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

抽象的。迟发性阿尔茨海默病(LOAD)是最常见的神经退行性疾病，但其 原因在很大程度上仍不清楚。LOAD的巨大缺失遗传率被归因于，至少部分是由于 目前没有用传统的“单基因座”方法研究的机制。为此，我们的目标是研究 多基因风险评分(PR)的作用，它通过将多个 整个基因组的风险基因座，提供了个体遗传风险概况。大量研究证实， 负载中富含一种多基因成分。大多数可再生能源系统都是在欧洲大陆开发的 在西班牙裔/拉丁裔(HL)人群中，并没有针对LOAD的特定血统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≥为1%)，而忽略了 已被证明在LOAD发病机制中起关键作用的稀有变异。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PR， 常见和罕见的变种。由于常见变异和罕见变异之间的连锁不平衡很低，我们 假设这两个PR在疾病预测和患者风险分层方面是独立的。 对于常见的变异类型(Cvprs)，我们在加勒比海拉美裔美国人中有强大的初步数据，最终结果是 这是我们小组最近出版的一本书。此外，我们将采用我们的团队RV开发的一种新方法- ExCaliber，它将大量基因上的罕见变异负担结合到预测性罕见变异中 多基因风险评分(Rvprs)。RvGRS特别需要使用HL，因为1)它们被浓缩 与欧洲人相比，2)有更高的发病率和患病率 人口。 我们将研究三个HL种群，它们显示出不同比例的欧洲人、非洲人和美洲印第安人 血统：加勒比海拉美裔、墨西哥人和秘鲁人。这些队列的表型很深， LOAD，有GWAS数据和全外显子组/基因组测序数据(WGS)和血浆AD生物标记物 可用于子样本。我们将首先(目标1)使用与以下内容相关联的常见变体生成cvPRSS 在每个西班牙裔队列中加载。我们还将生成替代的本地祖先-加权的PR和测试 每一个cvprs在HL队列中的可转移性，最终将构建一个跨祖先prs。然后(瞄准 2)我们将为那些有WGS的个体生成rvprs，并比较两种prs的性能。我们 还将测试一款结合了cvprs和rvprs的型号。最后，我们将验证目标1中的这些新PRS和 目的2利用负荷相关的内表型，探索一种多性状群体识别方法(目标3)。

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).