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

原发性开角型青光眼多基因风险预测中优先考虑多样性

基本信息

批准号：
10642856
负责人：
Jessica N Cooke Bailey
金额：
$ 63.87万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10642856
关键词：
Affect Africa African African American population African ancestry Age American Area Biological Blindness Classification Clinical Complex Data Data Set Databases Development Disease Disease Progression Disparity Early Diagnosis European Evaluation Future Gene Frequency Genes Genetic Genetic study Genomic Segment Ghana Glaucoma Health Heritability Individual Intervention Linkage Disequilibrium Maps Mediator Meta-Analysis Monitor Outcome Pathway Analysis Pathway interactions Patients Performance Persons Phenotype Population Population Heterogeneity Predictive Value Prevalence Preventive care Preventive treatment Primary Open Angle Glaucoma Publishing Quality of life Race Research Risk Risk Factors Role Sampling Secure Signal Transduction Site Testing Universities Variant Vision admixture mapping aspirate burden of illness case control clinical application clinically relevant diverse data falls gene discovery genetic architecture genome wide association study high risk high risk population improved novel polygenic risk score precision medicine predictive tools preservation risk prediction risk variant screening segregation

项目摘要

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.

项目摘要：优先考虑原发性开角型青光眼多基因风险预测的多样性青光眼是全球导致不可逆转失明的主要原因。原发性开角型青光眼 (POAG) 最常见的青光眼类型，在非洲血统的个体中更为普遍和严重。很遗憾，来自这个祖先群体的个体在全基因组关联研究中代表性不足（GWAS）到目前为止。此外，基于欧洲血统的 GWAS 数据的多基因风险评分 (PRS) 人口不能转移给不同（非欧洲）血统的个体。鉴于人们的愿望精准医学、PRS 展现出临床潜力，但仍存在不足，部分原因是这些领域缺乏多样性研究。我们假设临床上可实施的 PRS 可以通过包括非洲和非洲- 基因发现和 PRS 开发的后裔个体。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的三个目标将产生有史以来最大的非洲人和非洲人后裔 POAG 荟萃分析个人和有史以来第一个以非洲血统为重点的 POAG PRS。在目标 1 中，我们将进行荟萃分析 47,078 个样本（18,037 个病例，29,041 个对照）用于鉴定非洲人和非洲人后裔中的新 POAG 基因座人口。鉴于大多数 GWAS 主要是在欧洲人和欧洲人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对非洲和非洲人后裔人群样本中病例对照 GWAS 的荟萃分析。在目标 2 中，我们将对每个数据集的混合映射结果进行荟萃分析，以识别非洲血统特定的 POAG 基因座。我们假设混合作图将识别非洲血统共同存在的基因组区域与 POAG 风险分离。目标 1 和 2 中的重要位点将被精细绘制并评估以供选择签名。在目标 3 中，我们将在非洲和非洲人后裔基础数据集元中构建和优化 POAG PRS 分析。然后，我们将评估测试数据集中用于 POAG 分类的新颖且已发布的 PRS。我们假设祖先信息的 POAG PRS 将更好地预测 POAG 和相关临床结果非洲和非洲裔人口与主要来自欧洲裔数据的人口进行比较。目标 1 和 2 的荟萃分析结果以及我们在目标 3 中优化的 PRS 的变体将进行途径分析，以确定与 POAG 风险相关的生物途径和统计驱动基因。在从长远来看，我们希望从这个项目中获得的信息能够让人们对 POAG 有更广泛的了解跨不同血统群体的遗传学，并为临床应用提供基础 POAG 的祖先知情 PRS。