Prioritizing diversity in polygenic risk prediction of primary open-angle glaucoma

项目总结：原发性开角型青光眼多基因风险预测的优先多样性 青光眼是世界范围内导致不可逆性失明的主要原因。原发性开角型青光眼（POAG）， 青光眼是最常见的类型，在非洲血统的个体中更普遍和严重。不幸的是， 来自这一祖先群体的个体在全基因组关联研究中的代表性不足 （GWAS）迄今为止。此外，多基因风险评分（PRS）的基础上GWAS数据从欧洲血统 人口不能转移到不同（非欧洲）血统的个人。考虑到 精确医学，PRS显示出临床潜力，但部分由于缺乏多样性， 问题研究我们假设，临床上可实施的减贫战略可以通过包括非洲和非洲- 在基因发现和PRS发展中的血统个体。 为了告知和改善精确的眼部健康，我们将优先考虑POAG多基因风险预测的多样性 提出了三个目标，将产生有史以来最大的非洲和非洲裔POAG Meta分析， 这是有史以来第一个以非洲血统为重点的POAG PRS。在目标1中，我们将对以下内容进行荟萃分析 47，078份样本（18，037例病例，29，041例对照），以确定非洲人和非洲裔人的新POAG基因座 人口。鉴于大多数GWAS主要是在欧洲和欧洲后裔中进行的， 人群中，我们假设未发现的POAG风险位点将通过利用 非洲和非洲裔人群样本中病例对照GWAS的荟萃分析。在目标2中，我们将 荟萃分析我们每个数据集的混合物映射结果，以识别非洲血统特异性POAG 的位点我们假设混合物图谱将确定非洲血统共同存在的基因组区域， 与POAG风险隔离。将对来自目标1和2的重要基因座进行精细定位并进行选择评价 签名.在目标3中，我们将在非洲和非洲裔基础数据集Meta数据中构建和优化POAG PRS。 分析。然后，我们将在测试数据集中评估新的和已发表的用于POAG分类的PRS。我们 假设祖先知情的POAG PRS将更好地预测POAG和相关临床结局， 非洲和非洲裔人口与主要来自欧洲裔数据的人口相比。 将对目标1和2的荟萃分析结果以及目标3中优化PRS的变体进行 途径分析，以确定与POAG风险有关的生物学途径和统计学驱动基因。在 从长远来看，我们希望从该项目中获得的信息将有助于更广泛地了解POAG 遗传学在不同的祖先群体，并提供了临床适用性的基础 POAG的祖先知情PRS。

PROJECT SUMMARY: Prioritizing diversity in polygenic risk prediction of primary open-angle glaucoma Glaucoma is the leading worldwide cause of irreversible blindness. Primary open-angle glaucoma (POAG), the most common type of glaucoma, is more prevalent and severe in individuals of African ancestry. Unfortunately, individuals from this ancestral group have been under-represented in genome-wide association studies (GWAS) thus far. Furthermore, polygenic risk scores (PRS) based on GWAS data from European-descent populations are not transferable to individuals of diverse (non-European) ancestry. Given the aspirations of precision medicine, PRS demonstrate clinical potential but fall short, in part, due to the lack of diversity in these studies. We hypothesize that clinically-implementable PRS can be achieved by including African and African- descent individuals in gene discovery and PRS development. To inform and improve precision ocular health, we will prioritize diversity in polygenic risk prediction of POAG with three proposed aims that will yield the largest-ever meta analyses of POAG in African and African-descent individuals and the first-ever African-ancestry focused POAG PRS. In Aim 1, we will perform meta-analyses of 47,078 samples (18,037 cases, 29,041 controls) to identify novel POAG loci in African and African-descent populations. Given that most GWAS have been performed in mainly European and European-descent populations, we hypothesize that undiscovered POAG risk loci will be detected by leveraging the power of meta-analysis of case-control GWAS in African and African-descent population samples. In Aim 2, we will meta-analyze admixture mapping results for each of our datasets to identify African ancestry-specific POAG loci. We hypothesize that admixture mapping will identify genomic regions where African ancestry co- segregates with POAG risk. Significant loci from Aims 1 and 2 will be fine-mapped and evaluated for selection signatures. In Aim 3, we will build and optimize POAG PRS in African and African-descent base dataset meta- analyses. We will then evaluate novel and published PRS for POAG classification in test datasets. We hypothesize that ancestrally-informed POAG PRS will better predict POAG and relevant clinical outcomes in African and African-descent populations compared to those derived from primarily European-descent data. Meta-analysis results from Aims 1 and 2 as well as variants from our optimized PRS in Aim 3 will undergo pathway analyses to identify biological pathways and statistical driver genes implicated in POAG risk. In the long-term, we hope that the information gained from this project will inform a broader understanding of POAG genetics across diverse ancestry groups and provide the foundational basis for the clinical applicability of ancestrally-informed PRS for POAG.