Screening by Glaucoma Polygenic Risk Score to Identify Primary Open-Angle Glaucoma in Two Biobanks: an Interim Report

Abstract

Purpose : Hundreds of common genetic variants for primary open-angle glaucoma (POAG) have been discovered. While studies suggest the utility of a glaucoma polygenic risk score (PRS), it is unclear if recalling patients based on PRS aids in POAG diagnosis. Here, we provide an interim report of a study comparing individuals with high PRS to those with low PRS.

Methods : Imputed genotype data from 449,186 UK Biobank participants included 14,171 OAG cases. Using the Lassosum method, we estimated per-allele weighted POAG effects, revealing 144,020 SNPs with non-zero effects for the PRS construction. POAG PRSs were computed for >54,000 individuals in Mount Sinai BioMe and >45,000 in the Mass General Brigham Biobank. Scores were standard normalized within each genotype-inferred ancestry group. Individuals 35-90 years old in the top and bottom PRS deciles were invited for a comprehensive eye exam. Staff remained masked to PRS until 2 evaluators reached a consensus on POAG status. Diagnosis relied primarily on structural and functional data. A two-sample t-test compared the average mean defect (MD) on Humphrey visual field (VF) tests between top and bottom PRS deciles. Multivariate logistic regression, adjusted for age, sex, and genetically inferred ancestry, assessed the relationship between PRS and POAG.

Results : The mean age (standard deviation) of 201 subjects was 66.2 ± 9.6 years, with 58.2% females. Genetically inferred ancestries were 64.1% European, 26.4% African (AFR), 6.0% American mixed race (AMR), and 3.5% Asian. Clinical evidence of POAG was found in 38/106 (35.9%) of subjects in the top PRS decile and 4/95 (4.2%) in the bottom PRS decile. Among patients with reliable VFs (75%), the average MD in the top vs. bottom PRS deciles were -2.26 ± 3.90 dB vs. -0.89 ± 1.96 dB (p = 0.0072). Overall, the odds ratio (OR) for POAG in the top vs. bottom PRS deciles was 12.7 (95% confidence interval (CI): 4.3 - 37.3). POAG ORs for AFR (OR = 9.9) and AMR (OR = 5.3) subgroups trended in the positive direction but exhibited unstable 95% CIs due to small sample sizes.

Conclusions : This cross-sectional study shows that 36% of subjects in the highest decile of genetic risk had evidence of POAG, compared to 4% in the lowest decile. These results suggest that this PRS demonstrates utility in detecting glaucoma. Studies regarding the cross-ancestry utility of the PRS for glaucoma screening are ongoing.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.