An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans

Robert A Scott; Laura J Scott; Reedik Mägi; Letizia Marullo; Kyle J Gaulton; Marika Kaakinen; Natalia Pervjakova; Tune H Pers; Andrew D Johnson; John D Eicher; Anne U Jackson; Teresa Ferreira; Yeji Lee; Clement Ma; Valgerdur Steinthorsdottir; Gudmar Thorleifsson; Lu Qi; Natalie R Van Zuydam; Anubha Mahajan; Han Chen; Peter Almgren; Ben F Voight; Harald Grallert; Martina Müller-Nurasyid; Janina S Ried; Nigel W Rayner; Neil Robertson; Lennart C Karssen; Elisabeth M van Leeuwen; Sara M Willems; Christian Fuchsberger; Phoenix Kwan; Tanya M Teslovich; Pritam Chanda; Man Li; Yingchang Lu; Christian Dina; Dorothee Thuillier; Loic Yengo; Longda Jiang; Thomas Sparso; Hans A Kestler; Himanshu Chheda; Lewin Eisele; Stefan Gustafsson; Mattias Frånberg; Rona J Strawbridge; Rafn Benediktsson; Astradur B Hreidarsson; Augustine Kong; Gunnar Sigurðsson; Nicola D Kerrison; Jian'an Luan; Liming Liang; Thomas Meitinger; Michael Roden; Barbara Thorand; Tõnu Esko; Evelin Mihailov; Caroline Fox; Ching-Ti Liu; Denis Rybin; Bo Isomaa; Valeriya Lyssenko; Tiinamaija Tuomi; David J Couper; James S Pankow; Niels Grarup; Christian T Have; Marit E Jørgensen; Torben Jørgensen; Allan Linneberg; Marilyn C Cornelis; Rob M van Dam; David J Hunter; Peter Kraft; Qi Sun; Sarah Edkins; Katharine R Owen; John R B Perry; Andrew R Wood; Eleftheria Zeggini; Juan Tajes-Fernandes; Goncalo R Abecasis; Lori L Bonnycastle; Peter S Chines; Heather M Stringham; Heikki A Koistinen; Leena Kinnunen; Bengt Sennblad; Thomas W Mühleisen; Markus M Nöthen; Sonali Pechlivanis; Damiano Baldassarre; Karl Gertow; Steve E Humphries; Elena Tremoli; Norman Klopp; Julia Meyer; Gerald Steinbach; Roman Wennauer; Johan G Eriksson; Satu Mӓnnistö; Leena Peltonen; Emmi Tikkanen; Guillaume Charpentier; Elodie Eury; Stéphane Lobbens; Bruna Gigante; Karin Leander; Olga McLeod; Erwin P Bottinger; Omri Gottesman; Douglas Ruderfer; Matthias Blüher; Peter Kovacs; Anke Tonjes; Nisa M Maruthur; Chiara Scapoli; Raimund Erbel; Karl-Heinz Jöckel; Susanne Moebus; Ulf de Faire; Anders Hamsten; Michael Stumvoll; Panagiotis Deloukas; Peter J Donnelly; Timothy M Frayling; Andrew T Hattersley; Samuli Ripatti; Veikko Salomaa; Nancy L Pedersen; Bernhard O Boehm; Richard N Bergman; Francis S Collins; Karen L Mohlke; Jaakko Tuomilehto; Torben Hansen; Oluf Pedersen; Inês Barroso; Lars Lannfelt; Erik Ingelsson; Lars Lind; Cecilia M Lindgren; Stephane Cauchi; Philippe Froguel; Ruth J F Loos; Beverley Balkau; Heiner Boeing; Paul W Franks; Aurelio Barricarte Gurrea; Domenico Palli; Yvonne T van der Schouw; David Altshuler; Leif C Groop; Claudia Langenberg; Nicholas J Wareham; Eric Sijbrands; Cornelia M van Duijn; Jose C Florez; James B Meigs; Eric Boerwinkle; Christian Gieger; Konstantin Strauch; Andres Metspalu; Andrew D Morris; Colin N A Palmer; Frank B Hu; Unnur Thorsteinsdottir; Kari Stefansson; Josée Dupuis; Andrew P Morris; Michael Boehnke; Mark I McCarthy; Inga Prokopenko; DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium

doi:10.2337/db16-1253

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An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans

