Understanding the clinical impact of cumulative genetic risk to glaucoma

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Primary open-angle glaucoma (POAG), the most common glaucoma subtype, is a prototypical common complex disease with a strong polygenetic component. This proposal is aligned with the NIH roadmap, leveraging the decade-long effort of gene discovery for POAG into precision medicine approaches that facilitate an early glaucoma diagnosis while outlining strategies to prevent glaucoma-related blindness. In this study, we propose 3 specific aims. 1) We will assemble all of the common gene variants discovered for POAG over the past decade into a multi-ancestry panel to test whether they predict glaucoma in 4 independent study populations (the UK Biobank, a health professional case-control study embedded in a population based sample, and patients from 2 hospital-based biobanks (total sample size: over 12,000 POAG cases in ~600,286 subjects). 2) Hospital-based biobanks offer an opportunity to contributed precision based medical knowledge about glaucoma. We will invite 800 patients from two hospital-based biobanks with low and high glaucoma polygenetic risk score (PRS) for systematic clinical evaluation. This detailed phenotype-genotype correlation will provide unique insights into glaucoma and will demonstrate the utility of such biobanks to identify previously undiagnosed disease, an unmet need in the field of glaucoma. 3) While a glaucoma PRS is probably the strongest predictor of glaucoma, we anticipate that a considerable number of subjects with high PRS will not demonstrate glaucomatous disease; conversely, some subjects with low PRS will have glaucoma. We will explore whether genetic variants such as MYOC Q368X and unique environmental factors (dietary nitrate intake from vegetable sources, estrogen exposure duration in women and dental health status) modify the relation between our PRS and glaucoma in our 4 study populations. By formulating and applying a multi- ancestral glaucoma PRS to an ethnically-diverse group of subjects, this proposal will highlight the role of a glaucoma genetic informativity panel as a screening tool. This proposal will advance the major objective of promoting POAG to the status of a precision-based medicine discipline. Finally, it will identify specific disease prevention strategies that could be implemented before a diagnosis is made.