The Clinical Usefulness of a Glaucoma Polygenic Risk Score in 4 Population-Based European Ancestry Cohorts

We used a polygenic risk score (PRS) to identify high-risk groups for primary open-angle glaucoma (POAG) within population-based cohorts.

Secondary analysis of 4 prospective population-based studies.

We included four European-ancestry cohorts: the United States-based Nurses' Health Study, Nurses' Health Study 2, and the Health Professionals Follow-up Study and the Rotterdam Study (RS) in The Netherlands. The United States cohorts included female nurses and male health professionals ≤ 55 years of age. The RS included residents ≤ 45 years of age living in Rotterdam, The Netherlands.

Polygenic risk score weights were estimated by applying the lassosum method on imputed genotype and phenotype data from the UK Biobank. This resulted in 144 020 variants, single nucleotide polymorphism and insertions or deletions, with nonzero βs that we used to calculate a PRS in the target populations. Using multivariable Cox proportional hazard models, we estimated the relationship between the standardized PRS and relative risk for POAG. Additionally, POAG prediction was tested by calculating these models' concordance (Harrell's C statistic). Finally, we assessed the association between PRS tertiles and glaucoma-related traits.

The relative risk for POAG and Harrell's C statistic.

Among 1046 patients and 38 809‬ control participants, the relative risk (95% confidence interval) for POAG for participants in the highest PRS quintile was 3.99 (3.08-5.18) times higher in the United States cohorts and 4.89 (2.93-8.17) times higher in the RS, compared with participants with median genetic risk (third quintile). Combining age, sex, intraocular pressure of more than 25 mmHg, and family history resulted in a meta-analyzed concordance of 0.75 (95% CI, 0.73-0.75). Adding the PRS to this model improved the concordance to 0.82 (95% CI, 0.80-0.84). In a meta-analysis of all cohorts, patients in the highest tertile showed a larger cup-to-disc ratio at diagnosis, by 0.10 (95% CI, 0.06-0.14), and a 2.07-fold increased risk of requiring glaucoma surgery (95% CI, 1.19-3.60).

Incorporating a PRS into a POAG predictive model improves identification concordance from 0.75 up to 0.82, supporting its potential for guiding more cost-effective screening strategies.

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.