A Multitrait Polygenic Risk Score for Open-Angle Glaucoma Stratifies Risk of Pigmentary Glaucoma in Pigment Dispersion Syndrome

Antonia Kolovos; Ayub Qassim; Henry N Marshall; Thi Thi Nguyen; Joshua Schmidt; Mark M Hassall; Victoria Tang; Giorgina Maxwell; John Landers; Richard Mills; Stewart Lake; Stuart L Graham; Angela Schulz; Anna Galanopoulos; Robert J Casson; Ivan Goldberg; Michael Coote; Stephen Best; Jed Lusthaus; Paul R Healey; Leslie Burnett; Marc Töteberg-Harms; Erin A Boese; Andrew E Pouw; Puya Gharahkhani; Todd Scheetz; Alex W Hewitt; Stuart MacGregor; Owen M Siggs; Emmanuelle Souzeau; John H Fingert; Jamie E Craig

doi:10.1016/j.ogla.2025.10.005

A Multitrait Polygenic Risk Score for Open-Angle Glaucoma Stratifies Risk of Pigmentary Glaucoma in Pigment Dispersion Syndrome

Ophthalmol Glaucoma. 2025 Oct 21:S2589-4196(25)00216-9. doi: 10.1016/j.ogla.2025.10.005. Online ahead of print.

Authors

Antonia Kolovos¹, Ayub Qassim², Henry N Marshall³, Thi Thi Nguyen², Joshua Schmidt³, Mark M Hassall², Victoria Tang³, Giorgina Maxwell³, John Landers², Richard Mills², Stewart Lake², Stuart L Graham⁴, Angela Schulz⁴, Anna Galanopoulos⁵, Robert J Casson⁵, Ivan Goldberg⁶, Michael Coote⁷, Stephen Best⁸, Jed Lusthaus⁶, Paul R Healey⁹, Leslie Burnett¹⁰, Marc Töteberg-Harms¹¹, Erin A Boese¹¹, Andrew E Pouw¹¹, Puya Gharahkhani¹², Todd Scheetz¹¹, Alex W Hewitt¹³, Stuart MacGregor¹², Owen M Siggs¹⁰, Emmanuelle Souzeau³, John H Fingert¹¹, Jamie E Craig²

Affiliations

¹ Flinders Eye and Vision, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia; Department of Ophthalmology, Flinders Medical Centre, Adelaide, South Australia, Australia. Electronic address: antonia.kolovos@flinders.edu.au.
² Flinders Eye and Vision, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia; Department of Ophthalmology, Flinders Medical Centre, Adelaide, South Australia, Australia.
³ Flinders Eye and Vision, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia.
⁴ Faculty of Medicine, Health and Human Sciences, Ophthalmology and Vision Science, Macquarie University, Sydney, New South Wales, Australia.
⁵ Ophthalmic Research Laboratories, University of Adelaide, Adelaide Health and Medical Sciences Building, Adelaide, South Australia, Australia.
⁶ Discipline of Ophthalmology, University of Sydney, Sydney Eye Hospital, Sydney, New South Wales, Australia.
⁷ Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.
⁸ Eye Department, Greenlane Clinical Centre, Auckland District Health Board, Auckland, New Zealand.
⁹ Department of Ophthalmology, Centre for Vision Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
¹⁰ Genomics and Inherited Diseases, Garvan Institute of Medical Research, Sydney, New South Wales, Australia; Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia.
¹¹ Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa; Institute for Vision Research, University of Iowa, Iowa City, Iowa.
¹² Statistical Genetics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
¹³ Centre for Ophthalmology and Visual Science, University of Western Australia, Lions Eye Institute, Perth, Western Australia, Australia; Department of Ophthalmology, Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.

PMID: 41130539
DOI: 10.1016/j.ogla.2025.10.005

Abstract

Objective: Pigment dispersion syndrome (PDS) is a known risk factor for glaucoma, with at least 1 in 10 patients with PDS developing glaucoma. There are no standardized clinical tools to stratify the risk of glaucoma onset or progression in the context of PDS. This study investigated whether multitrait polygenic risk scores (PRSs) built from variants collectively associated with open-angle glaucoma, intraocular pressure (IOP), and vertical cup:disc ratio (VCDR) could stratify individuals with PDS for their risk of glaucoma development.

Design: Cross-sectional study of 2 independent PDS cohorts: the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG, n = 264), and the Glaucoma Services at the University of Iowa Carver College of Medicine (n = 203).

Participants: Participants of European ancestry with PDS were classified as PDS-Glaucoma (n = 288), PDS-Glaucoma Suspect (n = 110), or PDS-No Glaucoma (n = 69).

Methods: Previously published and validated PRS for open-angle glaucoma, IOP, and VCDR were expressed as a percentile or quintile of an ancestrally matched normal population. Multivariable logistic and linear regressions and survival analyses were performed.

Main outcome measures: Odds of pigmentary glaucoma and odds of clinically relevant outcomes.

Results: Participants from ANZRAG with PDS in the top quintile of an open-angle glaucoma-PRS had greater odds of glaucoma diagnosis compared with the bottom quintile (adjusted odds ratio [OR], 5.29; 95% confidence interval [CI], 1.57-21.28; P = 0.011). This observation was replicated among participants with PDS from the University of Iowa (adjusted OR, 4.07; 95% CI, 1.24-13.85; P = 0.021). Among those with PDS-Glaucoma across both cohorts combined, participants in the top quintile of glaucoma-PRS compared with the bottom quintile were diagnosed 8 years earlier (95% CI, 5.17-10.41; P < 0.001), recorded a maximum IOP 8 mmHg higher (95% CI, 2.89-11.95; P = 0.001), were at greater risk of escalation to incisional surgery (adjusted OR, 1.37; 95% CI, 1.03-1.87; P = 0.038), and were at greater risk of additional incisional surgeries to the same eye (adjusted OR, 1.27; 95% CI, 1.08-1.52; P = 0.006). A PRS for IOP also differentiated pigmentary glaucoma status; a PRS for VCDR did not.

Conclusions: A multitrait PRS for open-angle glaucoma stratifies risk of glaucoma onset and disease severity among individuals with PDS.

Financial disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Keywords: Genetics; Glaucoma; Pigment dispersion syndrome; Pigmentary glaucoma; Polygenic risk.