Step change in glaucoma polygenic risk score performance enables clinical utility.

Authors

Stuart MacGregor, Guiyan Ni, Mathias Seviiri, Antonia Kolovos, Ngoc Quynh Le, Mark M Hassall, Josh Schmidt, Puya Gharahkhani, Victoria Tang, Emmanuelle Souzeau, Ayub Qassim, Priyanka Nandakumar, Suyash Shringarpure, Julie M Granka, Jessica N Cooke Bailey, Tin Aung, John Landers, Stuart L Graham, Paul R Healey, Anthony P Khawaja, Louis R Pasquale, Janey L Wiggs, Joan O'Brien, Robert N Weinreb, Colin E Willoughby, Andrew Lotery, Paul Mitchell, David A Mackey, Alex W Hewitt, Nick Haan, Owen M Siggs, Jamie E Craig

Published in

Ophthalmology. Nov 12, 2026. Epub Nov 12, 2026.

Abstract

Open-angle glaucoma (OAG) is the leading cause of irreversible blindness and is highly heritable. Despite effective treatments, approximately 50% of cases remain undiagnosed. We aimed to develop and validate a clinically applicable, genetics-based risk prediction tool for OAG across diverse ancestries.
Genetic association study and risk prediction analysis.
More than 6 million individuals contributing genome-wide association study data from multiple ancestry groups.
We constructed a comprehensive polygenic risk score (PRS) for OAG using a multitrait modeling framework that integrated glaucoma-related traits, including intraocular pressure, optic disc parameters, and ocular hypertension. PRS performance was evaluated for OAG risk across major ancestry groups and assessed for associations with age at diagnosis, treatment escalation, surgical outcomes, and familial risk.
Odds ratios (ORs) for OAG by PRS percentile, age at disease onset, absolute risk estimates, treatment escalation, glaucoma surgery, and OAG risk in first-degree relatives.
In Australian individuals of European ancestry, those in the top 10% of the PRS distribution had a 10-fold increased risk of OAG compared with the remainder (OR 10.04, 95% CI 7.43-13.59), substantially outperforming our previously published PRS (OR 4.2). Similar performance was observed in U.S. European ancestry data (OR 9.09, 95% CI 5.09-16.26). In UK Biobank Europeans the OR for the top 10% versus the remainder was 4.91 (95% CI 4.25-5.69). Although performance was attenuated in other ancestry groups (OR top 10% vs. remainder: 4.01 in South Asian, 3.39 in East Asian, and ranging from 2.26 to 3.81 in African ancestry populations depending on cohort), high PRS percentiles corresponded to elevated absolute risk across all groups. On average, individuals in the highest-risk decile developed glaucoma approximately 25 years earlier than those in the lowest decile and had ∼100-fold (OR 96.83, 95% CI 52.61-178.21) higher risk. The PRS also predicted treatment escalation in early disease, prevalent and incident glaucoma surgery, and OAG risk among first-degree relatives.
This enhanced PRS, available for clinical use through an accredited genotyping workflow, enables effective risk stratification for OAG across diverse ancestries, facilitating earlier identification and treatment of high-risk individuals while supporting resource rationalisation for those at low risk. Performance is strongest in European ancestry populations, and further work is needed to improve equity of performance across ancestries.

PMID:
43020385
Bibliographic data and abstract were imported from PubMed on 13 Nov 2026.

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