Polygenic Risk Scores for Alzheimer's Disease in Hispanic/Latinx Populations

西班牙裔/拉丁裔人群阿尔茨海默病的多基因风险评分

• 批准号: 10662781
• 负责人: Guillaume Pare
• 金额: $ 186.86万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662781
• 关键词: Admixture; African; African American; Alzheimer' s Disease; Amerindian; Awareness; Biological Markers; Blood; Caribbean Hispanic; Clinical; Clinical Trials; Clinical stratification; Cognitive; Data; Disease; Ethnic Origin; European; European ancestry; Exhibits; Frequencies; Gene Frequency; Genes; Genetic; Genetic Determinism; Genetic Risk; Genome; Heritability; Hispanic; Incidence; Individual; Joints; Late Onset Alzheimer Disease; Latinx; Latinx population; Linkage Disequilibrium; Measures; Methods; Mexican; Minor; Minority Groups; Modeling; Multivariate Analysis; Native American Ancestry; Neurodegenerative Disorders; Neuropsychology; Not Hispanic or Latino; Pathogenesis; Patient risk; Performance; Peruvian; Phenotype; Plasma; Polygenic Traits; Population; Prevalence; Publications; Role; Sample Size; Sampling; Sum; Testing; Universities; Variant; cohort; disorder risk; endophenotype; exome; exome sequencing; genetic information; genetic variant; genome sequencing; genome wide association study; genome-wide analysis; improved; innovation; neglect; neuroimaging; novel strategies; patient stratification; polygenic risk score; rare variant; risk prediction; risk stratification; risk variant; trait; whole genome

ABSTRACT. Late-onset Alzheimer's disease (LOAD) is the most common neurodegenerative disease, but its causes remain largely unclear. LOAD's large missing heritability has been attributed, at least partially, to mechanisms not currently investigated by traditional “single-locus” approaches. To this end, we aim to study the role of Polygenic risk scores (PRS), which capture sparse genetic information by summing up multiple risk loci across the genome, providing an individual genetic risk profile. Numerous studies have confirmed that LOAD is enriched with a polygenic component. Most of PRS have been developed in European-descend populations and no ancestry-specific PRS for LOAD have been developed in Hispanic/Latinx (HL). Furthermore, most PRS rely on common genetic variants (minor allele frequency ≥1%), neglecting the contribution of rare variants which have been shown to be critical in LOAD pathogenesis. To this end, we will generate traditional and innovative PRS leveraging large HL cohorts available at Columbia University, employing common and rare variants. Because linkage disequilibrium between common and rare variants is low, we hypothesize that these two PRS will be independent in terms of disease prediction and patient risk stratification. For common variants PRS (cvPRS), we have strong preliminary data in Caribbean Hispanics that culminated in a recent publication from our group. In addition, we will employ a new approach developed by our group, RV- EXCALIBER, which combines rare variant burden over a large number of genes into predictive rare variant polygenic risk score (rvPRS). Employing HL is particularly indicated for rvGRS because 1) they are enriched with rare variants and 2) have higher incidence and prevalence of LOAD compared to European descend populations. We will study three HL populations that exhibit different proportions of European, African and Amerindian ancestry: 1) Caribbean Hispanics 2) Mexicans and 3) Peruvians. These cohorts are deeply phenotyped for LOAD, have GWAS data and whole-exome/genome sequencing data (WGS) and plasma AD-biomarkers available for a sub-sample. We will first (Aim 1) generate a cvPRSs using common variants associated with LOAD within each Hispanic cohort. We will also generate an alternative local ancestry-weighted PRS and test the transferability of each cvPRS across HL cohorts and finally will construct a trans-ancestry PRS. Then (Aim 2) we will generate rvPRSs for those individuals with WGS and compare the performances of the two PRSs. We will also test a model that combine cvPRS and rvPRS. Finally, we will validate these new PRSs from Aim 1 and Aim 2 employing LOAD-related endophenotypes and explore a multi-trait PRS approach (Aim 3).

抽象的。晚发的阿尔茨海默氏病（负载）是最常见的神经退行性疾病，但它 原因仍然在很大程度上不清楚。负载的遗传力很大，至少部分归因于 当前未通过传统的“单核”方法研究的机制。为此，我们的目标是学习 多基因风险评分（PRS）的作用，通过总结多个来捕获稀疏的遗传信息 整个基因组的风险基因座，提供单个遗传风险特征。许多研究证实 负载富含多基因组件。大多数PR已在欧洲延期中开发 在西班牙裔/拉丁裔（HL）中，已经开发了种群和未针对祖先的PR。 此外，大多数PR依赖于常见的遗传变异（次要等位基因频率≥1％），忽略了 稀有变体的贡献已被证明在负载发病机理中至关重要。为此，我们将 利用哥伦比亚大学提供的大型HL队列生成传统和创新的PRS，雇用 常见和稀有变体。由于共同变体和稀有变体之间的连锁disteStiLibrium较低，我们 假设这两个PR将独立于疾病预测和患者风险分层。 对于普通变体PR（CVPR），我们在加勒比海西班牙裔中有强大的初步数据 我们小组的最新出版物。此外，我们将采用我们小组RV-开发的新方法 Excaliber，将大量基因上的稀有变体燃烧结合到预测性稀有变体中 多基因风险评分（RVPRS）。使用HL对于RVGR特别指示，因为1）它们富集 与欧洲的下降相比 人群。 我们将研究三个HL人群，这些人群暴露了不同比例的欧洲，非洲和美国 祖先：1）加勒比西班牙裔2）墨西哥人和3）秘鲁人。这些队列被深深表现为 负载，具有GWAS数据和全外观/基因组测序数据（WGS）和等离子体AD-BIOMARKER 可用于子样本。我们将（AIM 1）使用与 在每个西班牙裔队列中加载。我们还将生成替代的本地血统加权PR和测试 每个CVPR在HL队列中的可传递性，最后将构建一个翻译PR。然后（目标 2）我们将为那些具有WGS的人生成RVPRS，并比较两个PRS的性能。我们 还将测试结合CVPR和RVPR的模型。最后，我们将从AIM 1验证这些新PRS和 AIM 2采用与负载相关的内型型并探索多特征PRS方法（AIM 3）。