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

William K Scott; Jessica N Cooke Bailey; Stephanie J Loomis; Jae H Kang; R Rand Allingham; Puya Gharahkhani; Chiea Chuen Khor; Kathryn P Burdon; Hugues Aschard; Daniel I Chasman; Robert P Igo Jr; Pirro G Hysi; Craig A Glastonbury; Allison Ashley-Koch; Murray Brilliant; Andrew A Brown; Donald L Budenz; Alfonso Buil; Ching Yu Cheng; William G Christen; Hyon Choi; Gary Curhan; Immaculata De Vivo; John H Fingert; Paul J Foster; Charles Fuchs; Douglas Gaasterland; Terry Gaasterland; Alex W Hewitt; Frank Hu; David J Hunter; Anthony P Khawaja; Richard K Lee; Zheng Li; Paul R Lichter; David A Mackey; Peter McGuffin; Paul Mitchell; Sayoko E Moroi; Shamira A Perera; Keating W Pepper; Qibin Qi; Tony Realini; Julia E Richards; Paul M Ridker; Eric Rimm; Robert Ritch; Marylyn Ritchie; Joel S Schuman; Kuldev Singh; Arthur J Sit; Yeunjoo E Song; Rulla M Tamimi; Fotis Topouzis; Ananth C Viswanathan; Shefali Setia Verma; Douglas Vollrath; Jie Jin Wang; Nicole Weisschuh; Bernd Wissinger; Gadi Wollstein; Tien Y Wong; Brian L Yaspan; Donald J Zack; Kang Zhang; Epic-Norfolk Eye Study; Robert N Weinreb; Margaret A Pericak-Vance; Christopher J Hammond; Tin Aung; Yutao Liu; Eranga N Vithana; Stuart MacGregor; Jamie E Craig; Peter Kraft; Gareth Howell; Michael A Hauser; Louis R Pasquale; Jonathan L Haines; Janey L Wiggs; Kerrin Small

doi:10.1038/ng.3482

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

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

William K Scott, Jessica N Cooke Bailey, Stephanie J Loomis, Jae H Kang, R Rand Allingham, Puya Gharahkhani, Chiea Chuen Khor, Kathryn P Burdon, Hugues Aschard, Daniel I Chasman, …

Nature genetics, Vol.48(2), pp.189-194

02/2016

DOI: 10.1038/ng.3482

PMCID: PMC4731307

PMID: 26752265

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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.

Genetic Predisposition to Disease

Genome-Wide Association Study

Glaucoma, Open-Angle - genetics

Humans

Polymorphism, Single Nucleotide

Forkhead Transcription Factors - genetics

Thioredoxin Reductase 2 - genetics

Ataxin-2 - genetics

Details

Title: Subtitle: Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma
Creators: William K Scott - University of Miami Hospital
Jessica N Cooke Bailey - Case Western Reserve University
Stephanie J Loomis - Massachusetts Eye and Ear Infirmary
Jae H Kang - Brigham and Women's Hospital
R Rand Allingham - Duke University
Puya Gharahkhani - QIMR Berghofer Medical Research Institute
Chiea Chuen Khor - National University of Singapore
Kathryn P Burdon - Flinders University
Hugues Aschard - Harvard Medical School
Daniel I Chasman - Brigham and Women's Hospital
Robert P Igo Jr - Case Western Reserve University
Pirro G Hysi - Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
Craig A Glastonbury - Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
Allison Ashley-Koch - Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
Murray Brilliant - Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, Wisconsin, USA
Andrew A Brown - University of Geneva
Donald L Budenz - Department of Ophthalmology, University of North Carolina, Chapel Hill, North Carolina, USA
Alfonso Buil - Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
Ching Yu Cheng - National University of Singapore
William G Christen - Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Hyon Choi - Section of Rheumatology and Clinical Epidemiology Unit, Boston University School of Medicine, Boston, Massachusetts, USA
Gary Curhan - Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
Immaculata De Vivo - Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
John H Fingert - Department of Anatomy and Cell Biology, University of Iowa, College of Medicine, Iowa City, Iowa, USA
Paul J Foster - Department of Ophthalmology, University College London, London, UK
Charles Fuchs - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
Douglas Gaasterland - Eye Doctors of Washington, Chevy Chase, Maryland, USA
Terry Gaasterland - Scripps Genome Center, University of California at San Diego, San Diego, California, USA
Alex W Hewitt - Department of Ophthalmology, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia
Frank Hu - Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA
David J Hunter - Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts, USA
Anthony P Khawaja - Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge School of Clinical Medicine, Cambridge, UK
Richard K Lee - Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA
Zheng Li - Division of Human Genetics, Genome Institute of Singapore, Singapore
Paul R Lichter - Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, USA
David A Mackey - Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Western Australia, Australia
Peter McGuffin - Medical Research Council Social Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, King's College London, London, UK
Paul Mitchell - Centre for Vision Research, Westmead Millennium Institute, University of Sydney, Westmead, New South Wales, Australia
Sayoko E Moroi - Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, USA
Shamira A Perera - Duke-National University of Singapore Graduate Medical School, Singapore
Keating W Pepper - The Jackson Laboratory, Bar Harbor, Maine, USA
Qibin Qi - Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, USA
Tony Realini - Department of Ophthalmology, West Virginia University Eye Institute, Morgantown, West Virginia, USA
Julia E Richards - Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, USA
Paul M Ridker - Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Eric Rimm - Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA
Robert Ritch - Einhorn Clinical Research Center, Department of Ophthalmology, New York Eye and Ear Infirmary of Mount Sinai, New York, New York, USA
Marylyn Ritchie - Center for Systems Genomics, Pennsylvania State University, University Park, Pennsylvania, USA
Joel S Schuman - Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
Kuldev Singh - Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, California, USA
Arthur J Sit - Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, USA
Yeunjoo E Song - Department of Epidemiology and Biostatistics, Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
Rulla M Tamimi - Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Fotis Topouzis - Department of Ophthalmology, School of Medicine, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece
Ananth C Viswanathan - National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, London, UK
Shefali Setia Verma - Center for Systems Genomics, Pennsylvania State University, University Park, Pennsylvania, USA
Douglas Vollrath - Department of Genetics, Stanford University School of Medicine, Palo Alto, California, USA
Jie Jin Wang - Centre for Vision Research, Westmead Millennium Institute, University of Sydney, Westmead, New South Wales, Australia
Nicole Weisschuh - Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany
Bernd Wissinger - Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany
Gadi Wollstein - Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
Tien Y Wong - Singapore Eye Research Institute, Singapore National Eye Centre, Singapore
Brian L Yaspan - Genentech, San Francisco, California, USA
Donald J Zack - Wilmer Eye Institute, Johns Hopkins University Hospital, Baltimore, Maryland, USA
Kang Zhang - Hamilton Glaucoma Center, Shiley Eye Institute, University of California, San Diego, San Diego, California, USA
Epic-Norfolk Eye Study - Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, Georgia, USA
Robert N Weinreb - Hamilton Glaucoma Center, Shiley Eye Institute, University of California, San Diego, San Diego, California, USA
Margaret A Pericak-Vance - Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA
Christopher J Hammond - Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
Tin Aung - Eye Academic Clinical Program, Duke-National University of Singapore Graduate Medical School, Singapore
Yutao Liu - James and Jean Culver Vision Discovery Institute, Georgia Regents University, Augusta, Georgia, USA
Eranga N Vithana - Eye Academic Clinical Program, Duke-National University of Singapore Graduate Medical School, Singapore
Stuart MacGregor - QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
Jamie E Craig - Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia
Peter Kraft - Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts, USA
Gareth Howell - The Jackson Laboratory, Bar Harbor, Maine, USA
Michael A Hauser - Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
Louis R Pasquale - Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Jonathan L Haines - Department of Epidemiology and Biostatistics, Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
Janey L Wiggs - Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA
Kerrin Small - King's College London
Resource Type: Journal article
Publication Details: Nature genetics, Vol.48(2), pp.189-194
Publisher: United States
DOI: 10.1038/ng.3482
PMID: 26752265
PMCID: PMC4731307
ISSN: 1061-4036
eISSN: 1546-1718
Grant note: R01 EY015872 / NEI NIH HHS G0401527 / Medical Research Council Wellcome Trust P30 EY014104 / NEI NIH HHS R01 EY023512 / NEI NIH HHS C864/A14136 / Cancer Research UK R01EY022305 / NEI NIH HHS MR/K006584/1 / Medical Research Council R01 EY023754 / NEI NIH HHS R01 EY022305 / NEI NIH HHS SRF/01/010 / Department of Health KL2 TR000428 / NCATS NIH HHS R01 EY015473 / NEI NIH HHS U01 HG006389 / NHGRI NIH HHS UM1 CA182913 / NCI NIH HHS R01 EY010886 / NEI NIH HHS UL1 TR000427 / NCATS NIH HHS G1000143 / Medical Research Council R01 EY022306 / NEI NIH HHS
Language: English
Date published: 02/2016
Academic Unit: Ophthalmology and Visual Sciences
Record Identifier: 9983980051002771

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