Abstract Glaucoma, a leading cause of irreversible blindness, is a highly heritable human disease. Previous genome-wide association studies have identified over 100 loci for the most common form, primary open-angle glaucoma. Two key glaucoma-associated traits also show high heritability: intraocular pressure and optic nerve head excavation damage quantified as the vertical cup-to-disc ratio. Here, since much of glaucoma heritability remains unexplained, we conducted a large-scale multitrait genome-wide association study in participants of European ancestry combining primary open-angle glaucoma and its two associated traits (total sample size over 600,000) to substantially improve genetic discovery power (263 loci). We further increased our power by then employing a multiancestry approach, which increased the number of independent risk loci to 312, with the vast majority replicating in a large independent cohort from 23andMe, Inc. (total sample size over 2.8 million; 296 loci replicated at P < 0.05, 240 after Bonferroni correction). Leveraging multiomics datasets, we identified many potential druggable genes, including neuro-protection targets likely to act via the optic nerve, a key advance for glaucoma because all existing drugs only target intraocular pressure. We further used Mendelian randomization and genetic correlation-based approaches to identify novel links to other complex traits, including immune-related diseases such as multiple sclerosis and systemic lupus erythematosus. Subject terms: Genome-wide association studies, Gene expression
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Xikun Han, Puya Gharahkhani, Andrew R Hamel et al.. Large-scale multitrait genome-wide association analyses identify hundreds of glaucoma risk loci. Nature Genetics. (2023). https://doi.org/10.1038/s41588-023-01428-5 Xikun Han, Puya Gharahkhani, Andrew R Hamel, Jue Sheng Ong, Miguel E Rentería, Puja Mehta, Xianjun Dong, Francesca Pasutto, Christopher Hammond, Terri L Young, Pirro Hysi, Andrew J Lotery, Eric Jorgenson, Hélène Choquet, Michael Hauser, Jessica N Cooke Bailey, Toru Nakazawa, Masato Akiyama, Yukihiro Shiga, Zachary L Fuller, Xin Wang, Alex W Hewitt, Jamie E Craig, Louis R Pasquale, David A Mackey, Janey L Wiggs, Anthony P Khawaja, Ayellet V Segrè, Stuart MacGregor
1Statistical Genetics Lab, QIMR Berghofer Medical Research Institute, Brisbane, Queensland Australia 2Faculty of Medicine, University of Queensland, Brisbane, Queensland Australia 3School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Queensland Australia 4Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA USA 5Broad Institute of Harvard and MIT, Cambridge, MA USA 6Mental Health and Neuroscience Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland Australia 7Genomics and Bioinformatics Hub, Brigham and Women’s Hospital, Boston, MA USA 8Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA USA 9Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität, Erlangen-Nürnberg, Erlangen, Germany 10Twin Research and Genetic Epidemiology, King’s College London, London, UK 11Department of Ophthalmology and Visual Sciences, University of Wisconsin–Madison, Madison, WI USA 12University Hospital Southampton NHS Foundation Trust, Southampton, UK 13Faculty of Medicine, University of Southampton, Southampton, UK 14Regeneron Pharmaceuticals, Inc., Tarrytown, NY USA 15Division of Research, Kaiser Permanente Northern California (KPNC), Oakland, CA USA 16Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan 17Department of Medicine, Duke University, Durham, NC USA 18Department of Ophthalmology, Duke University, Durham, NC USA 19Singapore Eye Research Institute, Singapore, Singapore 20Duke-NUS Medical School, Singapore, Singapore 21Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH USA 22Cleveland Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, OH USA 23Department of Ophthalmology, Tohoku University Graduate School of Medicine, Sendai, Japan 24Department of Retinal Disease Control, Tohoku University Graduate School of Medicine, Sendai, Japan 25Department of Advanced Ophthalmic Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan 26Department of Ophthalmic Imaging and Information Analytics, Tohoku University Graduate School of Medicine, Sendai, Japan 27Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan 28Department of Neuroscience, Université de Montréal, Montréal, Quebec Canada 29Neuroscience Division, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montréal, Quebec Canada 3023andMe, Inc., Sunnyvale, CA USA 31Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania Australia 32Centre for Eye Research Australia, University of Melbourne, Melbourne, Victoria Australia 33Department of Ophthalmology, Flinders Medical Centre, Flinders University, Bedford Park, South Australia Australia 34Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY USA 35Centre for Ophthalmology and Visual Science, University of Western Australia, Lions Eye Institute, Perth, Western Australia Australia 36NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK 