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

NEIGHBORHOOD Consortium; ANZRAG consortium; BioBank Japan Project; FinnGen study; UK Biobank Eye and Vision Consortium; GIGA Study Group; 23 and Me Research Team

doi:10.1038/s41467-020-20851-4

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

NEIGHBORHOOD Consortium, ANZRAG consortium, BioBank Japan Project, FinnGen study, UK Biobank Eye and Vision Consortium, GIGA Study Group, 23 and Me Research Team

Research output: Contribution to journal › Article › peer-review

176 Citations (Scopus)

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.

Original language	English
Article number	1258
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-20851-4
Publication status	Published - Dec 2021

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10.1038/s41467-020-20851-4

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@article{e4d6904ac64a419a8ed2cd376301a3f2,

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

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.",

author = "{NEIGHBORHOOD Consortium} and {ANZRAG consortium} and {BioBank Japan Project} and {FinnGen study} and {UK Biobank Eye and Vision Consortium} and {GIGA Study Group} and {23 and Me Research Team} and Puya Gharahkhani and Eric Jorgenson and Pirro Hysi and Khawaja, {Anthony P.} and Sarah Pendergrass and Xikun Han and Ong, {Jue Sheng} and Hewitt, {Alex W.} and Segr{\`e}, {Ayellet V.} and Rouhana, {John M.} and Hamel, {Andrew R.} and Igo, {Robert P.} and Helene Choquet and Ayub Qassim and Josyula, {Navya S.} and {Cooke Bailey}, {Jessica N.} and Bonnemaijer, {Pieter W.M.} and Adriana Iglesias and Siggs, {Owen M.} and Young, {Terri L.} and Veronique Vitart and Thiadens, {Alberta A.H.J.} and Juha Karjalainen and Steffen Uebe and Melles, {Ronald B.} and Nair, {K. Saidas} and Robert Luben and Mark Simcoe and Nishani Amersinghe and Cree, {Angela J.} and Rene Hohn and Alicia Poplawski and Chen, {Li Jia} and Rong, {Shi Song} and Tin Aung and Vithana, {Eranga Nishanthie} and Allingham, {R. Rand} and Murray Brilliant and Budenz, {Donald L.} and Bailey, {Jessica N.Cooke} and Fingert, {John H.} and Douglas Gaasterland and Teresa Gaasterland and Haines, {Jonathan L.} and Michael Hauser and Lee, {Richard K.} and Lichter, {Paul R.} and Yutao Liu and Catey Bunce and Lupton, {Michelle K.}",

note = "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 S{\`a}rl, 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: {\textcopyright} 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = dec,

doi = "10.1038/s41467-020-20851-4",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries

AU - NEIGHBORHOOD Consortium

AU - ANZRAG consortium

AU - BioBank Japan Project

AU - FinnGen study

AU - UK Biobank Eye and Vision Consortium

AU - GIGA Study Group

AU - 23 and Me Research Team

AU - Gharahkhani, Puya

AU - Jorgenson, Eric

AU - Hysi, Pirro

AU - Khawaja, Anthony P.

AU - Pendergrass, Sarah

AU - Han, Xikun

AU - Ong, Jue Sheng

AU - Hewitt, Alex W.

AU - Segrè, Ayellet V.

AU - Rouhana, John M.

AU - Hamel, Andrew R.

AU - Igo, Robert P.

AU - Choquet, Helene

AU - Qassim, Ayub

AU - Josyula, Navya S.

AU - Cooke Bailey, Jessica N.

AU - Bonnemaijer, Pieter W.M.

AU - Iglesias, Adriana

AU - Siggs, Owen M.

AU - Young, Terri L.

AU - Vitart, Veronique

AU - Thiadens, Alberta A.H.J.

AU - Karjalainen, Juha

AU - Uebe, Steffen

AU - Melles, Ronald B.

AU - Nair, K. Saidas

AU - Luben, Robert

AU - Simcoe, Mark

AU - Amersinghe, Nishani

AU - Cree, Angela J.

AU - Hohn, Rene

AU - Poplawski, Alicia

AU - Chen, Li Jia

AU - Rong, Shi Song

AU - Aung, Tin

AU - Vithana, Eranga Nishanthie

AU - Allingham, R. Rand

AU - Brilliant, Murray

AU - Budenz, Donald L.

AU - Bailey, Jessica N.Cooke

AU - Fingert, John H.

AU - Gaasterland, Douglas

AU - Gaasterland, Teresa

AU - Haines, Jonathan L.

AU - Hauser, Michael

AU - Lee, Richard K.

AU - Lichter, Paul R.

AU - Liu, Yutao

AU - Bunce, Catey

AU - Lupton, Michelle K.

N1 - 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.

PY - 2021/12

Y1 - 2021/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85101839427&partnerID=8YFLogxK

U2 - 10.1038/s41467-020-20851-4

DO - 10.1038/s41467-020-20851-4

M3 - Article

C2 - 33627673

AN - SCOPUS:85101839427

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1258

ER -

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

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