Genome-wide analyses identify 68 new loci associated with intraocular pressure and improve risk prediction for primary open-angle glaucoma

Abstract

Glaucoma is the leading cause of irreversible blindness globally ¹ . Despite its gravity, the disease is frequently undiagnosed in the community ² . Raised intraocular pressure (IOP) is the most important risk factor for primary open-angle glaucoma (POAG)^3,4. Here we present a meta-analysis of 139,555 European participants, which identified 112 genomic loci associated with IOP, 68 of which are novel. These loci suggest a strong role for angiopoietin-receptor tyrosine kinase signaling, lipid metabolism, mitochondrial function and developmental processes underlying risk for elevated IOP. In addition, 48 of these loci were nominally associated with glaucoma in an independent cohort, 14 of which were significant at a Bonferroni-corrected threshold. Regression-based glaucoma-prediction models had an area under the receiver operating characteristic curve (AUROC) of 0.76 in US NEIGHBORHOOD study participants and 0.74 in independent glaucoma cases from the UK Biobank. Genetic-prediction models for POAG offer an opportunity to target screening and timely therapy to individuals most at risk.

Figure 1

Scatter plot demonstrating the correlation of effect estimates for SNP associations with IOP in our GWAS meta-analysis with effect estimates for SNP associations with POAG in the NEIGHBORHOOD study. Each point represents one SNP from the 120 independent IOP-associated SNPs (derived from the conditional analysis of our IOP GWAS meta-analysis; 13 of 133 SNPs were not available in NEIGHBORHOOD). The color of each point represents the statistical significance of the SNP association with IOP (see key). Effect estimates are per risk allele.

Figure 2

ROC curves for performance of the POAG-predictive model in HTG (left; n=1,298) and NTG (right; n=561) subsets versus controls (n = 2,606) from a subset of the NEIGHBORHOOD study with individual level genotype data available.