| Title: | Polygenic Risk Scores for Glaucoma Onset in the Ocular Hypertension Treatment Study |
| Journal: | JAMA Ophthalmology |
| Published: | 1 Apr 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/38483402/ |
| DOI: | https://doi.org/10.1001/jamaophthalmol.2024.0151 |
Publication 9995
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Abstract
Importance: Primary open-angle glaucoma (POAG) is a highly heritable disease, with 127 identified risk loci to date. Polygenic risk score (PRS) may provide a clinically useful measure of aggregate genetic burden and improve patient risk stratification.</p>
Objective: To assess whether a PRS improves prediction of POAG onset in patients with ocular hypertension.</p>
Design, Setting, and Participants: This was a post hoc analysis of the Ocular Hypertension Treatment Study. Data were collected from 22 US sites with a mean (SD) follow-up of 14.0 (6.9) years. A total of 1636 participants were followed up from February 1994 to December 2008; 1077 participants were enrolled in an ancillary genetics study, of which 1009 met criteria for this analysis. PRS was calculated using summary statistics from the largest cross-ancestry POAG meta-analysis, with weights trained using 8 813 496 variants from 449 186 cross-ancestry participants in the UK Biobank. Data were analyzed from July 2022 to December 2023.</p>
Exposures: From February 1994 to June 2002, participants were randomized to either topical intraocular pressure-lowering medication or close observation. After June 2002, both groups received medication.</p>
Main Outcomes and Measures: Outcome measures were hazard ratios for POAG onset. Concordance index and time-dependent areas under the receiver operating characteristic curve were used to compare the predictive performance of multivariable Cox proportional hazards models.</p>
Results: Of 1009 included participants, 562 (55.7%) were female, and the mean (SD) age was 55.9 (9.3) years. The mean (SD) PRS was significantly higher for 350 POAG converters (0.24 [0.95]) compared with 659 nonconverters (-0.12 [1.00]) (P < .001). POAG risk increased 1.36% (95% CI, 1.08-1.64) with each higher PRS decile, with conversion ranging from 9.52% (95% CI, 7.09-11.95) in the lowest PRS decile to 21.81% (95% CI, 19.37-24.25) in the highest decile. Comparison of low-risk and high-risk PRS tertiles showed a 2.0-fold increase in 20-year POAG risk for participants of European and African ancestries. In the subgroup randomized to delayed treatment, each increase in PRS decile was associated with a 0.52-year (95% CI, 0.01-1.03) decrease in age at diagnosis (P = .047). No significant linear association between PRS and age at POAG diagnosis was present in the early treatment group. Prediction models significantly improved with the addition of PRS as a covariate (C index = 0.77) compared with the Ocular Hypertension Treatment Study baseline model (C index = 0.75) (P < .001). Each 1-SD higher PRS conferred a mean hazard ratio of 1.25 (95% CI, 1.13-1.44) for POAG onset.</p>
Conclusions and Relevance: Higher PRS was associated with increased risk for POAG in patients with ocular hypertension. The inclusion of a PRS improved the prediction of POAG onset.</p>
Trial Registration: ClinicalTrials.gov Identifier: NCT00000125.</p>
12 Authors
- Rishabh K. Singh
- Yan Zhao
- Tobias Elze
- John Fingert
- Mae Gordon
- Michael A. Kass
- Yuyang Luo
- Louis R. Pasquale
- Todd Scheetz
- Ayellet V. Segrè
- Janey L. Wiggs
- Nazlee Zebardast
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