Journal article

Open access

Peer reviewed

An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans

Robert A Scott, Laura J Scott, Reedik Mägi, Letizia Marullo, Kyle J Gaulton, Marika Kaakinen, Natalia Pervjakova, Tune H Pers, Andrew D Johnson, John D Eicher, …

Diabetes (New York, N.Y.), Vol.66(11), pp.2888-2902

01/11/2017

DOI: https://doi.org/10.2337/db16-1253

PMCID: PMC5652602

PMID: 28566273

Abstract

Diabetes Mellitus, Type 2 - genetics

Gene Expression Regulation - physiology

Genetic Variation

Genome-Wide Association Study

Humans

Whites

To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci ( < 5 × 10 ), including variants near the , , and genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.

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Title: An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans
Creators - without role: Robert A Scott - MRC Epidemiology Unit
Laura J Scott - University of Michigan–Ann Arbor
Reedik Mägi - University of Tartu
Letizia Marullo - University of Ferrara
Kyle J Gaulton - Wellcome Centre for Human Genetics
Marika Kaakinen - Genomics England
Natalia Pervjakova - University of Tartu
Tune H Pers - Broad Institute
Andrew D Johnson - Framingham Heart Study
John D Eicher - Framingham Heart Study
Anne U Jackson - University of Michigan–Ann Arbor
Teresa Ferreira - Wellcome Centre for Human Genetics
Yeji Lee - University of Michigan–Ann Arbor
Clement Ma - University of Michigan–Ann Arbor
Valgerdur Steinthorsdottir - deCODE Genetics
Gudmar Thorleifsson - deCODE Genetics
Lu Qi - Harvard University
Natalie R Van Zuydam - University of Oxford
Anubha Mahajan - University of Oxford
Han Chen - The University of Texas Health Science Center at Houston
Peter Almgren - Lund University
Ben F Voight - University of Pennsylvania
Harald Grallert - Helmholtz Zentrum München
Martina Müller-Nurasyid - Helmholtz Zentrum München
Janina S Ried - Helmholtz Zentrum München
Nigel W Rayner - University of Oxford
Neil Robertson - Wellcome Centre for Human Genetics
Lennart C Karssen - Erasmus MC
Elisabeth M van Leeuwen - Erasmus MC
Sara M Willems - MRC Epidemiology Unit
Christian Fuchsberger - University of Michigan–Ann Arbor
Phoenix Kwan - University of Michigan–Ann Arbor
Tanya M Teslovich - University of Michigan–Ann Arbor
Pritam Chanda - High Throughput Biology
Man Li - Bloomberg
Yingchang Lu - Icahn School of Medicine at Mount Sinai
Christian Dina - Centre Hospitalier Universitaire de Nantes
Dorothee Thuillier - European Genomic Institute for Diabetes
Loic Yengo - European Genomic Institute for Diabetes
Longda Jiang - Genomics England
Thomas Sparso - Novo Nordisk Foundation
Hans A Kestler - Leibniz Institute on Aging – Fritz Lipmann Institute
Himanshu Chheda - University of Helsinki
Lewin Eisele - Institut für Medizinische Informatik, Biometrie und Epidemiologie
Stefan Gustafsson - Science for Life Laboratory
Mattias Frånberg - Karolinska Institutet
Rona J Strawbridge - Karolinska Institutet
Rafn Benediktsson - University of Iceland
Astradur B Hreidarsson - Reykjavík University
Augustine Kong - deCODE Genetics
Gunnar Sigurðsson - Reykjavík University
Nicola D Kerrison - MRC Epidemiology Unit
Jian'an Luan - University of Cambridge
Liming Liang - Harvard University
Thomas Meitinger - Helmholtz Zentrum München
Michael Roden - German Center for Diabetes Research
Barbara Thorand - Helmholtz Zentrum München
Tõnu Esko - Broad Institute
Evelin Mihailov - University of Tartu
Caroline Fox - Framingham Heart Study
Ching-Ti Liu - Boston University
Denis Rybin - Boston University
Bo Isomaa - Department of Social Services and Health Care, Jakobstad, Finland
Valeriya Lyssenko - Lund University
Tiinamaija Tuomi - University of Helsinki
David J Couper - University of North Carolina at Chapel Hill
