Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma

EPIC-Norfolk Eye Study; David Broadway; Michelle  Chan; David Garway-Heath; Shabina  Hayat; Nicola Kerrison; Kay-Tee Khaw; Claudia  Langenberg; Jian’an Luan; Robert Luben; Robert Scott; Nicholas Wareham; Jennifer  Yip; Jing Hua  Zhao; ANZRAG Consortium; Shiwani Sharma; Sarah Martin; Tiger Zhou; Emmanuelle Souzeau; John Landers; Jude Fitzgerald; Richard Mills; Rhys Fogarty; Stuart Graham; Robert Casson; Mark Chehade; Sonja Klebe; Jonathan Ruddle; Ivan Goldberg; Andrew White; Paul Healey; Grant W. Montgomery; Nicholas G. Martin; Graham Radford-Smith; David Whiteman; Matthew H. Law; Matthew  Brown; Katie Cremin

doi:10.1038/ng.3482

Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma

EPIC-Norfolk Eye Study, David Broadway, Michelle Chan, David Garway-Heath, Shabina Hayat, Nicola Kerrison, Kay-Tee Khaw, Claudia Langenberg, Jian’an Luan, Robert Luben, Robert Scott, Nicholas Wareham, Jennifer Yip, Jing Hua Zhao, ANZRAG Consortium, Shiwani Sharma, Sarah Martin, Tiger Zhou, Emmanuelle Souzeau, John LandersJude Fitzgerald, Richard Mills, Rhys Fogarty, Stuart Graham, Robert Casson, Mark Chehade, Sonja Klebe, Jonathan Ruddle, Ivan Goldberg, Andrew White, Paul Healey, Grant W. Montgomery, Nicholas G. Martin, Graham Radford-Smith, David Whiteman, Matthew H. Law, Matthew Brown, Katie Cremin

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Abstract

Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10 -11) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10 -10); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10 -10). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.

Original language	English
Pages (from-to)	189-194
Number of pages	6
Journal	Nature Genetics
Volume	48
Issue number	2
DOIs	https://doi.org/10.1038/ng.3482
Publication status	Published - 11 Jan 2016

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EPIC-Norfolk Eye Study, Broadway, D., Chan, M., Garway-Heath, D., Hayat, S., Kerrison, N., Khaw, K.-T., Langenberg, C., Luan, J., Luben, R., Scott, R., Wareham, N., Yip, J., Zhao, J. H., ANZRAG Consortium, Sharma, S., Martin, S., Zhou, T., Souzeau, E., ... Cremin, K. (2016). Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma. Nature Genetics, 48(2), 189-194. https://doi.org/10.1038/ng.3482

@article{33ac5390e54145af878e988923193bac,

title = "Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma",

abstract = "Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10 -11) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10 -10); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10 -10). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.",

author = "{Bailey Cooke}, Jessica and Stephanie Loomis and Jae Kang and R Allingham and Puya Gharahkhani and Chiea-Chuen Khor and Kathryn Burdon and Hugues Aschard and Daniel Chasman and Robert Igo and Pirro Hysi and Craig Glastonbury and Allison Koch and Murray Brilliant and Andrew Brown and Donald Budenz and Alfonso Buil and Ching-Yu Cheng and Hyon Choi and William Christen and Gary Curhan and {De Vivo}, Immaculata and John Fingert and Paul Foster and Charles Fuchs and Douglas Gaasterland and Terry Gaasterland and Alex Hewitt and Frank Hu and David Hunter and Anthony Khawaja and Richard Lee and Zheng Li and Paul Lichter and David Mackey and Peter McGuffin and Paul Mitchell and Sayoko Moroi and Shamira Perera and Keating Pepper and Qibin Qi and Tony Realini and Julia Richards and Paul Ridker and Eric Rimm and Robert Ritch and Marylyn Ritchie and Joel Schuman and William Scott and Kuldev Singh and Arthur Sit and Yeunjoo Song and Rulla Tamimi and Fotis Topouzis and Ananth Viswanathan and Shefali Verma and Douglas Vollrath and Wang, {Jie Jin} and Nicole Weisschuh and Bernd Wissinger and Gadi Wollstein and Tien Wong and Brian Yaspan and Donald Zack and Kang Zhang and {EPIC-Norfolk Eye Study} and David Broadway and Michelle Chan and David Garway-Heath and Shabina Hayat and Nicola Kerrison and Kay-Tee Khaw and Claudia Langenberg and Jian{\textquoteright}an Luan and Robert Luben and Robert Scott and Nicholas Wareham and Jennifer Yip and Zhao, {Jing Hua} and {ANZRAG Consortium} and Shiwani Sharma and Sarah Martin and Tiger Zhou and Emmanuelle Souzeau and John Landers and Jude Fitzgerald and Richard Mills and Rhys Fogarty and Stuart Graham and Robert Casson and Mark Chehade and Sonja Klebe and Jonathan Ruddle and Ivan Goldberg and Andrew White and Paul Healey and Montgomery, {Grant W.} and Martin, {Nicholas G.} and Graham Radford-Smith and David Whiteman and Law, {Matthew H.} and Matthew Brown and Katie Cremin and Robert Weinreb and Margaret Pericak-Vance and Kerrin Small and Christopher Hammond and Tin Aung and Yutao Liu and Eranga Vithana and Stuart Macgregor and Jamie Craig and Peter Kraft and Gareth Howell and Michael Hauser and Louis Pasquale and Jonathan Haines and Janey Wiggs",

