High Polygenic Risk Associated With Rapid Structural, Functional Progression in Early POAG

A high glaucoma polygenic risk was associated with glaucoma progression in the early stages of primary open-angle glaucoma (POAG).

A new study has determined that high glaucoma polygenic risk was associated with faster structural and functional progression in patients with early primary open-angle glaucoma (POAG), even when receiving more intensive treatment.

Published in JAMA Ophthalmology, the study also found a polygenic risk score (PRS) was used effectively to identify patients who could benefit from more intensive treatment.

PRSs are a probabilistic summary of a patient’s genetic risk of a disease or trait; they have been increasingly used as a tool for disease risk prediction and phenotyping and are able to effectively stratify risk of glaucoma and the rate of optical coherence tomography (OCT) thinning. The current prospective longitudinal study investigated the association of polygenic risk with visual field progression in in patients with POAG.

Data for this study were collected from February 2012 to June 2020. Participants from the Progression Risk of Glaucoma: Relevant SNPs With Significant Association (PROGRESSA) study were sampled and genotyped. Samples from the prospective cohort based in Queensland, Australia, QSkin, were used as well.

There were data on 1777 eyes from 896 patients for structural progression analyses and 1563 eyes from 808 patients for functional progression analyses. The mean (SD) age of the group was 62.1 (9.9) years, and 488 (44%) participants were men. Genetic ancestry reported was more than 99% European ancestry, with 1087 (98.5%) patients self-reporting European ancestry.

A multitrait glaucoma PRS was used to assess the association of polygenic risk to glaucoma progression. A high polygenic risk was determined as the top 5% of the normative population distribution, which captured 11.97% of the PROGRESSA cohort. Glaucoma progression outcomes were compared structurally and functionally. The mean visual field mean deviation was –1.1 (2.0) dB and was not different between the PRS groups at baseline (–0.40 dB; 95% CI, 0.06 to –0.85).

The top 5% of the PRS group had a higher likelihood of visual field worsening compared with the bottom 95% PRS group (HR, 1.5; 95% CI, 1.13-1.97) despite receiving higher treatment intensity (mean, 1.57 [1.48] vs 1.15 [1.52] drops, selective laser trabeculoplasty procedures, and/or trabeculectomies).

Patients in the top 5% PRS had a faster rate of peripapillary retinal nerve fiber layer (pRNFL) thinning compared with the bottom 95% PRS group (mean, –1.64 [1.40] vs –1.36 [1.30] mm/year; 95% CI, –0.05 to –0.49 mm/year) when investigating longitudinal structural progression that was represented by the rate of OCT-derived pRNFL thinning in the fastest quadrant and had a mean follow up of 4.7 (1.7) years. Patients in the top 5% PRS group also had a higher likelihood of fast pRNFL progression vs the bottom 95% (odds ratio, 1.5; 95% CI, 1.1-2.2).

The bottom 20% of the normative population PRS group, which had the lowest genetic risk, had slower visual field worsening compared with the intermediate 75% group but this was not statistically significant after the 3-year follow up (HR, 0.52; 95% CI, 0.28-0.96). The bottom 20% PRS group also had a slower rate of pRNFL progression compared with the intermediate group by 0.27 mm/year (95% CI, 0.02-0.05).

There were some limitations to this study. The lack of an untreated control arm in this cohort made directly investigating an impossibility, and the derivation from European populations for the glaucoma PRS limited generalizability to other populations.

The researchers concluded that the study demonstrated an association between glaucoma polygenic risk and the worsening of visual field and structure in the early stages of glaucoma.


Siggs OM, Qassim A, Han X, et al. Association of high polygenic risk with visual field worsening despite treatment in early primary open-angle glaucoma. JAMA Ophthalmol. Published online November 10, 2022. doi:10.1001/jamaophthalmol.2022.4688

Related Videos
Screenshot of Eleonora Lad, MD, PhD, smiling
Screenshot of Eleonora Lad, MD, PhD, smiling during a Zoom video interview
Related Content
© 2023 MJH Life Sciences
All rights reserved.