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.

项目概要/摘要 阿尔茨海默病 (AD) 是美国第六大死因，影响约 580 万人 目前，与其他主要死亡原因不同，AD 造成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造成负担 未来几年，AD 的风险将继续增加，其中包括遗传因素和因素。 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，因此，它是。 合理地调查使用遗传风险来识别当前未受影响但处于高风险的个体 AD 的一种重要评估方法是使用多基因风险评分 (PRS)。 PRS 通过综合多种（通常是数百或数千）因素的影响来捕捉 AD 的遗传风险。 一般来说，PRS 只是给定权重的总和，通常源自基因组。 广泛关联研究汇总统计数据，对于给定的单核苷酸多态性 (SNP) 乘以 SNP 的拷贝数已被用于为其他人的干预、筛查和生活规划提供信息。 尽管取得了这些成功，PRS 方法仍存在一些局限性，包括在慢性疾病中缺乏使用。 非欧洲和高度相关的人群，例如使用国家研究所的数据的创始人人群。 关于衰老的阿尔茨海默氏病测序项目 (ADSP) 和阿米什衰老与记忆合作 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 旨在开发基于途径的遗传风险评分，用于分析人群中 AD 的遗传风险。 已在 ADSP 数据中识别出 58,925 名具有全基因组测序数据的个体，其中包括 8,856 名 具有非洲血统的个体、4,000 名亚洲血统个体、9,835 名西班牙裔个体 此数据源。 CAAMP 数据代表了分析大量多样化人群的测序数据的独特机会。 包括 2,100 多个密切相关的阿米什人，阿米什人是一个创始人群体，是阿米什人的后裔。 十八世纪移民到美国的瑞士再洗礼派移民他们过着相对的生活。 文化上孤立的生活方式，因此与其他人相比，在遗传和环境上大多是同质的 人们进一步认为，阿米什人的欧洲血统群体具有丰富的变异，这在欧洲人中是罕见的。 一般美国人口，可以检测到这些数据中的每一个可能无法捕获的影响。 来源在使用 PRS 方法解决当前问题方面提供了独特的优势 我的中心假设是。 标准 PRS 方法必须根据目标人群的血统和 该提案将完善 PRS 在临床和研究环境中的使用。 对于非欧洲人和创始人人群来说，更好地了解这些影响将有助于减轻负担。 随着 PRS 越来越多地被用来告知相对风险，健康差异也越来越明显。

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.