Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-05-22

AUTHORS

Jason Flannick, Josep M. Mercader, Christian Fuchsberger, Miriam S. Udler, Anubha Mahajan, Jennifer Wessel, Tanya M. Teslovich, Lizz Caulkins, Ryan Koesterer, Francisco Barajas-Olmos, Thomas W. Blackwell, Eric Boerwinkle, Jennifer A. Brody, Federico Centeno-Cruz, Ling Chen, Siying Chen, Cecilia Contreras-Cubas, Emilio Córdova, Adolfo Correa, Maria Cortes, Ralph A. DeFronzo, Lawrence Dolan, Kimberly L. Drews, Amanda Elliott, James S. Floyd, Stacey Gabriel, Maria Eugenia Garay-Sevilla, Humberto García-Ortiz, Myron Gross, Sohee Han, Nancy L. Heard-Costa, Anne U. Jackson, Marit E. Jørgensen, Hyun Min Kang, Megan Kelsey, Bong-Jo Kim, Heikki A. Koistinen, Johanna Kuusisto, Joseph B. Leader, Allan Linneberg, Ching-Ti Liu, Jianjun Liu, Valeriya Lyssenko, Alisa K. Manning, Anthony Marcketta, Juan Manuel Malacara-Hernandez, Angélica Martínez-Hernández, Karen Matsuo, Elizabeth Mayer-Davis, Elvia Mendoza-Caamal, Karen L. Mohlke, Alanna C. Morrison, Anne Ndungu, Maggie C. Y. Ng, Colm O’Dushlaine, Anthony J. Payne, Catherine Pihoker, Wendy S. Post, Michael Preuss, Bruce M. Psaty, Ramachandran S. Vasan, N. William Rayner, Alexander P. Reiner, Cristina Revilla-Monsalve, Neil R. Robertson, Nicola Santoro, Claudia Schurmann, Wing Yee So, Xavier Soberón, Heather M. Stringham, Tim M. Strom, Claudia H. T. Tam, Farook Thameem, Brian Tomlinson, Jason M. Torres, Russell P. Tracy, Rob M. van Dam, Marijana Vujkovic, Shuai Wang, Ryan P. Welch, Daniel R. Witte, Tien-Yin Wong, Gil Atzmon, Nir Barzilai, John Blangero, Lori L. Bonnycastle, Donald W. Bowden, John C. Chambers, Edmund Chan, Ching-Yu Cheng, Yoon Shin Cho, Francis S. Collins, Paul S. de Vries, Ravindranath Duggirala, Benjamin Glaser, Clicerio Gonzalez, Ma Elena Gonzalez, Leif Groop, Jaspal Singh Kooner, Soo Heon Kwak, Markku Laakso, Donna M. Lehman, Peter Nilsson, Timothy D. Spector, E. Shyong Tai, Tiinamaija Tuomi, Jaakko Tuomilehto, James G. Wilson, Carlos A. Aguilar-Salinas, Erwin Bottinger, Brian Burke, David J. Carey, Juliana C. N. Chan, Josée Dupuis, Philippe Frossard, Susan R. Heckbert, Mi Yeong Hwang, Young Jin Kim, H. Lester Kirchner, Jong-Young Lee, Juyoung Lee, Ruth J. F. Loos, Ronald C. W. Ma, Andrew D. Morris, Christopher J. O’Donnell, Colin N. A. Palmer, James Pankow, Kyong Soo Park, Asif Rasheed, Danish Saleheen, Xueling Sim, Kerrin S. Small, Yik Ying Teo, Christopher Haiman, Craig L. Hanis, Brian E. Henderson, Lorena Orozco, Teresa Tusié-Luna, Frederick E. Dewey, Aris Baras, Christian Gieger, Thomas Meitinger, Konstantin Strauch, Leslie Lange, Niels Grarup, Torben Hansen, Oluf Pedersen, Philip Zeitler, Dana Dabelea, Goncalo Abecasis, Graeme I. Bell, Nancy J. Cox, Mark Seielstad, Rob Sladek, James B. Meigs, Steve S. Rich, Jerome I. Rotter, David Altshuler, Noël P. Burtt, Laura J. Scott, Andrew P. Morris, Jose C. Florez, Mark I. McCarthy, Michael Boehnke

ABSTRACT

Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10−3) and candidate genes from knockout mice (P = 5.2 × 10−3). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000–185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts. More... »