year = "2016",

month = jan,

day = "11",

doi = "10.1038/ng.3482",

language = "English",

volume = "48",

pages = "189--194",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "2",

}

EPIC-Norfolk Eye Study, Broadway, D, Chan, M, Garway-Heath, D, Hayat, S, Kerrison, N, Khaw, K-T, Langenberg, C, Luan, J, Luben, R, Scott, R, Wareham, N, Yip, J, Zhao, JH, ANZRAG Consortium, Sharma, S, Martin, S, Zhou, T, Souzeau, E , Landers, J, Fitzgerald, J, Mills, R, Fogarty, R, Graham, S, Casson, R, Chehade, M, Klebe, S, Ruddle, J, Goldberg, I, White, A, Healey, P, Montgomery, GW, Martin, NG, Radford-Smith, G, Whiteman, D, Law, MH, Brown, M & Cremin, K 2016, 'Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma', Nature Genetics, vol. 48, no. 2, pp. 189-194. https://doi.org/10.1038/ng.3482

TY - JOUR

T1 - Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma

AU - Bailey Cooke, Jessica

AU - Loomis, Stephanie

AU - Kang, Jae

AU - Allingham, R

AU - Gharahkhani, Puya

AU - Khor, Chiea-Chuen

AU - Burdon, Kathryn

AU - Aschard, Hugues

AU - Chasman, Daniel

AU - Igo, Robert

AU - Hysi, Pirro

AU - Glastonbury, Craig

AU - Koch, Allison

AU - Brilliant, Murray

AU - Brown, Andrew

AU - Budenz, Donald

AU - Buil, Alfonso

AU - Cheng, Ching-Yu

AU - Choi, Hyon

AU - Christen, William

AU - Curhan, Gary

AU - De Vivo, Immaculata

AU - Fingert, John

AU - Foster, Paul

AU - Fuchs, Charles

AU - Gaasterland, Douglas

AU - Gaasterland, Terry

AU - Hewitt, Alex

AU - Hu, Frank

AU - Hunter, David

AU - Khawaja, Anthony

AU - Lee, Richard

AU - Li, Zheng

AU - Lichter, Paul

AU - Mackey, David

AU - McGuffin, Peter

AU - Mitchell, Paul

AU - Moroi, Sayoko

AU - Perera, Shamira

AU - Pepper, Keating

AU - Qi, Qibin

AU - Realini, Tony

AU - Richards, Julia

AU - Ridker, Paul

AU - Rimm, Eric

AU - Ritch, Robert

AU - Ritchie, Marylyn

AU - Schuman, Joel

AU - Scott, William

AU - Singh, Kuldev

AU - Sit, Arthur

AU - Song, Yeunjoo

AU - Tamimi, Rulla

AU - Topouzis, Fotis

AU - Viswanathan, Ananth

AU - Verma, Shefali

AU - Vollrath, Douglas

AU - Wang, Jie Jin

AU - Weisschuh, Nicole

AU - Wissinger, Bernd

AU - Wollstein, Gadi

AU - Wong, Tien

AU - Yaspan, Brian

AU - Zack, Donald

AU - Zhang, Kang

AU - EPIC-Norfolk Eye Study

AU - Broadway, David

AU - Chan, Michelle

AU - Garway-Heath, David

AU - Hayat, Shabina

AU - Kerrison, Nicola

AU - Khaw, Kay-Tee

AU - Langenberg, Claudia

AU - Luan, Jian’an

AU - Luben, Robert

AU - Scott, Robert

AU - Wareham, Nicholas

AU - Yip, Jennifer

AU - Zhao, Jing Hua

AU - ANZRAG Consortium

AU - Sharma, Shiwani

AU - Martin, Sarah

AU - Zhou, Tiger

AU - Souzeau, Emmanuelle

AU - Landers, John

AU - Fitzgerald, Jude

AU - Mills, Richard

AU - Fogarty, Rhys

AU - Graham, Stuart

AU - Casson, Robert

AU - Chehade, Mark

AU - Klebe, Sonja

AU - Ruddle, Jonathan

AU - Goldberg, Ivan

AU - White, Andrew

AU - Healey, Paul

AU - Montgomery, Grant W.

AU - Martin, Nicholas G.

AU - Radford-Smith, Graham

AU - Whiteman, David

AU - Law, Matthew H.

AU - Brown, Matthew

AU - Cremin, Katie

AU - Weinreb, Robert

AU - Pericak-Vance, Margaret

AU - Small, Kerrin

AU - Hammond, Christopher

AU - Aung, Tin

AU - Liu, Yutao

AU - Vithana, Eranga

AU - Macgregor, Stuart

AU - Craig, Jamie

AU - Kraft, Peter

AU - Howell, Gareth

AU - Hauser, Michael

AU - Pasquale, Louis

AU - Haines, Jonathan

AU - Wiggs, Janey

PY - 2016/1/11

Y1 - 2016/1/11

N2 - Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10 -11) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10 -10); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10 -10). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.

AB - Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10 -11) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10 -10); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10 -10). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.

UR - http://purl.org/au-research/grants/NHMRC/535074

UR - http://purl.org/au-research/grants/NHMRC/1031362

UR - http://purl.org/au-research/grants/NHMRC/1023911

UR - http://www.scopus.com/inward/record.url?scp=84956703568&partnerID=8YFLogxK

U2 - 10.1038/ng.3482

DO - 10.1038/ng.3482

M3 - Article

SN - 1061-4036

VL - 48

SP - 189

EP - 194

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -

Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma

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