James S Pankow - University of Minnesota
Niels Grarup - Novo Nordisk Foundation
Christian T Have - Novo Nordisk Foundation
Marit E Jørgensen - Steno Diabetes Center
Torben Jørgensen - Capital Region of Denmark
Allan Linneberg - Capital Region of Denmark
Marilyn C Cornelis - Northwestern University
Rob M van Dam - Harvard University
David J Hunter - Harvard University
Peter Kraft - Harvard University
Qi Sun - Harvard University
Sarah Edkins - Wellcome Sanger Institute
Katharine R Owen - Oxford Centre for Diabetes, Endocrinology and Metabolism
John R B Perry - MRC Epidemiology Unit
Andrew R Wood - University of Exeter
Eleftheria Zeggini - Wellcome Sanger Institute
Juan Tajes-Fernandes - Wellcome Centre for Human Genetics
Goncalo R Abecasis - University of Michigan–Ann Arbor
Lori L Bonnycastle - National Institutes of Health
Peter S Chines - National Institutes of Health
Heather M Stringham - University of Michigan–Ann Arbor
Heikki A Koistinen - Finnish Institute for Health and Welfare
Leena Kinnunen - Finnish Institute for Health and Welfare
Bengt Sennblad - Karolinska Institutet
Thomas W Mühleisen - University of Bonn
Markus M Nöthen - University of Bonn
Sonali Pechlivanis - Institut für Medizinische Informatik, Biometrie und Epidemiologie
Damiano Baldassarre - Centro Cardiologico Monzino
Karl Gertow - Karolinska Institutet
Steve E Humphries - UCL Australia
Elena Tremoli - Centro Cardiologico Monzino
Norman Klopp - Helmholtz Zentrum München
Julia Meyer - Helmholtz Zentrum München
Gerald Steinbach - University of Ulm
Roman Wennauer - Erasmus MC
Johan G Eriksson - Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland
Satu Mӓnnistö - Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland
Leena Peltonen - Broad Institute
Emmi Tikkanen - University of Helsinki
Guillaume Charpentier - Endocrinology-Diabetology Unit, Corbeil-Essonnes Hospital, Corbeil-Essonnes, France
Elodie Eury - University of Lille
Stéphane Lobbens - CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille, France
Bruna Gigante - Karolinska Institutet
Karin Leander - Karolinska Institutet
Olga McLeod - Karolinska Institutet
Erwin P Bottinger - Icahn School of Medicine at Mount Sinai
Omri Gottesman - Icahn School of Medicine at Mount Sinai
Douglas Ruderfer - Icahn School of Medicine at Mount Sinai
Matthias Blüher - Department of Medicine, University of Leipzig, Leipzig, Germany
Peter Kovacs - Department of Medicine, University of Leipzig, Leipzig, Germany
Anke Tonjes - Department of Medicine, University of Leipzig, Leipzig, Germany
Nisa M Maruthur - Johns Hopkins University
Chiara Scapoli - University of Ferrara
Raimund Erbel - Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Essen, Germany
Karl-Heinz Jöckel - Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Essen, Germany
Susanne Moebus - Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Essen, Germany
Ulf de Faire - Karolinska Institutet
Anders Hamsten - Karolinska Institutet
Michael Stumvoll - Department of Medicine, University of Leipzig, Leipzig, Germany
Panagiotis Deloukas - Queen Mary University of London
Peter J Donnelly - University of Oxford
Timothy M Frayling - University of Exeter
Andrew T Hattersley - University of Exeter
Samuli Ripatti - Genomics
Veikko Salomaa - Department of Health, National Institute for Health and Welfare, Helsinki, Finland
Nancy L Pedersen - Karolinska Institutet
Bernhard O Boehm - Nanyang Technological University
Richard N Bergman - Cedars-Sinai Medical Center
Francis S Collins - National Human Genome Research Institute
Karen L Mohlke - Department of Genetics, University of North Carolina, Chapel Hill, NC
Jaakko Tuomilehto - King Abdulaziz University
Torben Hansen - University of Southern Denmark
