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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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      1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 1 , 12 , 12 , 13 , 14 , 15 , 16 , 15 , 7 , 17 , 18 , 19 , 11 , 3 , 20 , 3 , 21 , 22 , 23 , 24 , 3 , 25 , 26 , 27 , 28 , 29 , 10 , 30 , 10 , 31 , 32 , 33 , 6 , 34 , 8 , 35 , 36 , 37 , 34 , 17 , 38 , 39 , 40 , 41 , 34 , 42 , 11 , 3 , 10 , 30 , 43 , 44 , 45 , 46 , 47 , 48 , 1 , 3 , 49 , 23 , 44 , 50 , 37 , 51 , 51 , 45 , 7 , 17 , 52 , 53 , 54 , EPIC-Norfolk Eye Study, ANZRAG consortium, 54 , 46 , 12 , 12 , 17 , 18 , 56 , 57 , 17 , 18 , 5 , 9 , 10 , 31 , 39 , 4 , 13 , 2 , 3 , 1 , 2
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          Abstract

          Primary open angle glaucoma (POAG) is a leading cause of blindness world-wide. To identify new susceptibility loci, we meta-analyzed GWAS results from 8 independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significant SNPs in two Australian studies (1,252 cases and 2,592 controls), 3 European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of top SNPs identified three novel loci: rs35934224[T] within TXNRD2 (odds ratio (OR) = 0.78, P = 4.05×10 −11 encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] within 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 novel targets for preventative therapies.

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          Most cited references57

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          Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis.

          Glaucoma is the leading cause of global irreversible blindness. Present estimates of global glaucoma prevalence are not up-to-date and focused mainly on European ancestry populations. We systematically examined the global prevalence of primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG), and projected the number of affected people in 2020 and 2040. Systematic review and meta-analysis. Data from 50 population-based studies (3770 POAG cases among 140,496 examined individuals and 786 PACG cases among 112 398 examined individuals). We searched PubMed, Medline, and Web of Science for population-based studies of glaucoma prevalence published up to March 25, 2013. Hierarchical Bayesian approach was used to estimate the pooled glaucoma prevalence of the population aged 40-80 years along with 95% credible intervals (CrIs). Projections of glaucoma were estimated based on the United Nations World Population Prospects. Bayesian meta-regression models were performed to assess the association between the prevalence of POAG and the relevant factors. Prevalence and projection numbers of glaucoma cases. The global prevalence of glaucoma for population aged 40-80 years is 3.54% (95% CrI, 2.09-5.82). The prevalence of POAG is highest in Africa (4.20%; 95% CrI, 2.08-7.35), and the prevalence of PACG is highest in Asia (1.09%; 95% CrI, 0.43-2.32). In 2013, the number of people (aged 40-80 years) with glaucoma worldwide was estimated to be 64.3 million, increasing to 76.0 million in 2020 and 111.8 million in 2040. In the Bayesian meta-regression model, men were more likely to have POAG than women (odds ratio [OR], 1.36; 95% CrI, 1.23-1.52), and after adjusting for age, gender, habitation type, response rate, and year of study, people of African ancestry were more likely to have POAG than people of European ancestry (OR, 2.80; 95% CrI, 1.83-4.06), and people living in urban areas were more likely to have POAG than those in rural areas (OR, 1.58; 95% CrI, 1.19-2.04). The number of people with glaucoma worldwide will increase to 111.8 million in 2040, disproportionally affecting people residing in Asia and Africa. These estimates are important in guiding the designs of glaucoma screening, treatment, and related public health strategies. Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.
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            Principal components analysis corrects for stratification in genome-wide association studies.

