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

PubMed ID: 37386247

Author(s): Han X, Gharahkhani P, Hamel AR, Ong JS, Renteria 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, Segre AV; 23andMe Research Team; International Glaucoma Genetics Consortium; MacGregor S. Large-scale multitrait genome-wide association analyses identify hundreds of glaucoma risk loci. Nat Genet. 2023 Jul;55(7):1116-1125. doi: 10.1038/s41588-023-01428-5. Epub 2023 Jun 29. PMID 37386247

Journal: Nature Genetics, Volume 55, Issue 7, Jul 2023

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.