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      Genome-wide analysis of multiethnic cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma

      1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ,   10 , 11 , 12 , 1 , 13 , 14 , 1 , 15 , 14 , 6 , 7 , 16 , 2 , 3 , 5 , 3 , 17 , 18 , 2 , 3 , 9 , 7 , 19 , 20 , 21 , 21 , 22 , 23 , 13 , 4 , 24 , 8 , 25 , 26 , 6 , 27 , 7 , 2 , 4 , 28 , 29 , 30 , 19 , 7 , 31 , 32 , 7 , 33 , 16 , 6 , 34 , 35 , 36 , 37 ,   38 , 4 , 5 , 39 , 27 , 28 , 29 , 40 , 41 , 7 , 26 , 42 , 43 , 44 , 45 , 46 , 7 , 47 , 48 , 13 , 49 , 50 , 51 , 52 , 11 , 53 , 54 , 7 , 47 , 48 , 2 , 3 , 4 , 5 , 55 , 11 , 7 , 48 , 6 , 7 , 56 , 57 , 14 , 6 , 58 , 25 , 32 , 45 , 56 , 57 , 1 , 6 , 7 , 1 , 46 , 16 , 2 , 3 , 4 , BMES GWAS Group 59 , NEIGHBORHOOD Consortium 59 , Wellcome Trust Case Control Consortium 2 59 , 60 , 13 , 38 , 46 , 45 , 7 , 1 , , 2 , 3 ,

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          Abstract

          Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma and IOP variability may herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multiethnic participants for IOP. We confirm genetic association of known loci for IOP and primary open angle glaucoma (POAG) and identify four new IOP loci located on chromosome 3q25.31 within the FNDC3B gene (p=4.19×10 −08 for rs6445055), two on chromosome 9 (p=2.80×10 −11 for rs2472493 near ABCA1 and p=6.39×10 −11 for rs8176693 within ABO) and one on chromosome 11p11.2 (best p=1.04×10 −11 for rs747782). Separate meta-analyses of four independent POAG cohorts, totaling 4,284 cases and 95,560 controls, show that three of these IOP loci are also associated with POAG.

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          Most cited references 60

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          Measuring inconsistency in meta-analyses.

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            Quantifying heterogeneity in a meta-analysis.

            The extent of heterogeneity in a meta-analysis partly determines the difficulty in drawing overall conclusions. This extent may be measured by estimating a between-study variance, but interpretation is then specific to a particular treatment effect metric. A test for the existence of heterogeneity exists, but depends on the number of studies in the meta-analysis. We develop measures of the impact of heterogeneity on a meta-analysis, from mathematical criteria, that are independent of the number of studies and the treatment effect metric. We derive and propose three suitable statistics: H is the square root of the chi2 heterogeneity statistic divided by its degrees of freedom; R is the ratio of the standard error of the underlying mean from a random effects meta-analysis to the standard error of a fixed effect meta-analytic estimate, and I2 is a transformation of (H) that describes the proportion of total variation in study estimates that is due to heterogeneity. We discuss interpretation, interval estimates and other properties of these measures and examine them in five example data sets showing different amounts of heterogeneity. We conclude that H and I2, which can usually be calculated for published meta-analyses, are particularly useful summaries of the impact of heterogeneity. One or both should be presented in published meta-analyses in preference to the test for heterogeneity. Copyright 2002 John Wiley & Sons, Ltd.
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              The number of people with glaucoma worldwide in 2010 and 2020.

               H A Quigley (2006)
              To estimate the number of people with open angle (OAG) and angle closure glaucoma (ACG) in 2010 and 2020. A review of published data with use of prevalence models. Data from population based studies of age specific prevalence of OAG and ACG that satisfied standard definitions were used to construct prevalence models for OAG and ACG by age, sex, and ethnicity, weighting data proportional to sample size of each study. Models were combined with UN world population projections for 2010 and 2020 to derive the estimated number with glaucoma. There will be 60.5 million people with OAG and ACG in 2010, increasing to 79.6 million by 2020, and of these, 74% will have OAG. Women will comprise 55% of OAG, 70% of ACG, and 59% of all glaucoma in 2010. Asians will represent 47% of those with glaucoma and 87% of those with ACG. Bilateral blindness will be present in 4.5 million people with OAG and 3.9 million people with ACG in 2010, rising to 5.9 and 5.3 million people in 2020, respectively. Glaucoma is the second leading cause of blindness worldwide, disproportionately affecting women and Asians.
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                12 August 2014
                31 August 2014
                October 2014
                01 April 2015
                : 46
                : 10
                : 1126-1130
                Affiliations
                [1 ]Department of Twin Research and Genetic Epidemiology, King’s College London, UK
                [2 ]Singapore Eye Research Institute, Singapore National Eye Centre, Singapore
                [3 ]Department of Ophthalmology, National University of Singapore and National University Health System, Singapore
                [4 ]Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore
                [5 ]Duke-National University of Singapore, Graduate Medical School, Singapore
                [6 ]Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands
                [7 ]Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands
                [8 ]Statistical Genetics, QIMR Berghofer Medical Research Institute Royal Brisbane Hospital, Brisbane, Australia 4029
                [9 ]Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA
                [10 ]Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health and, Baltimore, MD, USA
                [11 ]National Human Genome Research Institute, National Institutes of Health, Baltimore, MD 21224, USA
                [12 ]MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh
                [13 ]Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Australia
                [14 ]Department of Ophthalmology, University Medical Center Mainz, Mainz, Germany
                [15 ]Institute of Ophthalmology, University College London, UK
                [16 ]deCODE/Amgen, 101 Reykjavik, Iceland
                [17 ]Division of Human Genetics, Genome Institute of Singapore, Singapore
                [18 ]Eye Clinic, 105 Reykjavik, Iceland
                [19 ]Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital University of Medical Science, Beijing, China 100730
                [20 ]Department of Internal Medicine II, University Medical Center Mainz, Mainz, Germany
                [21 ]Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA
                [22 ]NHS Princess Alexandra Eye Pavilion, Edinburgh, UK
                [23 ]Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Germany
                [24 ]Department of Statistics and Applied Probability, National University of Singapore, Singapore
                [25 ]Duke University, Duke Eye Center, Durham, NC, USA
                [26 ]Department of Ophthalmology, Duke University Medical Center, Durham, NC, USA
                [27 ]Institute of Medical Biometry and Statistics, University Hospital Schleswig-Holstein, Lübeck, Germany
                [28 ]Inserm, UMR774, Lille, France
                [29 ]Université Lille 2, Lille, France
                [30 ]Institut Pasteur de Lille, France
                [31 ]Centre for Population Health Sciences, University of Edinburgh Medical School, Edinburgh, UK
                [32 ]Channing Division of Network Medicine, Harvard Medical School, Boston, MA, USA
                [33 ]Department of Ophthalmology, Landspitali National University Hospital, Reykjavik, Iceland
                [34 ]Human Genetics & Genomic Medicine, Faulty of Medicine, University of Southampton, UK
                [35 ]Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, USA
                [36 ]Genetic Epidemiology, QIMR Berghofer Medical Research Institute Royal Brisbane Hospital, Brisbane, Australia
                [37 ]Department of Ophthalmology, University Medical Center Groningen, the Netherlands
                [38 ]Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Australia.
                [39 ]Department of Medicine, National University of Singapore and National University Health System, Singapore
                [40 ]Centre Hospitalier Régional Universitaire de Lille, France
                [41 ]Department of Ophthalmology, Portsmouth Hospitals NHS Trust, Portsmouth, UK
                [42 ]Department of Medicine, Duke University Medical Center, Durham, NC, USA
                [43 ]Faculty of Medicine, University of Iceland, Reykjavik, Iceland
                [44 ]The University of Queensland, Diamantina Institute, Woollongabba, Australia
                [45 ]Dept. Ophthalmology Harvard Medical School and Massachusetts Eye and Ear Infirmary, Boston, MA, USA
                [46 ]Department of Ophthalmology, Flinders University, Adelaide, Australia
                [47 ]Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands
                [48 ]Netherlands Consortium for Healthy Ageing, Netherlands Genomics Initiative, The Hague, the Netherlands
                [49 ]Institute of Clinical Chemistry and Laboratory Medicine, Mainz, Germany
                [50 ]Netherlands Institute for Neuroscience, Amsterdam, the Netherlands
                [51 ]Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands
                [52 ]Department of Ophthalmology, Academic Medical Center, Amsterdam, the Netherlands
                [53 ]School of Women’s and Infants’ Health, The University of Western Australia, Perth, Australia
                [54 ]Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands
                [55 ]Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, UK
                [56 ]Univ. Bordeaux, ISPED, Bordeaux, France
                [57 ]Inserm, Centre INSERM U897-Epidemiologie-Biostatistique Bordeaux, France
                [58 ]Glaucoma Service, the Rotterdam Eye Hospital, Rotterdam, the Netherlands
                [59 ]The full list of collaborators participating in these consortia is in the Supplementary Note
                [60 ]NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK
                Author notes

                AUTHOR CONTRIBUTIONS: P.G.H., C-Y.C., H.S., S.M., J.N.CB and R.W. performed analyses and drafted the manuscript; S.M., A.J.L., J.E.B-W., V.V., L.R.P., N.P., C.D., A.V., D.A.M., J.E.C., J.L.W., C.M.vD., C.J.H. and T.A. jointly conceived the project and supervised the work; P.G.H, H.S., R.W., A.N., A.W.H., A.M., C.V., R.H., G.T., B.A.O., S-M.S., W.D.R., E.V., C-C.K., D.D.G.D., J.L., J.L.H., Y.X.W., F.R., P.S.W., H.G.L., A.B.O., J.Z.L., B.W.F., R.C.W.W., T.Z., S.E.S., Y-Y.T., G.C-P, X.L., RR.A., J.E.R., A.S., Y.Z., C.B., A.I.I., L.X., J.F.W., J.H.K., L.C.K., K.S., V.J., A.G.U., N.M.J., U.T., J.R.V., N.A., S.E., S.E.M., N.G.M., S.Y., E-S.T., E.M.Vl., P.A., J.K., M.A.H., F.J., P.L., A.H., S.J.L., R.F., L.K., P.T.V.M.Dj., K.J.L., C.L.S., C.E.P., L.M.E.vK., C.M., C.C.W.K., K.P.B., T.D.S., T-Y.W., D.A.M., J.E.C. and A.B.S. were responsible for cohort-specific activities, data generation and analyses; T.L.Y. and K.S.S. responsible for expression and eQTL work; P.G.H., C-Y.C., H.S., S.M., T-Y.W., D.A.M., J.L.W., C.M.vD. and C.J.H. critically reviewed the manuscript.

                [**]

                These authors jointly directed this work

                []Correspondence should be addressed to aung_tin@ 123456yahoo.co.uk or chris.hammond@ 123456kcl.ac.uk
                Article
                EMS59965
                10.1038/ng.3087
                4177225
                25173106
                Categories
                Article

                Genetics

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