Step change in glaucoma polygenic risk score performance enables clinical utility and disease prediction across all major ancestries

Glaucoma is the leading cause of irreversible blindness; vision loss is preventable with timely treatment, but early detection is challenging, leaving [~]50% undiagnosed, highlighting the need for improved risk assessment tools. We developed a polygenic risk score (PRS) using data from >6 million individuals. PRS performance was exceptional in European ancestries; top 10% PRS individuals had 10-fold increased risk (OR=10.0) relative to the remainder. Performance remained good across all major ancestry groups; high-PRS individuals were at high absolute risk, especially Africans. High-risk individuals (top 10% PRS) developed glaucoma up to 25 years earlier than those in the lowest 10% and were at 100 times the risk. The PRS also predicted need for treatment escalation in early glaucoma and both prevalent and incident surgery. Risk profiling with this PRS which is clinically available, enables earlier identification and more timely treatment of high-risk individuals for preventable vision loss, with a reduced screening and monitoring burden for those at low-risk. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSGlaucoma is the leading cause of irreversible blindness worldwide. Early detection is essential because current treatments cannot restore lost vision. Population-wide screening using conventional risk factors for glaucoma (such as elevated intraocular pressure) is not currently cost-effective, though a better stratification method could improve early diagnosis rates and reduce over-monitoring of lower risk cases. Glaucoma is one of the most heritable common complex diseases, suggesting that genetics-based approaches could revolutionize risk stratification. Previous polygenic risk scores (PRS) indexing glaucoma genetic risk were limited by restricted applicability outside European ancestry populations, small discovery sample sizes, modest predictive power, poor clinical availability. The inability to cover a broad range of ancestries limited the practical clinical application of earlier versions of glaucoma PRS for risk stratification and patient management. Added value of this studyA novel PRS, trained on >6 million individuals, has significantly improved glaucoma risk prediction across major ancestry groups, identifying high-risk individuals (top 10% of risk versus remainder) with odds ratios up to 10 in Europeans and 3.4-7.5 in non-Europeans (larger than for any other common complex disease). The excellent PRS risk stratification remained after adjusting for intraocular pressure; adding PRS to a prediction model with age, sex and intraocular pressure increased the Area Under the Curve for predicting glaucoma status from 0.63 to 0.82. High-risk individuals (top 10% PRS) developed glaucoma up to 25 years earlier than those in the lowest 10% and were at 100 times greater risk. The PRS also predicted structural progression, the need for treatment initiation and escalation in early glaucoma, both prevalent and incident incisional surgery for glaucoma, and the likelihood of glaucoma being present in first-degree relatives. These improvements impart strong clinical utility for population risk stratification, and the personalised management of individuals with clinical features suggestive of early stage glaucoma. Implications of all the available evidenceThis clinically available, enhanced PRS enables accurate identification of both high- and low-risk individuals across diverse populations, supporting earlier diagnosis, targeted monitoring, and timely treatment. It provides a clinical tool which can be applied for precision prevention and management of glaucoma, enabling cost-effective, equitable, genetically-informed glaucoma risk stratification across the entire population.