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A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.
Fritsche, Lars G; Igl, Wilmar; Bailey, Jessica N Cooke; Grassmann, Felix; Sengupta, Sebanti; Bragg-Gresham, Jennifer L; Burdon, Kathryn P; Hebbring, Scott J; Wen, Cindy; Gorski, Mathias; Kim, Ivana K; Cho, David; Zack, Donald; Souied, Eric; Scholl, Hendrik P N; Bala, Elisa; Lee, Kristine E; Hunter, David J; Sardell, Rebecca J; Mitchell, Paul; Merriam, Joanna E; Cipriani, Valentina; Hoffman, Joshua D; Schick, Tina; Lechanteur, Yara T E; Guymer, Robyn H; Johnson, Matthew P; Jiang, Yingda; Stanton, Chloe M; Buitendijk, Gabriëlle H S; Zhan, Xiaowei; Kwong, Alan M; Boleda, Alexis; Brooks, Matthew; Gieser, Linn; Ratnapriya, Rinki; Branham, Kari E; Foerster, Johanna R; Heckenlively, John R; Othman, Mohammad I; Vote, Brendan J; Liang, Helena Hai; Souzeau, Emmanuelle; McAllister, Ian L; Isaacs, Timothy; Hall, Janette; Lake, Stewart; Mackey, David A; Constable, Ian J; Craig, Jamie E.
Afiliação
  • Fritsche LG; Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
  • Igl W; Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
  • Bailey JN; Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
  • Grassmann F; Institute of Human Genetics, University of Regensburg, Regensburg, Germany.
  • Sengupta S; Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
  • Bragg-Gresham JL; Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
  • Burdon KP; Kidney Epidemiology and Cost Center, Department of Internal Medicine-Nephrology, University of Michigan, Ann Arbor, Michigan, USA.
  • Hebbring SJ; School of Medicine, Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia.
  • Wen C; Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, Wisconsin, USA.
  • Gorski M; Department of Ophthalmology, University of California, San Diego and Veterans Affairs San Diego Health System, La Jolla, California, USA.
  • Kim IK; Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
  • Cho D; Retina Service, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
  • Zack D; Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • Souied E; Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • Scholl HP; Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • Bala E; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • Lee KE; Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • Hunter DJ; Institue de la Vision, Université Pierre et Marie Curie, Paris, France.
  • Sardell RJ; Hôpital Intercommunal de Créteil, Hôpital Henri Mondor, Université Paris Est Créteil, Créteil, France.
  • Mitchell P; Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • Merriam JE; Department of Ophthalmology, University of Bonn, Bonn, Germany.
  • Cipriani V; Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio, USA.
  • Hoffman JD; Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, USA.
  • Schick T; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
  • Lechanteur YT; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
  • Guymer RH; John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, USA.
  • Johnson MP; Centre for Vision Research, Department of Ophthalmology and Westmead Millennium Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
  • Jiang Y; Department of Ophthalmology, Columbia University, New York, New York, USA.
  • Stanton CM; University College London Institute of Ophthalmology, University College London, London, UK.
  • Buitendijk GH; Moorfields Eye Hospital, London, UK.
  • Zhan X; Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • Kwong AM; Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany.
  • Boleda A; Department of Ophthalmology, Radboud University Medical Centre, Nijmegen, the Netherlands.
  • Brooks M; Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia.
  • Gieser L; South Texas Diabetes and Obesity Institute, School of Medicine, University of Texas Rio Grande Valley, Brownsville, Texas, USA.
  • Ratnapriya R; Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
  • Branham KE; Medical Research Council (MRC) Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
  • Foerster JR; Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands.
  • Heckenlively JR; Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
  • Othman MI; Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
  • Vote BJ; Quantitative Biomedical Research Center, Department of Clinical Science, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  • Liang HH; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  • Souzeau E; Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
  • McAllister IL; Neurobiology, Neurodegeneration and Repair Laboratory (N-NRL), National Eye Institute, US National Institutes of Health, Bethesda, Maryland, USA.
  • Isaacs T; Neurobiology, Neurodegeneration and Repair Laboratory (N-NRL), National Eye Institute, US National Institutes of Health, Bethesda, Maryland, USA.
  • Hall J; Neurobiology, Neurodegeneration and Repair Laboratory (N-NRL), National Eye Institute, US National Institutes of Health, Bethesda, Maryland, USA.
  • Lake S; Neurobiology, Neurodegeneration and Repair Laboratory (N-NRL), National Eye Institute, US National Institutes of Health, Bethesda, Maryland, USA.
  • Mackey DA; Department of Ophthalmology and Visual Sciences, University of Michigan, Kellogg Eye Center, Ann Arbor, Michigan, USA.
  • Constable IJ; Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
  • Craig JE; Department of Ophthalmology and Visual Sciences, University of Michigan, Kellogg Eye Center, Ann Arbor, Michigan, USA.
Nat Genet ; 48(2): 134-43, 2016 Feb.
Article em En | MEDLINE | ID: mdl-26691988
ABSTRACT
Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Estudo de Associação Genômica Ampla / Degeneração Macular Tipo de estudo: Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2016 Tipo de documento: Article
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Estudo de Associação Genômica Ampla / Degeneração Macular Tipo de estudo: Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2016 Tipo de documento: Article