            Population stratification--allele frequency differences between cases and controls due to systematic ancestry differences-can cause spurious associations in disease studies. We describe a method that enables explicit detection and correction of population stratification on a genome-wide scale. Our method uses principal components analysis to explicitly model ancestry differences between cases and controls. The resulting correction is specific to a candidate marker's variation in frequency across ancestral populations, minimizing spurious associations while maximizing power to detect true associations. Our simple, efficient approach can easily be applied to disease studies with hundreds of thousands of markers.
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              Is Open Access

              METAL: fast and efficient meta-analysis of genomewide association scans

              Summary: METAL provides a computationally efficient tool for meta-analysis of genome-wide association scans, which is a commonly used approach for improving power complex traits gene mapping studies. METAL provides a rich scripting interface and implements efficient memory management to allow analyses of very large data sets and to support a variety of input file formats. Availability and implementation: METAL, including source code, documentation, examples, and executables, is available at http://www.sph.umich.edu/csg/abecasis/metal/ Contact: goncalo@umich.edu
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                17 December 2015
                11 January 2016
                February 2016
                11 July 2016
                : 48
                : 2
                : 189-194
                Affiliations
                [1 ]Department of Epidemiology and Biostatistics, Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, OH
                [2 ]Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA
                [3 ]Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
                [4 ]Department of Ophthalmology Duke University Medical Center, Durham, NC
                [5 ]QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
                [6 ]Division of Human Genetics, Genome Institute of Singapore
                [7 ]Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore
                [8 ]Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia
                [9 ]Department of Ophthalmology, Flinders University, Adelaide, SA, Australia
                [10 ]Department of Epidemiology, Harvard School of Public Health, Boston, MA
                [11 ]Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
                [12 ]Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK
                [13 ]Department of Medicine, Duke University Medical Center, Durham, NC
                [14 ]Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI
                [15 ]Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
                [16 ]Department of Ophthalmology, University of North Carolina, Chapel Hill, NC
                [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, MA
                [20 ]Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
                [21 ]Department of Ophthalmology University of Iowa, College of Medicine, Iowa City, IO
                [22 ]Department of Anatomy and Cell Biology, University of Iowa, College of Medicine, Iowa City, IO
                [23 ]National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital
                [24 ]Department of Ophthalmology, University of Cambridge, London
                [25 ]Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
                [26 ]Eye Doctors of Washington, Chevy Chase, MD
                [27 ]Scripps Genome Center, University of California at San Diego, San Diego, CA
                [28 ]Centre for Eye Research Australia, University of Melbourne, Australia
                [29 ]Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia
                [30 ]Department of Nutrition, Harvard School of Public Health, Boston, MA
                [31 ]Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, MA
                [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, FL
                [34 ]Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI
                [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, 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, ME
                [40 ]Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY
                [41 ]Department of Ophthalmology, West Virginia University Eye Institute, Morgantown, WV
                [42 ]Department of Epidemiology, University of Michigan, Ann Arbor, MI
                [43 ]Einhorn Clinical Research Center, Department of Ophthalmology, New York Eye and Ear Infirmary of Mt. Sinai, New York, NY
                [44 ]The Center for Systems Genomics, The Pennsylvania State University, University Park, PA
                [45 ]Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA
                [46 ]Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL
                [47 ]Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA
                [48 ]Department of Ophthalmology, Mayo Clinic, Rochester, MN
                [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, CA
                [51 ]Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Germany
                [52 ]Genentech, San Francisco, CA
                [53 ]Wilmer Eye Institute, Johns Hopkins University Hospital, Baltimore, MD
                [54 ]Hamilton Glaucoma Center, Shiley Eye Institute, University of California, San Diego, CA
                [56 ]Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, GA
                [57 ]James & Jean Culver Vision Discovery Institute, Georgia Regents University, Augusta, GA
                Author notes
                Correspondence: Janey L. Wiggs, janey_wiggs@ 123456meei.harvard.edu
                [55]

                A list of members and affiliations is provided in the Supplementary Note.

                [*]

                These authors contributed equally

                [#]

                These authors contributed equally.

                Article
                NIHMS744052
                10.1038/ng.3482
                4731307
                26752265
                b1417053-b807-4436-883c-981333881c20

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