Polygenic Risk Impacts Lifetime Risk and Prognosis of Glaucoma

PURPOSE: To investigate the clinical usefulness of a glaucoma polygenic risk score (PRS) for glaucoma by benchmarking published glaucoma PRSs and by assessing how the best-performing PRS performs for assessing glaucoma risk, age at onset, and glaucoma prognosis. DESIGN: Cohort study. PARTICIPANTS: Four hundred two thousand seven hundred thirty-nine individuals in FinnGen, with 21 609 individuals who received a glaucoma diagnosis after 40 years of age. MAIN OUTCOME MEASURES: Lifetime risk of glaucoma, the need and escalation of intraocular pressure-lowering medication, need for laser therapies, and need for incisional surgery. METHODS: Fourteen published glaucoma PRSs from the Polygenic Score Catalog were benchmarked comprehensively using Cox proportional hazards models. The best-performing PRS was selected to evaluate further the lifetime risk of glaucoma by 85 years of age using Kaplan-Meier survival analyses, both alone and alongside family history information. In addition, the impact of PRS on prognostic outcomes was assessed over a 20-year follow-up period. RESULTS: The PRS with the best performance had a hazard ratio (HR) of 3.32 (95% confidence interval [CI], 3.21-3.43) for glaucoma (≥90th PRS percentile vs. 20th-80th percentile). Lifetime risk of glaucoma increased considerably across PRS categories from 2.5% (95% CI, 1.7%-3.3%) among individuals in the less than first percentile, to 31.9% (95% CI, 30.5%-33.3%) in the 95th to 99th percentiles, and to 45.3% (95% CI, 42.3%-48.1%) in the 99th percentile or more. Family history and PRS contributed independently to glaucoma risk, with the PRS effect size decreasing only by 4.2% when adjusting the PRS effect for family history. Those in the highest PRS decile required more intensive glaucoma care, with higher cumulative incidences of medication escalation (60.6% vs. 38.4%), laser therapies (39.8% vs. 22.9%), and incisional surgeries (15.8% vs. 9.5%) compared with the lowest PRS decile over a 20-year follow-up. CONCLUSIONS: In this large biobank study, a glaucoma PRS effectively stratified individuals according to their lifetime risk of glaucoma, with substantial stratification evident already by midlife. The PRS provided a more precise risk assessment than family history alone, and it was effective in stratifying individuals based on several prognostic measures, including medical treatment escalation and surgical interventions. These findings support the potential usefulness of PRS-guided screening and management strategies in glaucoma, with future prospective studies warranted to evaluate the clinical implementation and cost-effectiveness. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.