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Abstract #109722 Published in IGR 24-1
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; Segrè AV; ; Macgregor SNature Genetics 2023; 55: 1116-1125
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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