广泛关联研究摘要统计，对于给定的单核苷酸多态(SNP)乘以 SNP的副本数量。PRSS已被用于为其他人的干预、筛查和生活规划提供信息 慢性病。尽管取得了这些成功，但PRS方法仍有几个局限性，包括在 非欧洲和高度相关的人群，如创始人群体。使用美国国家研究院的数据 老年性阿尔茨海默病测序项目(ADSP)与Amish协同老化与记忆研究 项目(CAAMP)，这项工作将研究在不同的创始人群体中使用PRSS的可能性 并旨在开发一种基于途径的遗传风险评分，用于跨人群分析AD的遗传风险。我 在ADSP数据中确认了58,925个具有全基因组测序数据的个体，其中包括8,856个 非洲血统的人，4,000名亚洲血统的人，9,835名西班牙裔人。此数据源 代表着一个独特的机会来分析大量和多样化的人群中的测序数据。CAAMP数据 包括2100多名关系密切的阿米什人。亚米希人，创业者群体，是 18世纪移居美国的瑞士再洗礼派移民。他们过着一种相对 文化上与世隔绝的生活方式，因此，与 一般的欧洲血统队列。亚米希人被进一步认为是因为变异而丰富的，这种变异在 一般的美国人口，允许检测的影响，否则可能无法捕获。这些数据中的每一个 SOURCES在使用减贫战略方法解决当前问题方面提供了独特的好处。我的中心假设是 标准减贫战略方法必须根据目标人口的血统和 总体样本的关联性。该提案将完善PRSS在临床和研究环境中的使用 面向非欧洲人和创业者群体。更好地了解这些影响将有助于减轻负担 由于PRSS越来越多地被用来告知相对风险，因此对健康差异的了解越来越多。

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.