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Nat Genet. 2016 Feb;48(2):189-94. doi: 10.1038/ng.3482. Epub 2016 Jan 11.

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

Author information

1
Department of Epidemiology and Biostatistics, Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
2
Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA.
3
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
4
Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, USA.
5
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
6
Division of Human Genetics, Genome Institute of Singapore, Singapore.
7
Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
8
Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
9
Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia.
10
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
11
Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
12
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
13
Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
14
Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, Wisconsin, USA.
15
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
16
Department of Ophthalmology, University of North Carolina, Chapel Hill, North Carolina, USA.
17
Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
18
Eye Academic Clinical Program, Duke-National University of Singapore Graduate Medical School, Singapore.
19
Section of Rheumatology and Clinical Epidemiology Unit, Boston University School of Medicine, Boston, Massachusetts, USA.
20
Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
21
Department of Ophthalmology, University of Iowa, College of Medicine, Iowa City, Iowa, USA.
22
Department of Anatomy and Cell Biology, University of Iowa, College of Medicine, Iowa City, Iowa, USA.
23
National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, London, UK.
24
Department of Ophthalmology, University College London, London, UK.
25
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
26
Eye Doctors of Washington, Chevy Chase, Maryland, USA.
27
Scripps Genome Center, University of California at San Diego, San Diego, California, USA.
28
Centre for Eye Research Australia, University of Melbourne, Melbourne, Victoria, Australia.
29
Department of Ophthalmology, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.
30
Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
31
Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts, USA.
32
Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge School of Clinical Medicine, Cambridge, UK.
33
Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA.
34
Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, USA.
35
Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Western Australia, Australia.
36
Medical Research Council Social Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, King's College London, London, UK.
37
Centre for Vision Research, Westmead Millennium Institute, University of Sydney, Westmead, New South Wales, Australia.
38
Duke-National University of Singapore Graduate Medical School, Singapore.
39
The Jackson Laboratory, Bar Harbor, Maine, USA.
40
Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, USA.
41
Department of Ophthalmology, West Virginia University Eye Institute, Morgantown, West Virginia, USA.
42
Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, USA.
43
Einhorn Clinical Research Center, Department of Ophthalmology, New York Eye and Ear Infirmary of Mount Sinai, New York, New York, USA.
44
Center for Systems Genomics, Pennsylvania State University, University Park, Pennsylvania, USA.
45
Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
46
Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA.
47
Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, California, USA.
48
Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, USA.
49
Department of Ophthalmology, School of Medicine, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece.
50
Department of Genetics, Stanford University School of Medicine, Palo Alto, California, USA.
51
Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
52
Genentech, San Francisco, California, USA.
53
Wilmer Eye Institute, Johns Hopkins University Hospital, Baltimore, Maryland, USA.
54
Hamilton Glaucoma Center, Shiley Eye Institute, University of California, San Diego, San Diego, California, USA.
55
Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, Georgia, USA.
56
James and Jean Culver Vision Discovery Institute, Georgia Regents University, Augusta, Georgia, USA.

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.

PMID:
26752265
PMCID:
PMC4731307
DOI:
10.1038/ng.3482
[Indexed for MEDLINE]
Free PMC Article

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