Oluf Pedersen - University of Copenhagen
Inês Barroso - University of Cambridge
Lars Lannfelt - Uppsala University
Erik Ingelsson - Stanford University School of Medicine
Lars Lind - Uppsala University Hospital
Cecilia M Lindgren - Broad Institute
Stephane Cauchi - Genomics
Philippe Froguel - University of Lille
Ruth J F Loos - Icahn School of Medicine at Mount Sinai
Beverley Balkau - University of Paris-Sud
Heiner Boeing - German Institute of Human Nutrition
Paul W Franks - Umeå University
Aurelio Barricarte Gurrea - CIBER Epidemiology and Public Health, Madrid, Spain
Domenico Palli - Florence
Yvonne T van der Schouw - University Medical Center Utrecht
David Altshuler - Massachusetts General Hospital
Leif C Groop - University of Helsinki
Claudia Langenberg - University of Cambridge
Nicholas J Wareham - University of Cambridge
Eric Sijbrands - Erasmus MC
Cornelia M van Duijn - Netherlands Consortium for Healthy Ageing
Jose C Florez - Massachusetts General Hospital
James B Meigs - Massachusetts General Hospital
Eric Boerwinkle - Baylor College of Medicine
Christian Gieger - Helmholtz Zentrum München
Konstantin Strauch - Genetic Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany
Andres Metspalu - University of Tartu
Andrew D Morris - University of Edinburgh
Colin N A Palmer - University of Dundee
Frank B Hu - Brigham and Women's Hospital
Unnur Thorsteinsdottir - University of Iceland
Kari Stefansson - University of Iceland
Josée Dupuis - Boston University
Andrew P Morris - University of Liverpool
Michael Boehnke - University of Michigan–Ann Arbor
Mark I McCarthy - Oxford Biomedical Research
Inga Prokopenko - University of Oxford
DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium
Publication Details: Diabetes (New York, N.Y.), Vol.66(11), pp.2888-2902
Grant note: U01 DK078616 / NIDDK NIH HHS RC2 DK088389 / NIDDK NIH HHS U01 HG004402 / NHGRI NIH HHS HHSN268201100007C / NHLBI NIH HHS R01 DK072193 / NIDDK NIH HHS ZIA HG000024 / Intramural NIH HHS U01 DK085545 / NIDDK NIH HHS HHSN268201100005G / NHLBI NIH HHS RG/08/008/25291 / British Heart Foundation P30 DK020541 / NIDDK NIH HHS HHSN268201100011C / NHLBI NIH HHS R01 AG028555 / NIA NIH HHS HHSN268201100011I / NHLBI NIH HHS HHSN268201100007I / NHLBI NIH HHS U01 HG004399 / NHGRI NIH HHS G0601261 / Medical Research Council U01 DK085526 / NIDDK NIH HHS HHSN268201100010C / NHLBI NIH HHS UL1 RR025005 / NCRR NIH HHS HHSN268201100005C / NHLBI NIH HHS R01 HL059367 / NHLBI NIH HHS MC_UU_12015/1 / Medical Research Council R01 DK073490 / NIDDK NIH HHS MC_UU_12015/2 / Medical Research Council T32 HG000040 / NHGRI NIH HHS HHSN268201100005I / NHLBI NIH HHS 098017 / Wellcome Trust R01 DK058845 / NIDDK NIH HHS R01 DK078616 / NIDDK NIH HHS Wellcome Trust S10 OD018522 / NIH HHS HHSN268201100012C / NHLBI NIH HHS HHSN268201100008I / NHLBI NIH HHS N01HG65403 / NHGRI NIH HHS R01 DK098032 / NIDDK NIH HHS R01 DK106236 / NIDDK NIH HHS HHSN268201100006C / NHLBI NIH HHS P30 DK046200 / NIDDK NIH HHS K24 DK080140 / NIDDK NIH HHS UM1 CA167552 / NCI NIH HHS U01 HG007417 / NHGRI NIH HHS R01 AG010175 / NIA NIH HHS R01 DK093757 / NIDDK NIH HHS U01 DK105535 / NIDDK NIH HHS R01 DK101478 / NIDDK NIH HHS HHSN268201100008C / NHLBI NIH HHS MR/M501633/2 / Medical Research Council MR/K007017/1 / Medical Research Council R01 HL086694 / NHLBI NIH HHS UM1 CA186107 / NCI NIH HHS U01 DK062370 / NIDDK NIH HHS MR/M501633/1 / Medical Research Council R01 AG033067 / NIA NIH HHS P30 DK020572 / NIDDK NIH HHS R01 HG000376 / NHGRI NIH HHS R01 HL087641 / NHLBI NIH HHS HHSN268201100009C / NHLBI NIH HHS MC_PC_13040 / Medical Research Council RG/14/5/30893 / British Heart Foundation HHSN268201100009I / NHLBI NIH HHS
Identifiers: 9934245708331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article