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Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries

Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries
Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.

2041-1723
Gharahkhani, Puya
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Jorgenson, Eric
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Hysi, Pirro
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Khawaja, Anthony P.
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Pendergrass, Sarah
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Segrè, Ayellet V.
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Rouhana, John M.
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Hamel, Andrew R.
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Igo, Robert P.
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Choquet, Helene
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Josyula, Navya S.
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Iglesias, Adriana
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Young, Terri L.
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Vitart, Veronique
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Karjalainen, Juha
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Uebe, Steffen
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Melles, Ronald B.
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Hohn, Rene
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Poplawski, Alicia
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Chen, Li Jia
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Rong, Shi Song
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Aung, Tin
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Martin, Sarah
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White, Andrew J.
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Carare, Roxana
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Ennis, Sarah
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Foster, Paul
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Gibson, Jane
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Lotery, Andrew J.
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Morgan, James E.
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Self, Jay
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Stratton, Irene
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Wang, Xin
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Martin, Nicholas G.
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Morgan, James E.
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Lotery, Andrew J.
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Cheng, Ching Yu
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NEIGHBORHOOD Consortium
ANZRAG consortium
Biobank Japan project
FinnGen study
UK Biobank Eye and Vision Consortium
GIGA study group
23 and Me Research Team
Gharahkhani, Puya
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Jorgenson, Eric
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Hysi, Pirro
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Khawaja, Anthony P.
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Pendergrass, Sarah
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Han, Xikun
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Ong, Jue Sheng
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Hewitt, Alex W.
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Segrè, Ayellet V.
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Rouhana, John M.
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Hamel, Andrew R.
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Igo, Robert P.
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Choquet, Helene
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Qassim, Ayub
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Josyula, Navya S.
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Cooke Bailey, Jessica N.
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Bonnemaijer, Pieter W.M.
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Iglesias, Adriana
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Siggs, Owen M.
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Young, Terri L.
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Vitart, Veronique
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Karjalainen, Juha
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Uebe, Steffen
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Melles, Ronald B.
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Nair, K. Saidas
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Luben, Robert
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Simcoe, Mark
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Amersinghe, Nishani
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Cree, Angela J.
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Hohn, Rene
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Poplawski, Alicia
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Chen, Li Jia
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Rong, Shi Song
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Aung, Tin
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Martin, Sarah
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White, Andrew J.
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Carare, Roxana
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Ennis, Sarah
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Foster, Paul
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Gibson, Jane
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Lotery, Andrew J.
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Morgan, James E.
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Self, Jay
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Stratton, Irene
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Wang, Xin
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Martin, Nicholas G.
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Morgan, James E.
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Lotery, Andrew J.
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Cheng, Ching Yu
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NEIGHBORHOOD Consortium, ANZRAG consortium, Biobank Japan project, FinnGen study, UK Biobank Eye and Vision Consortium, GIGA study group and 23 and Me Research Team (2021) Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries. Nature Communications, 12 (1), [1258]. (doi:10.1038/s41467-020-20851-4).

Record type: Article

Abstract

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.

Full text not available from this repository.

