Understanding the clinical impact of cumulative genetic risk to glaucoma

Primary open-angle glaucoma (POAG), the most common glaucoma subtype, is one of the most polygenic common complex ocular diseases and a leading cause of blindness worldwide. This proposal is aligned with the NIH roadmap, translating our previously derived POAG polygenic risk score (PRS) into precision medicine approaches that prevent glaucoma-related blindness. In this study, we propose 3 specific aims. 1) In the initial funding period, we detected definite+probable POAG in 20.8% of people in the highest decile of glaucoma PRS versus 2% in the lowest decile after a comprehensive screening exam. We also noted the tool was less effective in ethnic minorities compared to Europeans. We intend to update the POAG PRS using new cross- ancestry genomic data and validate it in 4 independent study samples (the UK Biobank, a health professional case-control study embedded in a population-based sample, and patients from 2 Hospital biobanks). We anticipate that the new PRS will have better predictive power in ethnic minorities than our original genetic tool. 2) We will test the hypothesis that patients in the highest POAG PRS decile (n=100 subjects) have more progressive functional and structural optic nerve degenerative changes compared to people in the lowest decile (n=100 subjects). We also anticipate that those in the highest PRS decile will have a more unfavorable IOP profile after the water drinking test. 3) Finally, we will develop and validate a genetic test that incorporates our updated PRS with blended low-pass whole genome-exome sequencing in clinic POAG patients across the spectrum of disease severity (n=1000 subjects). We will assess the impact of this test on patient perception and provider management in a CLIA (Clinical Laboratory Improvement Amendments) environment. Overall, this proposal will provide a robust tool to facilitate glaucoma detection across ancestries. The proposal will also provide new insights into the utility of the POAG PRS and bring us one step closer to precision care for POAG.