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Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways

  • Robert A. Scott
  • , Vasiliki Lagou
  • , Ryan P. Welch
  • , Eleanor Wheeler
  • , May E. Montasser
  • , Jian'An Luan
  • , Reedik MäGi
  • , Rona J. Strawbridge
  • , Emil Rehnberg
  • , Stefan Gustafsson
  • , Stavroula Kanoni
  • , Laura J. Rasmussen-Torvik
  • , Loïc Yengo
  • , Cecile Lecoeur
  • , Dmitry Shungin
  • , Serena Sanna
  • , Carlo Sidore
  • , Paul C.D. Johnson
  • , J. Wouter Jukema
  • , Toby Johnson
  • Anubha Mahajan, Niek Verweij, Gudmar Thorleifsson, Jouke Jan Hottenga, Sonia Shah, Albert V. Smith, Bengt Sennblad, Christian Gieger, Perttu Salo, Markus Perola, Nicholas J. Timpson, David M. Evans, Beate St Pourcain, Ying Wu, Jeanette S. Andrews, Jennie Hui, Lawrence F. Bielak, Wei Zhao, Momoko Horikoshi, Pau Navarro, Aaron Isaacs, Jeffrey R. O'Connell, Kathleen Stirrups, Veronique Vitart, Caroline Hayward, Tõnu Esko, Evelin Mihailov, Ross M. Fraser, Tove Fall, Benjamin F. Voight, Soumya Raychaudhuri, Han Chen, Cecilia M. Lindgren, Andrew P. Morris, Nigel W. Rayner, Neil Robertson, Denis Rybin, Ching Ti Liu, Jacques S. Beckmann, Sara M. Willems, Peter S. Chines, Anne U. Jackson, Hyun Min Kang, Heather M. Stringham, Kijoung Song, Toshiko Tanaka, John F. Peden, Anuj Goel, Andrew A. Hicks, Ping An, Martina MüLler-Nurasyid, Anders Franco-Cereceda, Lasse Folkersen, Letizia Marullo, Hanneke Jansen, Albertine J. Oldehinkel, Marcel Bruinenberg, James S. Pankow, Kari E. North, Nita G. Forouhi, Ruth J.F. Loos, Sarah Edkins, Tibor V. Varga, Göran Hallmans, Heikki Oksa, Mulas Antonella, Ramaiah Nagaraja, Stella Trompet, Ian Ford, Stephan J.L. Bakker, Augustine Kong, Meena Kumari, Bruna Gigante, Christian Herder, Patricia B. Munroe, Mark Caulfield, Jula Antti, Massimo Mangino, Kerrin Small, Iva Miljkovic, Yongmei Liu, Mustafa Atalay, Wieland Kiess, Alan L. James, Fernando Rivadeneira, Andre G. Uitterlinden, Colin N.A. Palmer, Alex S.F. Doney, Gonneke Willemsen, Johannes H. Smit, Susan Campbell, Ozren Polasek, Lori L. Bonnycastle, Serge Hercberg, Maria Dimitriou, Jennifer L. Bolton, Gerard R. Fowkes, Peter Kovacs, Jaana LindströM, Tatijana Zemunik, Stefania Bandinelli, Sarah H. Wild, Hanneke V. Basart, Wolfgang Rathmann, Harald Grallert, Winfried Maerz, Marcus E. Kleber, Bernhard O. Boehm, Annette Peters, Peter P. Pramstaller, Michael A. Province, Ingrid B. Borecki, Nicholas D. Hastie, Igor Rudan, Harry Campbell, Hugh Watkins, Martin Farrall, Michael Stumvoll, Luigi Ferrucci, Dawn M. Waterworth, Richard N. Bergman, Francis S. Collins, Jaakko Tuomilehto, Richard M. Watanabe, Eco J.C. De Geus, Brenda W. Penninx, Albert Hofman, Ben A. Oostra, Bruce M. Psaty, Peter Vollenweider, James F. Wilson, Alan F. Wright, G. Kees Hovingh, Andres Metspalu, Matti Uusitupa, Patrik K.E. Magnusson, Kirsten O. Kyvik, Jaakko Kaprio, Jackie F. Price, George V. Dedoussis, Panos Deloukas, Pierre Meneton, Lars Lind, Michael Boehnke, Alan R. Shuldiner, Cornelia M. Van Duijn, Andrew D. Morris, Anke Toenjes, Patricia A. Peyser, John P. Beilby, Antje KöRner, Johanna Kuusisto, Markku Laakso, Stefan R. Bornstein, Peter E.H. Schwarz, Timo A. Lakka, Rainer Rauramaa, Linda S. Adair, George Davey Smith, Tim D. Spector, Thomas Illig, Ulf De Faire, Anders Hamsten, Vilmundur Gudnason, Mika Kivimaki, Aroon Hingorani, Sirkka M. Keinanen-Kiukaanniemi, Timo E. Saaristo, Dorret I. Boomsma, Kari Stefansson, Pim Van Der Harst, Josée Dupuis, Nancy L. Pedersen, Naveed Sattar, Tamara B. Harris, Francesco Cucca, Samuli Ripatti, Veikko Salomaa, Karen L. Mohlke, Beverley Balkau, Philippe Froguel, Anneli Pouta, Marjo Riitta Jarvelin, Nicholas J. Wareham, Nabila Bouatia-Naji, Mark I. McCarthy, Paul W. Franks, James B. Meigs, Tanya M. Teslovich, Jose C. Florez*, Claudia Langenberg, Erik Ingelsson, Inga Prokopenko, Iněs Barroso
