A Multitrait Open-Angle Glaucoma Polygenic Risk Score Stratifies Risk of Glaucoma Diagnosis and Severity in Eyes with Pseudoexfoliation.
Kolovos Antonia, Qassim Ayub, Hassall Mark M, Marshall Henry N, Schmidt Joshua, Nguyen Thi Thi, He Weixiong, Mullany Sean, Hollitt Georgina L, Berry Ella C
AI Summary
Polygenic risk scores for glaucoma, IOP, and VCDR stratify glaucoma risk and severity in pseudoexfoliation patients, identifying those prone to earlier diagnosis and worse outcomes, aiding personalized management.
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.
MeSH Terms
Shields Classification
Key Concepts5
Participants in the top tertile of the glaucoma polygenic risk score (PRS) showed greater odds of receiving a pseudoexfoliative glaucoma (PEX-G) diagnosis (adjusted odds ratio [aOR], 4.22; 95% confidence interval [CI], 2.62-6.88; P < 0.001) in a retrospective multicohort study of 828 participants with PEX.
Participants in the top tertile of the glaucoma polygenic risk score (PRS) showed greater odds of bilateral central vision loss (aOR, 3.43; 95% CI, 1.49-8.99; P = 0.007) in a retrospective multicohort study of 828 participants with PEX.
Participants in the top tertile of the glaucoma polygenic risk score (PRS) showed greater odds of bilateral incisional surgery (aOR, 3.35; 95% CI, 1.33-10.24; P = 0.018) in a retrospective multicohort study of 828 participants with PEX.
Age at pseudoexfoliative glaucoma (PEX-G) diagnosis was 1 year younger with each increasing glaucoma polygenic risk score (PRS) decile (1.06 years; 95% CI, 0.59-1.53 years; P < 0.001) in a retrospective multicohort study of 828 participants with PEX.
Participants with manifest glaucoma and pseudoexfoliation showed a comparatively lower glaucoma polygenic risk score (PRS) than counterparts with primary open-angle glaucoma (POAG) in a retrospective multicohort study of 2460 participants with PEX and 3372 participants with POAG or suspected POAG.
Related Articles5
Comparison of microRNA expression in pseudoexfoliation syndrome with and without glaucoma.
Observational StudyCompound Heterozygous LTBP2 Mutations Associated With Juvenile-Onset Open-Angle Glaucoma and Marfan-Like Phenotype.
Case ReportClusterin deficiency in eyes with pseudoexfoliation syndrome may be implicated in the aggregation and deposition of pseudoexfoliative material.
Basic ScienceGenetics. High-risk glaucoma gene found in Nordic studies.
Basic ScienceRe: Kolovos et al.: A multi-trait open-angle glaucoma polygenic risk score stratifies risk of glaucoma diagnosis and severity in eyes with pseudoexfoliation (Ophthalmology. 2025;132:878-887).
LetterIs this article assigned to the wrong chapter(s)? Let us know.