A Multitrait Open-Angle Glaucoma Polygenic Risk Score Stratifies Risk of Glaucoma Diagnosis and Severity in Eyes with Pseudoexfoliation

Abstract

Purpose: Pseudoexfoliation syndrome (PEX) is a known risk factor for glaucoma, but its individual clinical course ranges from no glaucoma to total blindness. This study investigated whether polygenic risk scores (PRSs) built from variants collectively associated with open-angle glaucoma, intraocular pressure (IOP), and vertical cup-to-disc ratio (VCDR) can stratify individuals with pseudoexfoliation for the risk of glaucoma development.

Design: Retrospective multicohort study of 2 glaucoma registries and 1 population-based cohort.

Participants: For the primary analysis, participants (n = 828) were classified as having PEX with glaucoma, PEX with suspected glaucoma, or PEX with no glaucoma. For the secondary analysis, a cohort of participants (n = 2460) were classified as having PEX with glaucoma, having PEX with no glaucoma, and being unaffected, and an independent cohort of participants (n = 3372) were classified as having primary open-angle glaucoma (POAG) or suspected POAG.

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

Main outcome measures: The main outcome measures were odds of pseudoexfoliative glaucoma (PEX-G) and odds of clinically relevant outcomes.

Results: Participants in the top tertile of the glaucoma PRS showed greater odds of receiving a PEX-G diagnosis (adjusted odds ratio [aOR], 4.22; 95% confidence interval [CI], 2.62-6.88; P < 0.001), greater odds of bilateral central vision loss (aOR, 3.43; 95% CI, 1.49-8.99; P = 0.007), and greater odds of bilateral incisional surgery (aOR, 3.35; 95% CI, 1.33-10.24; P = 0.018). Age at PEX-G diagnosis was 1 year younger with each increasing glaucoma PRS decile (1.06 years; 95% CI, 0.59-1.53 years; P < 0.001). Participants with manifest glaucoma and pseudoexfoliation showed a comparatively lower glaucoma PRS than counterparts with POAG.

Conclusions: The PRSs for open-angle glaucoma, IOP, and VCDR stratify risk of glaucoma development and disease severity among individuals with PEX.

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

Keywords: Exfoliation; Genetics; Glaucoma; Open angle; Polygenic risk score.