Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2012-08-12

AUTHORS

Andrew P Morris, Benjamin F Voight, Tanya M Teslovich, Teresa Ferreira, Ayellet V Segré, Valgerdur Steinthorsdottir, Rona J Strawbridge, Hassan Khan, Harald Grallert, Anubha Mahajan, Inga Prokopenko, Hyun Min Kang, Christian Dina, Tonu Esko, Ross M Fraser, Stavroula Kanoni, Ashish Kumar, Vasiliki Lagou, Claudia Langenberg, Jian’an Luan, Cecilia M Lindgren, Martina Müller-Nurasyid, Sonali Pechlivanis, N William Rayner, Laura J Scott, Steven Wiltshire, Loic Yengo, Leena Kinnunen, Elizabeth J Rossin, Soumya Raychaudhuri, Andrew D Johnson, Antigone S Dimas, Ruth J F Loos, Sailaja Vedantam, Han Chen, Jose C Florez, Caroline Fox, Ching-Ti Liu, Denis Rybin, David J Couper, Wen Hong L Kao, Man Li, Marilyn C Cornelis, Peter Kraft, Qi Sun, Rob M van Dam, Heather M Stringham, Peter S Chines, Krista Fischer, Pierre Fontanillas, Oddgeir L Holmen, Sarah E Hunt, Anne U Jackson, Augustine Kong, Robert Lawrence, Julia Meyer, John R B Perry, Carl G P Platou, Simon Potter, Emil Rehnberg, Neil Robertson, Suthesh Sivapalaratnam, Alena Stančáková, Kathleen Stirrups, Gudmar Thorleifsson, Emmi Tikkanen, Andrew R Wood, Peter Almgren, Mustafa Atalay, Rafn Benediktsson, Lori L Bonnycastle, Noël Burtt, Jason Carey, Guillaume Charpentier, Andrew T Crenshaw, Alex S F Doney, Mozhgan Dorkhan, Sarah Edkins, Valur Emilsson, Elodie Eury, Tom Forsen, Karl Gertow, Bruna Gigante, George B Grant, Christopher J Groves, Candace Guiducci, Christian Herder, Astradur B Hreidarsson, Jennie Hui, Alan James, Anna Jonsson, Wolfgang Rathmann, Norman Klopp, Jasmina Kravic, Kaarel Krjutškov, Cordelia Langford, Karin Leander, Eero Lindholm, Stéphane Lobbens, Satu Männistö, Ghazala Mirza, Thomas W Mühleisen, Bill Musk, Melissa Parkin, Loukianos Rallidis, Jouko Saramies, Bengt Sennblad, Sonia Shah, Gunnar Sigurðsson, Angela Silveira, Gerald Steinbach, Barbara Thorand, Joseph Trakalo, Fabrizio Veglia, Roman Wennauer, Wendy Winckler, Delilah Zabaneh, Harry Campbell, Cornelia van Duijn, Andre G Uitterlinden, Albert Hofman, Eric Sijbrands, Goncalo R Abecasis, Katharine R Owen, Eleftheria Zeggini, Mieke D Trip, Nita G Forouhi, Ann-Christine Syvänen, Johan G Eriksson, Leena Peltonen, Markus M Nöthen, Beverley Balkau, Colin N A Palmer, Valeriya Lyssenko, Tiinamaija Tuomi, Bo Isomaa, David J Hunter, Lu Qi, , , , , , Alan R Shuldiner, Michael Roden, Ines Barroso, Tom Wilsgaard, John Beilby, Kees Hovingh, Jackie F Price, James F Wilson, Rainer Rauramaa, Timo A Lakka, Lars Lind, George Dedoussis, Inger Njølstad, Nancy L Pedersen, Kay-Tee Khaw, Nicholas J Wareham, Sirkka M Keinanen-Kiukaanniemi, Timo E Saaristo, Eeva Korpi-Hyövälti, Juha Saltevo, Markku Laakso, Johanna Kuusisto, Andres Metspalu, Francis S Collins, Karen L Mohlke, Richard N Bergman, Jaakko Tuomilehto, Bernhard O Boehm, Christian Gieger, Kristian Hveem, Stephane Cauchi, Philippe Froguel, Damiano Baldassarre, Elena Tremoli, Steve E Humphries, Danish Saleheen, John Danesh, Erik Ingelsson, Samuli Ripatti, Veikko Salomaa, Raimund Erbel, Karl-Heinz Jöckel, Susanne Moebus, Annette Peters, Thomas Illig, Ulf de Faire, Anders Hamsten, Andrew D Morris, Peter J Donnelly, Timothy M Frayling, Andrew T Hattersley, Eric Boerwinkle, Olle Melander, Sekar Kathiresan, Peter M Nilsson, Panos Deloukas, Unnur Thorsteinsdottir, Leif C Groop, Kari Stefansson, Frank Hu, James S Pankow, Josée Dupuis, James B Meigs, David Altshuler, Michael Boehnke, Mark I McCarthy,

ABSTRACT

To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis. More... »

