Polygenic Risk Score Enhances Prediction of Glaucoma Onset

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A post-hoc analysis of the Ocular Hypertension Treatment Study shows the inclusion of a PRS improved the prediction of POAG onset in patients with ocular hypertension.

Nazlee Zebardast, MD, MSc | Image Credit: Harvard Ophthalmology

Nazlee Zebardast, MD, MSc

Credit: Harvard Ophthalmology

A higher polygenic risk score (PRS) was associated with an increased risk for earlier development of primary open-angle glaucoma (POAG) among patients with ocular hypertension (OHTN), according to new research.1

This post-hoc analysis of the Ocular Hypertension Treatment Study (OHTS), involving more than 1000 participants, revealed the associated remained independent of most ocular phenotypic risk factors, genetically determined patient ancestry, and the follow-up phase of approximately 20 years.

“We show that a high POAG PRS, based on, to our knowledge, the largest genome-wide association study (GWAS) meta-analysis to data, was associated with increased risk of POAG conversion among patients with OHTN,” wrote the investigative team, led by Nazlee Zebardast, MD, MD, Massachusetts Eye and Ear, Harvard Medical School.

Identification of high-risk individuals and the need for therapeutic intervention is important to prevent glaucoma-related vision loss. POAG, a particularly heritable disease, has been linked with 127 identified common risk variants.2 Each variant contains a small effect on POAG, but a PRS can provide a clinically useful measure of a patient’s aggregate genetic burden.

A prediction model, involving age, IOP, central corneal thickness (CCT), vertical cup-disc ratio (VCDR), and visual field pattern standard deviation (PSD), developed for POAG, proved feasible for risk stratification in the OHTS.3 The current analysis used available genetic data from the study to determine whether underlying genetic risk improves risk stratification outside of the demographic factors and ocular biomarkers used in the prediction model.

The secondary analysis of the OHTS collected data from 22 US-based sites, with a mean follow-up of 14 years. In OHTS, participants were randomized to either topical IOP-lowering medication or close observation—after June 2002, all participants received medication. Among the original 1636 participants enrolled in OHTS, 1077 were enrolled in an ancillary genetics study and 1009 met the criteria for the current analysis.

Zebardast and colleagues calculated a POAG PRS using summary statistics from the largest known cross-ancestry POAG GWAS meta-analysis. The PRS was trained using 8,813,496 variants from 449,186 cross-ancestry participants in the UK Biobank. Participants were grouped into either deciles or low-risk, intermediate-risk, and high-risk tertiles based on PRS z scores

Among the 1009 participants included for analysis, 562 (55.7%) were female and the mean age was 55.9 years. Upon analysis, investigators found the mean PRS was significantly higher for POAG converters (0.24) compared with non-converters (–0.12) (difference, 0.36; 95% CI, 0.24 - 0.49; P <.001).

Further analysis showed the POAG risk increased by 1.36% (95% CI, 1.08 - 1.64) with each higher PRS decile, with linear regression showing an increase 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. When stratified by ancestry, a comparison of low-risk and high-risk PRS tertile demonstrated a 2.0-fold increase in POAG risk over 20 years for individuals of European and African descent.

A subcohort randomized to delayed OHTN treatment showed each decrease in PRS decile was linked with a 0.52-year (95% CI, 0.01 - 1.03) decrease in the age at diagnosis of POAG (P = .047). The early treatment group presented no significant linear association between PRS and age at POAG diagnosis.

Moreover, the prediction models were found to significantly improve with the inclusion of PRS as a covariate (C index, 0.77), compared with the OHTS baseline model (C index, 0.75) (P <.001). Each 1-SD higher PRS increased the 20-year risk for POAG by 25% (hazard ratio [HR], 1.25; 95% CI, 1.13 - 1.44) for POAG onset.

Zebardast and colleagues noted the prediction models showed improvement in the prediction of POAG onset with the addition of PRS, but the absolute increase in performance may be smaller than expected at the start of the study.

“As PRS presents a constant level of lifetime risk, its predictive power is most likely higher at earlier clinical stages and younger age prior to development of phenotypic markers,” they wrote.

References

  1. Singh RK, Zhao Y, Elze T, et al. Polygenic Risk Scores for Glaucoma Onset in the Ocular Hypertension Treatment Study. JAMA Ophthalmol. Published online March 14, 2024. doi:10.1001/jamaophthalmol.2024.0151
  2. Gharahkhani P, Jorgenson E, Hysi P, et al. Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries. Nat Commun. 2021;12(1):1258. Published 2021 Feb 24. doi:10.1038/s41467-020-20851-4
  3. Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120(6):701-830. doi:10.1001/archopht.120.6.701
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