*Corresponding author for this work
  • Cambridge University Hospitals NHS Foundation Trust
  • University of Oxford
  • University of Michigan, Ann Arbor
  • Wellcome Trust Sanger Institute
  • University of Maryland, Baltimore
  • University of Tartu
  • Karolinska Institutet
  • Northwestern University
  • Université de Lille
  • CNRS
  • Lund University
  • Umeå University
  • National Research Council of Italy
  • University of Sassari
  • University of Glasgow
  • Royal Netherlands Academy of Arts and Sciences
  • Leiden University
  • Queen Mary University of London
  • University of Groningen
  • deCODE Genetics
  • University of Amsterdam
  • University College London
  • Icelandic Heart Association
  • University of Iceland
  • Helmholtz Zentrum München - German Research Center for Environmental Health
  • National Institute for Health and Welfare
  • University of Helsinki
  • University of Bristol
  • University of North Carolina at Chapel Hill
  • Wake Forest University
  • Sir Charles Gairdner Hospital
  • University of Western Australia
  • PathWest Laboratory Medicine WA
  • University of Edinburgh
  • Erasmus University Rotterdam
  • University of Tartu
  • Broad Institute
  • University of Pennsylvania
  • Brigham and Women’s Hospital
  • Boston University
  • University of Lausanne
  • National Institutes of Health
  • GlaxoSmithKline
  • Illumina, Inc.
  • EURAC Research
  • Washington University St. Louis
  • Ludwig Maximilian University of Munich
  • University of Ferrara
  • University of Minnesota Twin Cities
  • Pirkanmaa Hospital District
  • German Diabetes Center Düsseldorf
  • King's College London
  • University of Pittsburgh
  • University of Eastern Finland
  • Leipzig University
  • Netherlands Consortium for Healthy Ageing (NCHAH) of the Genomics Initiative (NGI)
  • University of Dundee
  • VU University Medical Center
  • University of Split
  • Université Sorbonne Paris Cite-UREN (Unite de Recherche en Epidemiologie Nutritionnelle), U557 Inserm, U1125 Inra; Cnam, Université Paris 13, CRNH IdF
  • Harokopio University
  • Geriatric Department
  • Amsterdam University Medical Centers
  • Heinrich Heine University Düsseldorf
  • SYNLAB International GmbH
  • Heidelberg University 
  • Ludwigshafen Risk and Cardiovascular Health (LURIC) Study
  • Ulm University
  • General Central Hospital
  • University of Lübeck
  • Cedars-Sinai Medical Center
  • South Ostrobothnia Central Hospital
  • Hospital Universitario La Paz
  • University for Continuing Education Krems
  • University of Southern California
  • University of Washington
  • Group Health Cooperative
  • Odense Patient data Explorative Network (OPEN)
  • Institute of Regional Health Services Research
  • Centre de Recherche des Cordeliers
  • Uppsala University
  • Department of Veterans Affairs
  • Technische Universität Dresden
  • Hannover Medical School
  • University of Oulu
  • Finnish Diabetes Association
  • National Heart Lung and Blood Institute’s and Boston University’s Framingham Heart Study
  • Renal and Cardiovascular Epidemiology
  • Hammersmith Hospital
  • Imperial College London
  • PARCC - Paris-Centre de Recherche Cardiovasculaire
  • Oxford University Hospitals NHS Foundation Trust
  • Harvard University
  • Massachusetts General Hospital
  • Massachusetts Institute of Technology
  • University of Cambridge

Research output: Contribution to journalArticlepeer-review

Abstract

Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.

Original languageEnglish
Pages (from-to)991-1005
Number of pages15
JournalNature Genetics
Volume44
Issue number9
DOIs
Publication statusPublished - Sept 2012
Externally publishedYes

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