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

Author(s): Xikun Han 1,2,37 , Puya Gharahkhani 1,2,3,37, Andrew R. Hamel 4,5, Jue Sheng Ong 1, Miguel E. Rentería 2,3,6, Puja Mehta 4,5, Xianjun Dong 7,8, Francesca Pasutto 9, Christopher Hammond 10, Terri L. Young 11, Pirro Hysi 10, Andrew J. Lotery 12,13, Eric Jorgenson 14, Hélène Choquet 15,16, Michael Hauser17,18,19,20, Jessica N. Cooke Bailey 21,22, Toru Nakazawa23,24,25,26, Masato Akiyama 16,27, Yukihiro Shiga23,28,29, Zachary L. Fuller30, Xin Wang 30, Alex W. Hewitt 31,32, Jamie E. Craig33, Louis R. Pasquale 34, David A. Mackey35, Janey L. Wiggs 4,5, Anthony P. Khawaja 36, Ayellet V. Segrè4,5, 23andMe Research Team,*, International Glaucoma Genetics Consortium & Stuart MacGregor 1,2

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.

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