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Large-scale multitrait genome-wide association analyses identify hundreds of glaucoma risk loci
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group US
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10335935/ https://www.ncbi.nlm.nih.gov/pubmed/37386247 http://dx.doi.org/10.1038/s41588-023-01428-5 |
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author | Han, Xikun Gharahkhani, Puya Hamel, Andrew R. Ong, Jue Sheng Rentería, Miguel E. Mehta, Puja Dong, Xianjun Pasutto, Francesca Hammond, Christopher Young, Terri L. Hysi, Pirro Lotery, Andrew J. Jorgenson, Eric Choquet, Hélène Hauser, Michael Cooke Bailey, Jessica N. Nakazawa, Toru Akiyama, Masato Shiga, Yukihiro Fuller, Zachary L. Wang, Xin Hewitt, Alex W. Craig, Jamie E. Pasquale, Louis R. Mackey, David A. Wiggs, Janey L. Khawaja, Anthony P. Segrè, Ayellet V. MacGregor, Stuart |
author_facet | Han, Xikun Gharahkhani, Puya Hamel, Andrew R. Ong, Jue Sheng Rentería, Miguel E. Mehta, Puja Dong, Xianjun Pasutto, Francesca Hammond, Christopher Young, Terri L. Hysi, Pirro Lotery, Andrew J. Jorgenson, Eric Choquet, Hélène Hauser, Michael Cooke Bailey, Jessica N. Nakazawa, Toru Akiyama, Masato Shiga, Yukihiro Fuller, Zachary L. Wang, Xin Hewitt, Alex W. Craig, Jamie E. Pasquale, Louis R. Mackey, David A. Wiggs, Janey L. Khawaja, Anthony P. Segrè, Ayellet V. MacGregor, Stuart |
author_sort | Han, Xikun |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10335935 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group US |
record_format | MEDLINE/PubMed |
spelling | pubmed-103359352023-07-13 Large-scale multitrait genome-wide association analyses identify hundreds of glaucoma risk loci Han, Xikun Gharahkhani, Puya Hamel, Andrew R. Ong, Jue Sheng Rentería, Miguel E. Mehta, Puja Dong, Xianjun Pasutto, Francesca Hammond, Christopher Young, Terri L. Hysi, Pirro Lotery, Andrew J. Jorgenson, Eric Choquet, Hélène Hauser, Michael Cooke Bailey, Jessica N. Nakazawa, Toru Akiyama, Masato Shiga, Yukihiro Fuller, Zachary L. Wang, Xin Hewitt, Alex W. Craig, Jamie E. Pasquale, Louis R. Mackey, David A. Wiggs, Janey L. Khawaja, Anthony P. Segrè, Ayellet V. MacGregor, Stuart Nat Genet Article 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. Nature Publishing Group US 2023-06-29 2023 /pmc/articles/PMC10335935/ /pubmed/37386247 http://dx.doi.org/10.1038/s41588-023-01428-5 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Han, Xikun Gharahkhani, Puya Hamel, Andrew R. Ong, Jue Sheng Rentería, Miguel E. Mehta, Puja Dong, Xianjun Pasutto, Francesca Hammond, Christopher Young, Terri L. Hysi, Pirro Lotery, Andrew J. Jorgenson, Eric Choquet, Hélène Hauser, Michael Cooke Bailey, Jessica N. Nakazawa, Toru Akiyama, Masato Shiga, Yukihiro Fuller, Zachary L. Wang, Xin Hewitt, Alex W. Craig, Jamie E. Pasquale, Louis R. Mackey, David A. Wiggs, Janey L. Khawaja, Anthony P. Segrè, Ayellet V. MacGregor, Stuart Large-scale multitrait genome-wide association analyses identify hundreds of glaucoma risk loci |
title | Large-scale multitrait genome-wide association analyses identify hundreds of glaucoma risk loci |
title_full | Large-scale multitrait genome-wide association analyses identify hundreds of glaucoma risk loci |
title_fullStr | Large-scale multitrait genome-wide association analyses identify hundreds of glaucoma risk loci |
title_full_unstemmed | Large-scale multitrait genome-wide association analyses identify hundreds of glaucoma risk loci |
title_short | Large-scale multitrait genome-wide association analyses identify hundreds of glaucoma risk loci |
title_sort | large-scale multitrait genome-wide association analyses identify hundreds of glaucoma risk loci |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10335935/ https://www.ncbi.nlm.nih.gov/pubmed/37386247 http://dx.doi.org/10.1038/s41588-023-01428-5 |
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