| Title: | Large-scale multitrait genome-wide association analyses identify hundreds of glaucoma risk loci |
| Journal: | Nature Genetics |
| Published: | 29 Jun 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/37386247/ |
| DOI: | https://doi.org/10.1038/s41588-023-01428-5 |
| URL: | https://www.nature.com/articles/s41588-023-01428-5.pdf |
Publication 10914
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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.</p>
29 Authors
- 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
1 Application
| Application ID | Title |
|---|---|
| 25331 | Gene mapping and genetic correlation across complex traits |
Enabling scientific discoveries that improve human health