More information

Published date: 24 February 2021
Additional Information: Funding Information: This work was conducted using the UK Biobank Resource (application number 25331) and publicly available data from the International Glaucoma Genetics Consortium. This work was also supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (#1107098; 1116360, 1116495, 1023911), the Ophthalmic Research Institute of Australia, the BrightFocus Foundation, UK and Eire Glaucoma Society and Charitable Funds from Royal Liverpool University Hospital, and International Glaucoma Association-Royal College of Ophthalmologists. P.G. is supported by a NHMRC Investigator Grant (#1173390). S.M., J.E.C., K.P.B., and A.W.H. are supported by NHMRC Fellowships. A.P.K. was funded by a Moorfields Eye Charity Career Development Fellowship, a UK Research and Innovation Future Leaders Fellowship and an Alcon Research Institute Young Investigator Award. The EPIC-Norfolk study has received funding from the Medical Research Council (MR/N003284/1, MC-UU_12015/1, and MC_PC_13048) and Cancer Research UK (C864/A14136). The NEIGHBORHOOD consortium is supported by NIH grants P30 EY014104, R01 EY015473, and R01 EY022305. The FinnGen project is funded by two grants from Business Finland (HUS 4685/31/2016 and UH 4386/ 31/2016) and eleven industry partners (AbbVie Inc, AstraZeneca UK Ltd, Biogen MA Inc, Celgene Corporation, Celgene International II Sàrl, Genentech Inc, Merck Sharp & Dohme Corp, Pfizer Inc., GlaxoSmithKline, Sanofi, Maze Therapeutics Inc., Janssen Biotech Inc). This work was also supported by the National Eye Institute/National Institutes of Health [R01EY018246, and support from the National Institutes of Health Center for Inherited Disease Research to T.L.Y.]; a University of Wisconsin Centennial Scholars Award [to T.L.Y.]; and an unrestricted grant from Research to Prevent Blindness, Inc. to the UW-Madison Department of Ophthalmology and Visual Sciences [to T.L.Y.]. Additional acknowledgments are supplied in the Supplementary Information file. Funding Information: X.W. and A.A. are employed by and hold stock or stock options in 23andMe, Inc. J.W. is a consultant for Allergan, Editas, Maze, Regenxbio and has received sponsored research support from Aerpio Pharmaceuticals Inc. L.P. is a consultant for Eyenovia, Bausch + Lomb, Verily, and Nicox. T.L.Y. serves as a consultant to Aerpio Pharmaceuticals, Inc. A.P.K. is a consultant to Aerie, Allergan, Google Health, Novartis, Reichert, Santen and Thea. All remaining authors declare no competing interests. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

Identifiers

Local EPrints ID: 448453
URI: http://eprints.soton.ac.uk/id/eprint/448453
ISSN: 2041-1723
PURE UUID: 1dd8188f-95c9-401a-a78f-b58cbe787fa8
ORCID for Sarah Ennis: ORCID iD orcid.org/0000-0003-2648-0869
ORCID for Jane Gibson: ORCID iD orcid.org/0000-0002-0973-8285
ORCID for Andrew J. Lotery: ORCID iD orcid.org/0000-0001-5541-4305
ORCID for Jay Self: ORCID iD orcid.org/0000-0002-1030-9963
ORCID for Andrew J. Lotery: ORCID iD orcid.org/0000-0001-5541-4305

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Date deposited: 22 Apr 2021 16:46
Last modified: 23 Apr 2021 01:38

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Contributors

Author: Puya Gharahkhani
Author: Eric Jorgenson
Author: Pirro Hysi
Author: Anthony P. Khawaja
Author: Sarah Pendergrass
Author: Xikun Han
Author: Jue Sheng Ong
Author: Alex W. Hewitt
Author: Ayellet V. Segrè
Author: John M. Rouhana
Author: Andrew R. Hamel
Author: Robert P. Igo
Author: Helene Choquet
Author: Ayub Qassim
Author: Navya S. Josyula
Author: Jessica N. Cooke Bailey
Author: Pieter W.M. Bonnemaijer
Author: Adriana Iglesias
Author: Owen M. Siggs
Author: Terri L. Young
Author: Veronique Vitart
Author: Alberta A.H.J. Thiadens
Author: Juha Karjalainen
Author: Steffen Uebe
Author: Ronald B. Melles
Author: K. Saidas Nair
Author: Robert Luben
Author: Mark Simcoe
Author: Nishani Amersinghe
Author: Angela J. Cree
Author: Rene Hohn
Author: Alicia Poplawski
Author: Li Jia Chen
Author: Shi Song Rong
Author: Tin Aung
Author: Sarah Martin
Author: Andrew J. White
Author: Roxana Carare
Author: Sarah Ennis ORCID iD
Author: Paul Foster
Author: Jane Gibson ORCID iD
Author: James E. Morgan
Author: Jay Self ORCID iD
Author: Irene Stratton
Author: Xin Wang
Author: Nicholas G. Martin
Author: James E. Morgan
Author: Ching Yu Cheng
Corporate Author: NEIGHBORHOOD Consortium
Corporate Author: ANZRAG consortium
Corporate Author: Biobank Japan project
Corporate Author: FinnGen study
Corporate Author: UK Biobank Eye and Vision Consortium
Corporate Author: GIGA study group
Corporate Author: 23 and Me Research Team

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