Endophenotype Guided Genome-Wide Association Study to Enhance Genetic Risk Prediction of Primary Open-Angle Glaucoma in African Ancestry Populations

Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness, with genetic predisposition playing a major role. While most genetic studies have focused on variants directly associated with POAG, loci influencing POAG diagnosis and progression, through intermediate traits also known as endophenotypes, remain underexplored. These endophenotypes, including intraocular pressure (IOP), cup-to-disc ratio (CDR), and central corneal thickness (CCT), and more represent promising and potentially modifiable targets for intervention. Using the Primary Open-Angle African American Glaucoma Genetics (POAAGG) cohort, which consist of we first conducted GWAS on POAG-related endophenotypes. We then incorporated findings from a prior GWAS focused solely on POAG followed by mediation-based GWAS adjusting POAG for key endophenotypes. This allowed us to quantify direct and indirect SNP effects on POAG risk. We then constructed mediator-informed polygenic risk scores (PRS) combining both effects and evaluated predictive accuracy in 196 holdout samples (97 cases and 99 controls). Mediation-based GWAS identified genome-wide significant variants in NAT2 (for CCT) and MED16 (for CDR), while traditional POAG GWAS identified 46 loci most of which lost significance after mediation, highlighting strong indirect effects. Among PRS models, the CDR-informed PRS achieved the highest predictive accuracy (AUC = 0.99), outperforming the traditional POAG PRS (AUC = 0.71). PRS informed by IOP and MD also showed improved performance (AUC = 0.98 to 0.87). These findings highlight the power of incorporating endophenotypes into genetic analyses of POAG advancing our understanding of disease mechanisms, enhancing the precision of risk prediction, and paving the way toward endophenotype-guided therapeutic strategies in personalized glaucoma care.