Large-scale multitrait genome-wide association analyses identify hundreds of glaucoma risk loci

Han X, Gharahkhani P, Hamel AR, Ong JS, Rentería ME, Mehta P, Dong X, Pasutto F, Hammond C, Young TL, Hysi P, Lotery AJ, Jorgenson E, Choquet H, Hauser M, Cooke Bailey JN, Nakazawa T, Akiyama M, Shiga Y, Fuller ZL, Wang X, Hewitt AW, Craig JE, Pasquale LR, Mackey DA, Wiggs JL, Khawaja AP, Segrè AV, MacGregor S (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Book Volume: 55

Pages Range: 1116-1125

Journal Issue: 7

DOI: 10.1038/s41588-023-01428-5

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.

Authors with CRIS profile

Involved external institutions

QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) Veterans Affairs Healthcare System Boston and Harvard Medical School United States (USA) (US) Brigham and Women's Hospital (BWH) United States (USA) (US) King’s College London United Kingdom (GB) University of Wisconsin - Madison United States (USA) (US) University of Tasmania (UTAS) Australia (AU) Flinders University Australia (AU) Icahn School of Medicine at Mount Sinai United States (USA) (US) University of Western Australia (UWA) Australia (AU) Moorfields Eye Hospital NHS Foundation Trust United Kingdom (GB) University Hospital Southampton NHS United Kingdom (GB) Regeneron Pharmaceuticals, Inc. United States (USA) (US) Kaiser Permanente United States (USA) (US) Duke University United States (USA) (US) Case Western Reserve University United States (USA) (US) Kyushu University / 九州大学 Japan (JP) 23andMe United States (USA) (US)

How to cite

APA:

Han, X., Gharahkhani, P., Hamel, A.R., Ong, J.S., Rentería, M.E., Mehta, P.,... MacGregor, S. (2023). Large-scale multitrait genome-wide association analyses identify hundreds of glaucoma risk loci. Nature Genetics, 55(7), 1116-1125. https://dx.doi.org/10.1038/s41588-023-01428-5

MLA:

Han, Xikun, et al. "Large-scale multitrait genome-wide association analyses identify hundreds of glaucoma risk loci." Nature Genetics 55.7 (2023): 1116-1125.

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