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

ANZRAG consortium, Biobank Japan project, FinnGen study, UK Biobank Eye and Vision Consortium, GIGA study group, 23 and Me Research Team, NEIGHBORHOOD consortium

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17 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 languageEnglish
Article number1258
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - Dec 2021
Externally publishedYes

Bibliographical 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 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).

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