Poster #9: Aude Benigne Ikuzwe Sindikubwabo

Endophenotype-Informed Polygenic Risk Stratification for Primary Open-Angle Glaucoma in individuals of African Ancestry

Aude Benigne Ikuzwe Sindikubwabo1, Lannawill Caruth1, Yan Zhu2, Yuki Bradford3,6, Colleen Moorse3,6, Mina Halimitabrizi2, Leila Ghaffari2, Rebecca Salowe2, Roy Lee2, Anurag Verma3,6,7, Penn Medicine BioBank, Regeneron Genetic Center, Marijana Vujković4, Ahmara Gibbons Ross5, Joan O’Brien2*, Shefali Setia-Verma1* 1Department of Pathology and Laboratory Medicine, University of Pennsylvania ,Philadelphia, PA 19104, USA 2 Center for Genetics of Complex Disease, Department of Ophthalmology, University of Pennsylvania Philadelphia, PA 19104, USA 3Department of Medicine, Division of Translational Medicine and Human Genetics, University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA 19104, USA. 4Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA 5Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104, USA 6Institute for Biomedical Informatics, University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA 19104, USA 7Division of Informatics, Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA 19104

Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness, yet up to 50% of cases remain undiagnosed. Despite highly heritability, most genetic studies have focused on variants directly associated with disease risk, overlooking clinically relevant endophenotypes such as intraocular pressure (IOP) and cup-to-disc ratio (CDR), which lie along the causal pathway to POAG and may improve risk prediction and early detection. Using the POAAGG study (2,696 cases and 3,533 controls with IOP and CDR measurements) we performed endophenotype GWAS and endophenotype-adjusted GWAS of POAG to estimate SNP outcome associations conditional on each mediator, then constructed endophenotype-informed polygenic risk scores (PRS) and benchmarked them against previously established POAG PRS methods. Models were evaluated in an independent POAAGG testing cohort (n=271), externally validated in ~2,000 Penn Medicine Biobank (PMBB) individuals, and assessed for clinical utility in a longitudinal POAAGG “suspect” cohort (28 converters, 220 non-converters), with chart reviews of the top and bottom 5% of PRS distributions. Endophenotype-informed PRS outperformed previously established POAG PRS models and provide pathway-level attribution not available from a single aggregate POAG PGS score. In the “suspect” cohort, the IOP-informed PRS better stratified future converters from stable individuals. Manual chart review further supported the clinical interpretability: the CDR-informed score identified structural susceptibility to glaucomatous damage beyond EHR-based classification, while the IOP-informed score captured genetic susceptibility to pressure-related disease. Together, these findings show that endophenotype informed polygenic modeling can move glaucoma genetic risk prediction beyond aggregate discrimination toward a more clinically interpretable framework for risk stratification. In African ancestry populations, this approach may help identify biologically meaningful heterogeneity, support conversion-risk prediction, and prioritize individuals who could benefit from earlier surveillance.