PAGES

981-990

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  • Journal

    TITLE

    Nature Genetics

    ISSUE

    9

    VOLUME

    44

    Author Affiliations

  • Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
  • University of Pennsylvania - Perelman School of Medicine, Department of Pharmacology, Philadelphia, Pennsylvania, USA.
  • Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
  • Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
  • deCODE Genetics, Reykjavik, Iceland.
  • Center for Molecular Medicine, Karolinska University Hospital Solna, Stockholm, Sweden.
  • Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Research Unit of Molecular Epidemiology, Helmholtz Zentrum Muenchen, Neuherberg, Germany.
  • Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
  • Nantes University, Nantes, France.
  • Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
  • Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
  • Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
  • MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK.
  • Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
  • Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany.
  • University Lille 1, Laboratory of Mathematics, CNRS-UMR 8524, MODAL team, INRIA Lille Nord-Europe, Lille, France.
  • Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.
  • Harvard Biological and Biomedical Sciences Program, Harvard University, Boston, Massachusetts, USA.
  • Partners Center for Personalized Genomic Medicine, Boston, Massachusetts, USA.
  • National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, Massachusetts, USA.
  • Biomedical Sciences Research Center Al. Fleming, Vari, Greece.
  • Department of Preventive Medicine, Mount Sinai School of Medicine, New York, New York, USA.
  • Division of Genetics and Endocrinology, Children’s Hospital, Boston, Massachusetts, USA.
  • Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
  • Diabetes Research Center, Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
  • Division of Endocrinology and Metabolism, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Boston University Data Coordinating Center, Boston, Massachusetts, USA.
  • Collaborative Studies Coordinating Center, Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
  • Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
  • Department of Nutrition and Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
  • Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
  • Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
  • National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
  • Estonian Genome Center, University of Tartu, Tartu, Estonia.
  • Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.
  • HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway.
  • Centre for Genetic Epidemiology and Biostatistics, The University of Western Australia, Nedlands, Australia.
  • Institute of Genetic Epidemiology, Helmholtz Zentrum Muenchen, Neuherberg, Germany.
  • Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, University of Exeter, Magdalen Road, Exeter, UK.
  • Department of Internal Medicine, Levanger Hospital, Nord-Trøndelag Health Trust, Levanger, Norway.
  • Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
  • Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
  • Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
  • Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
  • Lund University Diabetes Centre, Department of Clinical Science Malmö, Scania University Hospital, Lund University, Malmö, Sweden.
  • Institute of Biomedicine, Physiology, University of Eastern Finland, Kuopio Campus, Kuopio, Finland.
  • Landspitali University Hospital, Reykjavík, Iceland.
  • Endocrinology-Diabetology Unit, Corbeil-Essonnes Hospital, Corbeil-Essonnes, France.
  • Pharmacogenomics Centre, Biomedical Research Institute, University of Dundee, Ninewells Hospital, Dundee, UK.
  • Icelandic Heart Association, Kopavogur, Iceland.
  • CNRS-UMR-8199, Institute of Biology and Lille 2 University, Pasteur Institute, Lille, France.
  • Vaasa Health Care Centre, Vaasa, Finland.
  • Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
  • Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
  • School of Population Health, The University of Western Australia, Nedlands, Australia.
  • School of Medicine and Pharmacology, University of Western Australia, Nedlands, Australia.
  • Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
  • Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
  • Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Australia.
  • University General Hospital Attikon, Athens, Greece.
  • South Karelia Central Hospital, Lappeenranta, Finland.
  • UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College London, London, UK.
  • Department of Clinical Chemistry and Central Laboratory, University of Ulm, Ulm, Germany.
  • Institute of Epidemiology II, Helmholtz Zentrum Muenchen, Neuherberg, Germany.
  • Centro Cardiologico Monzino, IRCCS, Milan, Italy.
  • MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Western General Hospital, Edinburgh, UK.
  • Netherland Genomics Initiative, Netherlands Consortium for Healthy Ageing and Centre for Medical Systems Biology, Rotterdam, The Netherlands.
  • Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Oxford, UK.
  • Molecular Medicine, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
  • Folkhälsan Research Center, Helsinki, Finland.
  • University Paris Sud 11, UMRS 1018, Villejuif, France.
  • Department of Medicine, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
  • Department of Social Services and Health Care, Jakobstad, Finland.
  • The members of these consortia are listed in the Supplementary Note
  • Program in Personalised and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
  • Department of Medicine/Metabolic Diseases, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
  • NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK.
  • Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway.
  • School of Pathology and Laboratory Medicine, The University of Western Australia, Nedlands, Australia.
  • Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.
  • Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.
  • Department of Medical Sciences, Uppsala University, Akademiska Sjukhuset, Uppsala, Sweden.
  • Department of Dietetics-Nutrition, Harokopio University, Athens, Greece.
  • Unit of General Practice, Oulu University Hospital, Oulu, Finland.
  • Pirkanmaa Hospital District, Tampere, Finland.
  • South Ostrobothnia Central Hospital, Seinäjoki, Finland.
  • Department of Medicine, Central Finland Central Hospital, Jyväskylä, Finland.
  • Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
  • Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Centre for Vascular Prevention, Danube-University Krems, Krems, Austria.
  • Division of Endocrinology and Diabetes, Department of Internal Medicine, University Medical Centre Ulm, Ulm, Germany.
  • Genomic Medicine, Imperial College London, Hammersmith Hospital, London, UK.
  • Department of Pharmacological Sciences, University of Milan, Milan, Italy.
  • Institute of Cardiovascular Science, University College London, London, UK.
  • Center for Non-Communicable Diseases Pakistan, Karachi, Pakistan.
  • Clinic of Cardiology, West German Heart Centre, University Hospital of Essen, University Duisburg-Essen, Essen, Germany.
  • Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.
  • Department of Statistics, University of Oxford, Oxford, UK.
  • Diabetes Genetics, Institute of Biomedical and Clinical Science, Peninsula Medical School, University of Exeter, Exeter, UK.
  • Human Genome Sequencing Center at Baylor College of Medicine, Houston, Texas, USA.
  • Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
  • Faculty of Medicine, University of Iceland, Reykjavík, Iceland.
  • Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, USA.
  • General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts, USA.
  • Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/ng.2383

    DOI

    http://dx.doi.org/10.1038/ng.2383

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1011024359

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/22885922


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