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).

摘要：迟发性阿尔茨海默病 (LOAD) 是最常见的神经退行性疾病，但其发病率较高。 LOAD 的大量遗传性缺失至少部分归因于其原因。 目前传统“单基因座”方法尚未研究的机制为此，我们的目标是研究。 多基因风险评分（PRS）的作用，它通过总结多个基因来捕获稀疏遗传信息 整个基因组的风险位点，提供个体遗传风险概况，大量研究已证实这一点。 LOAD 富含多基因成分，大部分 PRS 是在欧洲后裔中开发的。 西班牙裔/拉丁裔 (HL) 人群中尚未开发针对 LOAD 的特定血统 PRS。 此外，大多数 PRS 依赖于常见的遗传变异（次要等位基因频率≥1%），忽略了 罕见变异的贡献已被证明在 LOAD 发病机制中至关重要。 利用哥伦比亚大学现有的大量 HL 队列生成传统和创新的 PRS，雇用 由于常见和罕见变异之间的连锁不平衡性较低，因此我们 坚持认为这两个 PRS 在疾病预测和患者风险分层方面将是独立的。 对于常见变体 PRS (cvPRS)，我们在加勒比西班牙裔中拥有强有力的初步数据，最终 我们小组最近发表的一篇文章此外，我们将采用我们小组开发的一种新方法，RV- EXCALIBRE，它将大量基因的罕见变异负担组合成预测性罕见变异 多基因风险评分 (rvPRS) 特别适用于 rvGRS，因为 1) 它们得到了富集。 具有罕见变异，2) 与欧洲后裔相比，LOAD 的发生率和患病率更高 人口。 我们将研究三个具有不同比例的欧洲人、非洲人和美洲印第安人的 HL 人群 血统：1）加勒比西班牙裔2）墨西哥人和3）秘鲁人这些群体的表型很深。 LOAD，拥有 GWAS 数据和全外显子组/基因组测序数据 (WGS) 以及血浆 AD 生物标志物 我们将首先（目标 1）使用与相关的常见变体生成 cvPRS。 我们还将生成一个替代的本地血统加权 PRS 和测试。 每个 cvPRS 在 HL 队列中的可转移性，最终将构建一个跨血统的 PRS 然后（目标。 2) 我们将为那些具有 WGS 的个体生成 rvPRS，并比较两个 PRS 的表现。 还将测试结合 cvPRS 和 rvPRS 的模型最后，我们将验证目标 1 和 中的这些新 PRS。 目标 2 采用 LOAD 相关的内表型并探索多性状 PRS 方法（目标 3）。