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Editors Selection IGR 14-2

Prognostic factors: Polygenic risk factors for glaucoma progression

Comment by Janey Wiggs on:

106309 Association of High Polygenic Risk With Visual Field Worsening Despite Treatment in Early Primary Open-Angle Glaucoma, Siggs OM; Qassim A; Han X et al., JAMA ophthalmology, 2022; 141: 73-77

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A major advance in glaucoma genetics has been the development of polygenic risk scores (PRSs) derived from well-powered genome-wide association studies. A PRS is a summation of an individual's genetic risk of a disease or trait and PRSs have been studied for a wide range of disorders.¹ In this study Siggs et al. used a previously tested multi-trait glaucoma PRS associated with nerve fiber layer thinning in glaucoma patients.² This study addresses the important question of whether the PRS can also predict which individuals will have progressive disease. A longitudinal cohort of individuals suspected of having glaucoma or with early-manifest glaucoma were analyzed for structural and functional progression analysis. Rates of glaucoma worsening were analyzed in individuals in the top 5% as well as the bottom 95% and bottom 20% of the PRS over a five-year period. Differences in rates of progression were noted between the top 5% and remaining 95% as well as the top 5% and bottom 20%, suggesting that a high genetic burden as defined by this PRS may contribute to glaucoma progression rates. This is an interesting and important study, although there are several limitations: First, the slower progression in the lower 20% did not persist over the entire five-year study which may be due to vigorous treatment of progressing cases. Alternatively, the smaller sample in the top 5% at five years may also compromise the power of the analysis after year three. It wasn't possible to directly assess the impact of treatment because there was not a control group and the decision to treat was not directed by the study. An additional limitation is the lack of ethnic diversity which could compromise the generalizability of the results. Further studies to validate and explore the association of PRS and disease progression would be of interest.

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