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

Puya Gharahkhani; Eric Jorgenson; Pirro Hysi; Anthony P. Khawaja; Sarah Pendergrass; Xikun Han; Jue Sheng Ong; Alex W. Hewitt; Ayellet V. Segrè; John M. Rouhana; Andrew R. Hamel; Robert P. Igo; Helene Choquet; Ayub Qassim; Navya S. Josyula; Jessica N. Cooke Bailey; Pieter W.M. Bonnemaijer; Adriana Iglesias; Owen M. Siggs; Terri L. Young; Veronique Vitart; Alberta A.H.J. Thiadens; Juha Karjalainen; Steffen Uebe; Ronald B. Melles; K. Saidas Nair; Robert Luben; Mark Simcoe; Nishani Amersinghe; Angela J. Cree; Rene Hohn; Alicia Poplawski; Li Jia Chen; Shi Song Rong; Tin Aung; Eranga Nishanthie Vithana; NEIGHBORHOOD consortium; ANZRAG consortium; Biobank Japan project; FinnGen study; UK Biobank Eye and Vision Consortium; GIGA study group; 23 and Me Research Team; Gen Tamiya; Yukihiro Shiga; Masayuki Yamamoto; Toru Nakazawa; Hannah Currant; Ewan Birney; Xin Wang; Adam Auton; Michelle K. Lupton; Nicholas G  Martin; Adeyinka Ashaye; Olusola Olawoye; Susan E. Williams; Stephen Akafo; Michele Ramsay; Kazuki Hashimoto; Yoichiro Kamatani; Masato Akiyama; Yukihide Momozawa; Paul J Foster; Peng Tee Khaw; James E.  Morgan; Nicholas G.  Strouthidis; Peter Kraft; Jae H. Kang; Chi Pui Pang; Francesca Pasutto; Paul Mitchell; Andrew J. Lotery; Aarno Palotie; Cornelia M van Duijn; Jonathan L. Haines; Chris Hammond; Louis R. Pasquale; Caroline C W Klaver; Michael Hauser; Chiea Chuen  Khor; David A. Mackey; Michiaki Kubo; Ching-Yu Cheng; Jamie E. Craig; Stuart MacGregor; Janey L. Wiggs

doi:10.1038/s41467-020-20851-4

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

Puya Gharahkhani, Eric Jorgenson, Pirro Hysi, Anthony P. Khawaja, Sarah Pendergrass, Xikun Han, Jue Sheng Ong, Alex W. Hewitt, Ayellet V. Segrè, John M. Rouhana, Andrew R. Hamel, Robert P. Igo, Helene Choquet, Ayub Qassim, Navya S. Josyula, Jessica N. Cooke Bailey, Pieter W.M. Bonnemaijer, Adriana Iglesias, Owen M. Siggs, Terri L. YoungVeronique Vitart, Alberta A.H.J. Thiadens, Juha Karjalainen, Steffen Uebe, Ronald B. Melles, K. Saidas Nair, Robert Luben, Mark Simcoe, Nishani Amersinghe, Angela J. Cree, Rene Hohn, Alicia Poplawski, Li Jia Chen, Shi Song Rong, Tin Aung, Eranga Nishanthie Vithana, NEIGHBORHOOD consortium, ANZRAG consortium, Biobank Japan project, FinnGen study, UK Biobank Eye and Vision Consortium, GIGA study group, 23 and Me Research Team, Gen Tamiya, Yukihiro Shiga, Masayuki Yamamoto, Toru Nakazawa, Hannah Currant, Ewan Birney, Xin Wang, Adam Auton, Michelle K. Lupton, Nicholas G Martin, Adeyinka Ashaye, Olusola Olawoye, Susan E. Williams, Stephen Akafo, Michele Ramsay, Kazuki Hashimoto, Yoichiro Kamatani, Masato Akiyama, Yukihide Momozawa, Paul J Foster, Peng Tee Khaw, James E. Morgan, Nicholas G. Strouthidis, Peter Kraft, Jae H. Kang, Chi Pui Pang, Francesca Pasutto, Paul Mitchell, Andrew J. Lotery, Aarno Palotie, Cornelia M van Duijn, Jonathan L. Haines, Chris Hammond, Louis R. Pasquale, Caroline C W Klaver, Michael Hauser, Chiea Chuen Khor, David A. Mackey, Michiaki Kubo, Ching-Yu Cheng, Jamie E. Craig, Stuart MacGregor, Janey L. Wiggs

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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
Number of pages	16
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-20851-4
Publication status	Published - 24 Feb 2021

Bibliographical note

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.

