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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.

项目概述：优先考虑原发性开角型青光眼多基因风险预测的多样性