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

完善阿尔茨海默病多基因风险评分在不同人群和创始人群体中的应用

• 批准号: 10387471
• 负责人: Michael David Osterman
• 金额: $ 3.15万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-04-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10387471
• 关键词: Address; Affect; African; African ancestry; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; American; Amerindian; Amish; Asian ancestry; Biological; Biological Process; Cause of Death; Cessation of life; Chronic Disease; Clinical; Clinical Research; Coronary Arteriosclerosis; Data; Data Sources; Detection; Disease Outcome; Environment; Environmental Exposure; European; Fertility; Founder Generation; Future; Genes; Genetic; Genetic Risk; Genetic study; Genotype; Glare; Goals; HIV; Healthcare Systems; Heart Diseases; Heritability; Hispanic; Hispanic Populations; Immigrant; Incentives; Individual; Intervention; Late Onset Alzheimer Disease; Life; Life Style; Longevity; Memory; Methods; National Institute on Aging; Pathway interactions; Performance; Persons; Population; Population Heterogeneity; Quality of life; Relative Risks; Reporting; Research; Risk; Role; Sampling; Scoring Method; Single Nucleotide Polymorphism; Stratification; Stroke; Sum; Target Populations; Testing; Therapeutic Intervention; Time; Training; Twin Studies; United States; Variant; Weight; Work; aging population; attributable mortality; base; case control; cohort; comorbidity; disparity reduction; exome; genetic analysis; genome sequencing; genome wide association study; health disparity; high risk; improved; insight; malignant breast neoplasm; polygenic risk score; risk prediction; screening; sex; statistics; success; whole genome

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.

项目摘要/摘要 阿尔茨海默氏病（AD）是美国第六大死亡原因，影响约580万 美国人目前。与其他主要死亡原因不同，归因于AD的死亡已大大增加 自2000年以来。由于人口衰老，AD的伯恩（Burnen）和其他慢性疾病的医疗保健 未来几年的系统将继续增加。广告风险是多因素的，包括遗传和 环境组成部分。双胞胎研究表明，晚发广告的遗传力高达70％ 但可以取决于人口所在的人口和环境。因此，是 合理地调查使用遗传风险来识别当前未受影响的人 广告。评估人级风险的一种突出方法是使用多基因风险评分（PRS）。 PRS通过纳入多个（通常数百或数千的）的影响来捕获AD的遗传风险 风险和受保护的地方。通常，PR只是给定重量的总和，通常来自基因组 广泛的关联研究摘要统计数据，对于给定的单个核苷酸多态性（SNP）乘以 SNP的副本数量。 PRS已被用来为其他人提供干预，筛查和生活计划 慢性疾病。尽管取得了这些成功，但PRS方法仍有几个局限性，包括缺乏 非欧洲和高度相关的人群，例如创始人人口。使用国家研究所的数据 关于衰老的阿尔茨海默氏病测序项目（ADSP）和协作的阿米什人老化与记忆 项目（CAAMP），这项工作将研究使用潜水员和创始人人口的PRS的可能性 并旨在开发基于途径的遗传风险评分，以分析跨种群AD的遗传风险。我 已经确定了58,925个患有全基因组测序数据的人，包括8,856 具有非洲血统的人，4,000名亚洲血统，有9,835个西班牙裔人。此数据源 代表了一个独特的机会，可以分析大量多样化的人群中的测序数据。 CAAMP数据 包括超过2,100个与密切相关的阿米什人。阿米什人是创始人，是 瑞士洗礼移民在18世纪移民到美国。他们活着 与文化孤立的生活方式相比 欧洲一般血统队列。人们认为，阿米什人的变化很少 美国普通人群，允许检测可能不会捕获的影响。这些数据中的每一个 来源为解决PRS方法解决当前问题提供了独特的好处。我的中心假设是 该标准PRS方法必须根据目标人群的祖先和 总体样本的相关性。该提案将在临床和研究环境中完善PRS的使用 对于非欧洲和创始人人群。更好地了解这些效果将有助于减轻燃烧 越来越多地使用健康差异来告知相对风险。

项目成果

Founder population-specific weights yield improvements in performance of polygenic risk scores for Alzheimer disease in the Midwestern Amish.

• DOI: 10.1016/j.xhgg.2023.100241
• 发表时间: 2023-10-12
• 期刊: HUMAN GENETICS AND GENOMICS ADVANCES
• 作者: Osterman, Michael D.;Song, Yeunjoo E.;Lynn, Audrey;Miskimen, Kristy;Adams, Larry D.;Laux, Renee A.;Caywood, Laura J.;Prough, Michael B.;Clouse, Jason E.;Herington, Sharlene D.;Slifer, Susan H.;Fuzzell, Sarada L.;Hochstetler, Sherri D.;Main, Leighanne R.;Dorfsman, Daniel A.;Zaman, Andrew F.;Ogrocki, Paula;Lerner, Alan J.;Vance, Jeffery M.;Cuccaro, Michael L.;Scott, William K.;Pericak-Vance, Margaret A.;Haines, Jonathan L.
• 通讯作者: Haines, Jonathan L.