Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-12

AUTHORS

Kyle J Gaulton, Teresa Ferreira, Yeji Lee, Anne Raimondo, Reedik Mägi, Michael E Reschen, Anubha Mahajan, Adam Locke, N William Rayner, Neil Robertson, Robert A Scott, Inga Prokopenko, Laura J Scott, Todd Green, Thomas Sparso, Dorothee Thuillier, Loic Yengo, Harald Grallert, Simone Wahl, Mattias Frånberg, Rona J Strawbridge, Hans Kestler, Himanshu Chheda, Lewin Eisele, Stefan Gustafsson, Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Lu Qi, Lennart C Karssen, Elisabeth M van Leeuwen, Sara M Willems, Man Li, Han Chen, Christian Fuchsberger, Phoenix Kwan, Clement Ma, Michael Linderman, Yingchang Lu, Soren K Thomsen, Jana K Rundle, Nicola L Beer, Martijn van de Bunt, Anil Chalisey, Hyun Min Kang, Benjamin F Voight, Gonçalo R Abecasis, Peter Almgren, Damiano Baldassarre, Beverley Balkau, Rafn Benediktsson, Matthias Blüher, Heiner Boeing, Lori L Bonnycastle, Erwin P Bottinger, Noël P Burtt, Jason Carey, Guillaume Charpentier, Peter S Chines, Marilyn C Cornelis, David J Couper, Andrew T Crenshaw, Rob M van Dam, Alex S F Doney, Mozhgan Dorkhan, Sarah Edkins, Johan G Eriksson, Tonu Esko, Elodie Eury, João Fadista, Jason Flannick, Pierre Fontanillas, Caroline Fox, Paul W Franks, Karl Gertow, Christian Gieger, Bruna Gigante, Omri Gottesman, George B Grant, Niels Grarup, Christopher J Groves, Maija Hassinen, Christian T Have, Christian Herder, Oddgeir L Holmen, Astradur B Hreidarsson, Steve E Humphries, David J Hunter, Anne U Jackson, Anna Jonsson, Marit E Jørgensen, Torben Jørgensen, Wen-Hong L Kao, Nicola D Kerrison, Leena Kinnunen, Norman Klopp, Augustine Kong, Peter Kovacs, Peter Kraft, Jasmina Kravic, Cordelia Langford, Karin Leander, Liming Liang, Peter Lichtner, Cecilia M Lindgren, Eero Lindholm, Allan Linneberg, Ching-Ti Liu, Stéphane Lobbens, Jian'an Luan, Valeriya Lyssenko, Satu Männistö, Olga McLeod, Julia Meyer, Evelin Mihailov, Ghazala Mirza, Thomas W Mühleisen, Martina Müller-Nurasyid, Carmen Navarro, Markus M Nöthen, Nikolay N Oskolkov, Katharine R Owen, Domenico Palli, Sonali Pechlivanis, Leena Peltonen, John R B Perry, Carl G P Platou, Michael Roden, Douglas Ruderfer, Denis Rybin, Yvonne T van der Schouw, Bengt Sennblad, Gunnar Sigurðsson, Alena Stančáková, Gerald Steinbach, Petter Storm, Konstantin Strauch, Heather M Stringham, Qi Sun, Barbara Thorand, Emmi Tikkanen, Anke Tonjes, Joseph Trakalo, Elena Tremoli, Tiinamaija Tuomi, Roman Wennauer, Steven Wiltshire, Andrew R Wood, Eleftheria Zeggini, Ian Dunham, Ewan Birney, Lorenzo Pasquali, Jorge Ferrer, Ruth J F Loos, Josée Dupuis, Jose C Florez, Eric Boerwinkle, James S Pankow, Cornelia van Duijn, Eric Sijbrands, James B Meigs, Frank B Hu, Unnur Thorsteinsdottir, Kari Stefansson, Timo A Lakka, Rainer Rauramaa, Michael Stumvoll, Nancy L Pedersen, Lars Lind, Sirkka M Keinanen-Kiukaanniemi, Eeva Korpi-Hyövälti, Timo E Saaristo, Juha Saltevo, Johanna Kuusisto, Markku Laakso, Andres Metspalu, Raimund Erbel, Karl-Heinz Jöcke, Susanne Moebus, Samuli Ripatti, Veikko Salomaa, Erik Ingelsson, Bernhard O Boehm, Richard N Bergman, Francis S Collins, Karen L Mohlke, Heikki Koistinen, Jaakko Tuomilehto, Kristian Hveem, Inger Njølstad, Panagiotis Deloukas, Peter J Donnelly, Timothy M Frayling, Andrew T Hattersley, Ulf de Faire, Anders Hamsten, Thomas Illig, Annette Peters, Stephane Cauchi, Rob Sladek, Philippe Froguel, Torben Hansen, Oluf Pedersen, Andrew D Morris, Collin N A Palmer, Sekar Kathiresan, Olle Melander, Peter M Nilsson, Leif C Groop, Inês Barroso, Claudia Langenberg, Nicholas J Wareham, Christopher A O'Callaghan, Anna L Gloyn, David Altshuler, Michael Boehnke, Tanya M Teslovich, Mark I McCarthy, Andrew P Morris, DIAbetes Genetics Replication And Meta-analysis Consortium

