The Emerging Clinical Utility of Polygenic Prediction Models

We read with interest 3 studies examining the potential clinical utility of polygenic risk scores (PRSs) for primary open-angle glaucoma (POAG). A PRS is a quantitative metric, often incorporating information from thousands or even millions of genetic variants, which summarizes an individual’s genetic risk of a condition into 1 number. Glaucoma is one of the most heritable of all common human diseases. Recent very large genome-wide association studies (GWAS) have led to a step change in our understanding of glaucoma’s complex genetic causes. These GWAS were enabled by huge cohort studies, such as the UK Biobank, and a strong global collaborative community (the International Glaucoma Genetics Consortium). These GWAS inform the genetic variant weightings that underpin PRSs. The derived PRSs reflect the outcomes measured in the original GWAS. Therefore, to date, POAG PRSs primarily reflect the risk of POAG in the general population rather than more specific clinical parameters, such as disease severity or risk of progression. A high PRS helps to identify prevalent POAG in independent studies. Therefore, a potential clinical translation of these PRSs could be to enable targeted glaucoma screening. While a PRS alone is, of course, not diagnostic for glaucoma, it is a potential prescreening test enriching the proportion of POAG and thus increasing the positive predictive value of subsequent screening tests, such as intraocular pressure (IOP) and optic disc imaging.

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