PAGES

71-76

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  • Journal

    TITLE

    Nature

    ISSUE

    7759

    VOLUME

    570

    Author Affiliations

  • Program in Medical & Population Genetics, Broad Institute, Cambridge, MA, USA
  • Department of Medicine, Harvard Medical School, Boston, MA, USA
  • Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA
  • Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
  • Diabetes Translational Research Center, Indiana University, Indianapolis, IN, USA
  • Regeneron Genetics Center, Regeneron Pharmaceuticals, Tarrytown, NY, USA
  • Instituto Nacional de Medicina Genómica, Mexico City, Mexico
  • Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
  • Cardiovascular Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
  • Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA
  • Broad Institute of MIT and Harvard, Cambridge, MA, USA
  • Department of Medicine, University of Texas Health Science Center, San Antonio, TX, USA
  • Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
  • Biostatistics Center, George Washington University, Rockville, MD, USA
  • Department of Medicine and Epidemiology, University of Washington, Seattle, WA, USA
  • Department of Human Genetics, The University of Chicago, Chicago, IL, USA
  • Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA
  • Division of Genome Research, Center for Genome Science, National Institute of Health, Chungcheongbuk-do, South Korea
  • National Heart Lung and Blood Institute’s Framingham Heart Study, Framingham, MA, USA
  • Greenland Centre for Health Research, University of Greenland, Nuuk, Greenland
  • Minerva Foundation Institute for Medical Research, Helsinki, Finland
  • Department of Medicin, Kuopio University Hospital, Kuopio, Finland
  • Geisinger Health System, Danville, PA, USA
  • Department of Clinical Experimental Research, Rigshospitalet, Copenhagen, Denmark
  • Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
  • Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
  • Department of Clinical Science, University of Bergen, Bergen, Norway
  • Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Harvard University, Boston, MA, USA
  • University of North Carolina Chapel Hill, Chapel Hill, NC, USA
  • Department of Genetics, University of North Carolina Chapel Hill, Chapel Hill, NC, USA
  • Human Genetics Center, Department of Epidemiology Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA
  • Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
  • Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA
  • Seattle Children’s Hospital, Seattle, WA, USA
  • Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
  • Charles R. Bronfman Institute of Personalized Medicine, Mount Sinai School of Medicine, New York, NY, USA
  • Department of Health Services, University of Washington, Seattle, WA, USA
  • Preventive Medicine & Epidemiology, Medicine, Boston University School of Medicine, Boston, MA, USA
  • Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK
  • Department of Epidemiology, University of Washington, Seattle, WA, USA
  • Instituto Mexicano del Seguro Social SXXI, Mexico City, Mexico
  • Department of Pediatrics, Yale University, New Haven, CT, USA
  • Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China
  • Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
  • Health Science Center, Department of Biochemistry, Faculty of Medicine, Kuwait University, Safat, Kuwait
  • Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
  • Department of Biochemistry, The Robert Larner M.D. College of Medicine, University of Vermont, Burlington, VT, USA
  • Department of Nutrition, Harvard School of Public Health, Boston, MA, USA
  • Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA
  • Danish Diabetes Academy, Odense, Denmark
  • Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore, Singapore
  • Department of Genetics, Albert Einstein College of Medicine, New York, NY, USA
  • South Texas Diabetes and Obesity Institute, Brownsville, TX, USA
  • Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
  • Imperial College Healthcare NHS Trust, Imperial College London, London, UK
  • Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore, Singapore
  • Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore
  • Department of Biomedical Science, Hallym University, Chuncheon, South Korea
  • Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
  • Unidad de Diabetes y Riesgo Cardiovascular, Instituto Nacional de Salud Pública, Cuernavaca, Mexico
  • Centro de Estudios en Diabetes, Mexico City, Mexico
  • Institute for Molecular Genetics Finland, University of Helsinki, Helsinki, Finland
  • National Heart and Lung Institute, Cardiovascular Sciences, Imperial College London, London, UK
  • Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
  • Department of Clinical Sciences, Medicine, Lund University, Malmö, Sweden
  • Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK
  • Duke-NUS Medical School Singapore, Singapore, Singapore
  • Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
  • Instituto de Investigacion Sanitaria del Hospital Universario LaPaz (IdiPAZ), University Hospital LaPaz, Autonomous University of Madrid, Madrid, Spain
  • Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA
  • Instituto Nacional de Ciencias Medicas y Nutricion, Mexico City, Mexico
  • Center for Non-Communicable Diseases, Karachi, Pakistan
  • Department of Business Data Convergence, Chungbuk National University, Gyeonggi-do, South Korea
  • The Mindich Child Health and Development Insititute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  • Clinical Research Centre, Centre for Molecular Medicine, Ninewells Hospital and Medical School, Dundee, UK
  • Intramural Administration Management Branch, National Heart Lung and Blood Institute, NIH, Framingham, MA, USA
  • Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Medical Research Institute, Ninewells Hospital and Medical School, Dundee, UK
  • Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA
  • Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
  • Department of Statistics and Applied Probability, National University of Singapore, Singapore, Singapore
  • Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
  • Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA
  • Instituto de Investigaciones Biomédicas, Departamento de Medicina Genómica y Toxicología, Universidad Nacional Autónoma de México, Mexico City, Mexico
  • German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
  • Deutsches Forschungszentrum für Herz-Kreislauferkrankungen (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
  • Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Neuherberg, Germany
  • Department of Medicine, University of Colorado Denver, Aurora, CO, USA
  • Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  • Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
  • Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
  • Department of Epidemiology, Colorado School of Public Health, Aurora, CO, USA
  • Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA
  • Blood Systems Research Institute, San Francisco, CA, USA
  • McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada
  • Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA
  • Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, USA
  • Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
  • Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
  • Department of Biostatistics, University of Liverpool, Liverpool, UK
  • Program in Metabolism, Broad Institute, Cambridge, MA, USA
  • Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41586-019-1231-2

    DOI

    http://dx.doi.org/10.1038/s41586-019-1231-2

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1115158118

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/31118516


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