Funder

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. [...] 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.].

Keywords

Genome-wide association studies
Optic nerve diseases

ASJC Scopus subject areas

Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

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Gharahkhani, P., Jorgenson, E., Hysi, P., Khawaja, A. P., Pendergrass, S., Han, X., Ong, J. S., Hewitt, A. W., Segrè, A. V., Rouhana, J. M., Hamel, A. R., Igo, R. P., Choquet, H., Qassim, A., Josyula, N. S., Cooke Bailey, J. N., Bonnemaijer, P. W. M., Iglesias, A., Siggs, O. M., ... Wiggs, J. L. (2021). Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries. Nature Communications, 12(1), Article 1258. https://doi.org/10.1038/s41467-020-20851-4

Gharahkhani, P, Jorgenson, E, Hysi, P, Khawaja, AP, Pendergrass, S, Han, X, Ong, JS, Hewitt, AW, Segrè, AV, Rouhana, JM, Hamel, AR, Igo, RP, Choquet, H, Qassim, A, Josyula, NS, Cooke Bailey, JN, Bonnemaijer, PWM, Iglesias, A, Siggs, OM, Young, TL, Vitart, V, Thiadens, AAHJ, Karjalainen, J, Uebe, S, Melles, RB, Nair, KS, Luben, R, Simcoe, M, Amersinghe, N, Cree, AJ, Hohn, R, Poplawski, A, Chen, LJ, Rong, SS, Aung, T, Vithana, EN, NEIGHBORHOOD consortium, ANZRAG consortium, Biobank Japan project, FinnGen study, UK Biobank Eye and Vision Consortium, GIGA study group, 23 and Me Research Team, Tamiya, G, Shiga, Y, Yamamoto, M, Nakazawa, T, Currant, H, Birney, E, Wang, X, Auton, A, Lupton, MK, Martin, NG, Ashaye, A, Olawoye, O, Williams, SE, Akafo, S, Ramsay, M, Hashimoto, K, Kamatani, Y, Akiyama, M, Momozawa, Y, Foster, PJ, Khaw, PT, Morgan, JE, Strouthidis, NG, Kraft, P, Kang, JH, Pang, CP, Pasutto, F, Mitchell, P, Lotery, AJ, Palotie, A, van Duijn, CM, Haines, JL, Hammond, C, Pasquale, LR, Klaver, CCW, Hauser, M, Khor, CC, Mackey, DA, Kubo, M, Cheng, C-Y, Craig, JE, MacGregor, S & Wiggs, JL 2021, 'Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries', Nature Communications, vol. 12, no. 1, 1258. https://doi.org/10.1038/s41467-020-20851-4

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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.",

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AU - Khawaja, Anthony P.

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AU - Han, Xikun

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AU - Thiadens, Alberta A.H.J.

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AU - Morgan, James E.

AU - Strouthidis, Nicholas G.

AU - Kraft, Peter

AU - Kang, Jae H.

AU - Pang, Chi Pui

AU - Pasutto, Francesca

AU - Mitchell, Paul

AU - Lotery, Andrew J.

AU - Palotie, Aarno

AU - van Duijn, Cornelia M

AU - Haines, Jonathan L.

AU - Hammond, Chris

AU - Pasquale, Louis R.

AU - Klaver, Caroline C W

AU - Hauser, Michael

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AU - Cheng, Ching-Yu

AU - Craig, Jamie E.

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N1 - 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.

PY - 2021/2/24

Y1 - 2021/2/24

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.

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

Abstract

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Keywords

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