Genetic risk score to enhance glaucoma case detection: a prospective double-blind screening study (EyeLife) in the...

Early detection of glaucoma prevents blindness but its low population-based prevalence impedes cost-effective screening. We investigated whether genetic pre-screening could increase the prior probability. Design, methods, and primary analysis were pre-specified and published previously. In this prospective study, we invited 1829 participants aged 55 + from the Dutch Lifelines cohort, selecting from either the highest or lowest 20% of a GWAS-based genetic risk score distribution; subgroups had similar age and gender. Researchers were blinded to subgroup allocation; participants to genetic risk selection. Participants underwent perimetry, optical coherence tomography, fundus photography, tonometry, pachymetry, and visual acuity assessment. Abnormalities prompted a full ophthalmic examination. Participants were classified as definite, probable, or possible open-angle glaucoma, or as unaffected. We calculated the relative risk of combined definite and probable glaucoma for high versus low genetic risk, adjusting for age, sex, and genotyping platform. 1022 participants (median [interquartile range] age 64 [59-70] years, 53% female, Northwestern European ancestry) agreed to participate and were included, 487 with high and 535 with low genetic risk. Of these, 59 (age 70 [64-76] years) were classified as definite (29 with high and 2 with low genetic risk) or probable (21 and 7) glaucoma. Relative risk was 7.4 (95% confidence interval 3.7-14.7), indicating that participants with high genetic risk were over seven times more likely to be classified with glaucoma than those with low risk. Stratifying the general population based on genetic risk strongly increases the prior probability of glaucoma and may enable a cost-effective screening approach.