Glaucoma is the leading cause of irreversible blindness globally1. Despite its gravity, the disease is frequently undiagnosed in the community2. 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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This research was conducted by using the UK Biobank Resource under application no. 17615. UK Biobank was established by the Wellcome Trust medical charity, Medical Research Council, Department of Health, Scottish Government and Northwest Regional Development Agency. It also had funding from the Welsh Assembly Government, British Heart Foundation and Diabetes UK.
EPIC-Norfolk infrastructure and core functions are supported by grants from the Medical Research Council (G1000143) and Cancer Research UK (C864/A14136). The clinic for the third health examination was funded by Research into Ageing (262). Genotyping was funded by the Medical Research Council (MC_PC_13048). We thank all staff from the MRC Epidemiology laboratory team for the preparation and quality control of DNA samples. A.P.K. is supported by a Moorfields Eye Charity grant. P.J.F. received additional support from the Richard Desmond Charitable Trust (via Fight for Sight) and the Department for Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital and the UCL Institute of Ophthalmology for a specialist Biomedical Research Centre for Ophthalmology.
The NEIGHBORHOOD data collection and analysis is supported by NIH/NEI R01EY022305 (J.L.W.) and NIH/NEI P30 EY014104 (J.L.W.). Support for collection of cases and controls and analysis for individual datasets is as follows. Genotyping services for the NEIGHBOR study were provided by the Center for Inherited Disease Research (CIDR) and were supported by the National Eye Institute through grant HG005259-01 (J.L.W.). Genotyping for the MEEI dataset and some NHS and HPFS cases (GLAUGEN) was completed at the Broad Institute and was supported by GENEVA project grant HG004728 (L.R.P.) and U01-HG004424 (Broad Institute). Genotype data cleaning and analysis for the GLAUGEN study was supported by U01HG004446 (C. Laurie). Collecting and processing samples for the NEIGHBOR dataset was supported by the National Eye Institute through ARRA grants 3R01EY015872-05S1 (J.L.W.) and 3R01EY019126-02S1 (M. A. Hauser). Funding for the collection of NEIGHBOR cases and controls was provided by NIH grants EY015543 (R. R. Allingham); EY006827 (D. Gaasterland); HL73042, HL073389 and EY13315 (M. A. Hauser); CA87969, CA49449, UM1 CA186107, UM1 CA 167552 and EY009149 (P. R. Lichter); HG004608 (C. McCarty); EY008208 (F. A. Medeiros); EY015473 (L.R.P.); EY012118 (M. Pericak-Vance); EY015682 (A. Realini); EY011671 and EY09580 (J. E. Richards); EY013178 (J. S. Schuman); RR015574, EY015872, EY010886 and EY009847 (J.L.W.); and EY011008, EY144428, EY144448 and EY18660 (K. Zhang). The collection of Marshfield clinic cases and controls was supported by 1U02HG004608-01, 5U01HG006389-02 and NCATS/NIH grant UL1TR000427. In addition, some NHS/HPFS cases and controls and analysis of GWAS data were supported by R01 CA131332. The Women’s Genomes Health Study (WGHS) is supported by HL043851 and HL080467 from the National Heart, Lung, and Blood Institute and CA047988 from the National Cancer Institute, the Donald W. Reynolds Foundation and the Fondation Leducq, with collaborative scientific support and funding for genotyping provided by Amgen. POAG case identification in the WGHS was supported by 3R01 EY15473-5S1 (L.R.P.). J.L.W. and L.R.P. are supported by the Harvard Glaucoma Center for Excellence and an unrestricted grant from Research to Prevent Blindness. L.R.P. is also supported by a Harvard Medical School Distinguished Scholar award. M.S. is supported by a Fight for Sight PhD studentship. P.G.H. is supported by an FfS ECI fellowship. The statistical analyses were run in King’s College London Rosalind HPC LINUX Clusters and cloud server. C.J.H. and P.G.H. acknowledge the TFC Frost Charitable Trust Support for the KCL Department of Ophthalmology.