ABSTRACT

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease. More... »

PAGES

1415-1425

References to SciGraph publications

Journal

TITLE

Nature Genetics

ISSUE

12

VOLUME

47

Author Affiliations

  • Stanford University
  • Wellcome Centre for Human Genetics
  • University of Michigan–Ann Arbor
  • University of Oxford
  • University of Tartu
  • Wellcome Sanger Institute
  • Institute of Metabolic Science
  • Imperial College London
  • Broad Institute
  • University of Copenhagen
  • German Center for Diabetes Research
  • Stockholm University
  • Karolinska Institute
  • University of Ulm
  • Institute for Molecular Medicine Finland
  • Essen University Hospital
  • Uppsala University
  • Tulane University
  • Erasmus University Medical Center
  • Johns Hopkins University
  • Harvard University
  • Icahn School of Medicine at Mount Sinai
  • University of Pennsylvania
  • Lund University
  • University of Milan
  • University of Paris-Sud
  • National University Hospital of Iceland
  • Leipzig University
  • German Institute of Human Nutrition
  • National Human Genome Research Institute
  • Northwestern University
  • University of North Carolina at Chapel Hill
  • National University of Singapore
  • Folkhälsans Forskningscentrum
  • Institut de Biologie de Lille
  • Boston Children's Hospital
  • Umeå University
  • Kuopion Liikuntalääketieteen Tutkimuslaitos
  • Norwegian University of Science and Technology
  • University College London
  • Steno Diabetes Center
  • Aalborg University
  • National Institute for Health and Welfare
  • Hannover Medical School
  • Boston University
  • St Thomas' Hospital
  • Forschungszentrum Jülich
  • German Centre for Cardiovascular Research
  • University of Murcia
  • University of Bonn
  • Churchill Hospital
  • Istituto per lo Studio e la Prevenzione Oncologica
  • Levanger Hospital
  • Düsseldorf University Hospital
  • University Medical Center Utrecht
  • Science for Life Laboratory
  • Icelandic Heart Association
  • Ludwig Maximilian University of Munich
  • Brigham and Women's Hospital
  • University of Helsinki
  • University of Exeter
  • European Bioinformatics Institute
  • Instituto de Salud Carlos III
  • University of Barcelona
  • National Heart Lung and Blood Institute
  • Massachusetts General Hospital
  • Baylor College of Medicine
  • University of Minnesota
  • University of Iceland
  • Kuopio University Hospital
  • Uppsala University Hospital
  • Oulu University Hospital
  • Seinäjoen Keskussairaala
  • Finnish Diabetes Association
  • Central Finland Health Care District
  • University of Eastern Finland
  • Nanyang Technological University
  • University of Southern California
  • Minerva Foundation
  • King Abdulaziz University
  • The Arctic University of Norway
  • Queen Mary University of London
  • McGill University and Génome Québec Innovation Centre
  • University of Southern Denmark
  • University of Edinburgh
  • NIHR Cambridge Dementia Biomedical Research Unit
  • University of Liverpool
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/ng.3437

    DOI

    http://dx.doi.org/10.1038/ng.3437

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1041209717

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/26551672


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