Content area
Full Text
Glaucoma is the leading cause of irreversible blindness globally. Despite its gravity, the disease is frequently undiagnosed in the community. Raised intraocular pressure (IOP) is the most important risk factor for primary open-angle glaucoma (POAG). 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.
IOP is strongly associated with POAG, and population-based studies have suggested a 16% increase in risk for every mm Hg increase in IOP3. Lowering of IOP remains the only proven therapy to slow the progression of vision loss in POAG5. IOP heritability is estimated at 55% (ref. 6), and, to date, genome-wide association study (GWAS) meta-analyses have identified several loci associated with IOP7-9 and POAG10-12, which explain a minor proportion of disease heritability7 and have provided only limited insight into the underlying biological mechanisms. This relative lack of knowledge is partially due to the insufficient statistical power of previous association studies.
Here we present the largest GWAS of IOP to date, in 139,555 participants from three cohorts: UK Biobank13, EPIC-Norfolk14 and the previously reported combined results from 14 European studies in the International Glaucoma Genetics Consortium (IGGC)8. Additionally, we examined associations of 120 significant IOP loci with glaucoma among independent UK Biobank participants (not included in the IOP discovery GWAS) and with clinically diagnosed POAG among participants in a large multicenter case-control study (NEIGHBORHOOD)10.
First, a linear-mixed-model GWAS for IOP was carried out in UK Biobank participants (n = 103,382). The results were replicated in, then meta-analyzed with, the results from EPIC-Norfolk (n = 6,595) and the IGGC meta-analysis8 (n = 29,578). Cohort summary details are presented in Supplementary Table 1. All...