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

项目总结：在原发性开角型青光眼多基因风险预测中优先考虑多样性 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 最常见的青光眼类型，在非洲血统的人中更为普遍和严重。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)到目前为止。此外，基于来自欧洲血统的Gwas数据的多基因风险评分(PR) 种群不能转移给具有不同(非欧洲)血统的个体。鉴于……的抱负 精准医学显示出临床潜力，但还不够完善，部分原因是缺乏多样性。 学习。我们假设，临床上可实施的PRS可以通过包括非洲和非洲- 在基因发现和PRS发展中的后代个体。 为了告知和改善准确的眼睛健康，我们将优先考虑POAG的多基因风险预测的多样性。 提出的三个目标将产生有史以来最大的关于非洲人和非洲裔POAG的荟萃分析 个人和有史以来第一个非洲血统的POAG PR。在目标1中，我们将执行以下元分析 47,078个样本(18,037个病例，29,041个对照)以确定非洲人和非洲人后裔中新的POAG基因座 人口。鉴于大多数GWA主要是在欧洲人和欧洲人后裔中进行的 ，我们假设未发现的POAG风险基因座将通过利用 对非洲人和非洲人后裔人口样本的病例对照GWAs的荟萃分析。在目标2中，我们将 Meta分析每个数据集的混合映射结果，以识别非洲血统特定的POAG 精神错乱。我们假设，混合作图将识别非洲血统共同 与POAG风险隔离。来自目标1和目标2的重要基因座将被精细绘制和评估以供选择 签名。在目标3中，我们将在非洲和非洲裔基础数据集元数据集中建立和优化POAG PR 分析。然后，我们将在测试数据集中评估新颖的和已发表的用于POAG分类的PR。我们 假设祖先告知的POAG PR将更好地预测POAG和相关的临床结果 非洲人和非洲人后裔人口与主要来自欧洲人后裔数据的人口相比。 来自AIMS 1和AIMS 2的Meta分析结果以及我们在AIMS 3中优化的PR的变体将接受 路径分析，以确定与POAG风险有关的生物路径和统计驱动基因。在 从长远来看，我们希望从这个项目中获得的信息将有助于对POAG的更广泛的了解 跨不同祖先群体的遗传学，并为临床应用提供了基础基础 用于POAG的祖传通知的PR。

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.