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

Robert A. Scott; Laura J. Scott; Reedik Maegi; 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 Mueller-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 Franberg; Rona J. Strawbridge; Rafn Benediktsson; Astradur B. Hreidarsson; Augustine Kong; Gunnar Sigurdsson; Nicola D. Kerrison; Jian'an Luan; Liming Liang; Thomas Meitinger; Michael Roden; Barbara Thorand; Tonu 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. Jorgensen; Torben Jorgensen; 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. Muehleisen; Markus M. Noethen; Sonali Pechlivanis; Damiano Baldassarre; Karl Gertow; Steve E. Humphries; Elena Tremoli; Norman Klopp; Julia Meyer; Gerald Steinbach; Diabetes Genetics Replicat; Inga Prokopenko

doi:10.2337/db16-1253

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

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

Robert A. Scott, Laura J. Scott, Reedik Maegi, 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

PMID: 28566273

Abstract

Endocrinology & Metabolism

Life Sciences & Biomedicine

Science & Technology

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 (P < 5 x 10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 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: Robert A. Scott - University of Cambridge
Laura J. Scott - University of Michigan–Ann Arbor
Reedik Maegi - University of Tartu
Letizia Marullo - University of Ferrara
Kyle J. Gaulton - Stanford University
Marika Kaakinen - Genomics England
Natalia Pervjakova - University of Tartu
Tune H. Pers - University of Copenhagen
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 - Amgen
Gudmar Thorleifsson - Amgen
Lu Qi - Harvard University
Natalie R. Van Zuydam - University of Oxford
Anubha Mahajan - Wellcome Centre for Human Genetics
Han Chen - The University of Texas Health Science Center at Houston
Peter Almgren - Scania
Ben F. Voight - Supreme Council Of Health
Harald Grallert - German Center for Diabetes Research
Martina Mueller-Nurasyid - Helmholtz Zentrum München
Janina S. Ried - Helmholtz Zentrum München
Nigel W. Rayner - Wellcome Centre for Human Genetics
Neil Robertson - University of Oxford
Lennart C. Karssen - Erasmus MC
Elisabeth M. Van Leeuwen - Erasmus MC
Sara M. Willems - University of Cambridge
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 - Johns Hopkins University
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 - University of Copenhagen
Hans A. Kestler - Leibniz Institute on Aging - Fritz Lipmann Institute (FLI)
Himanshu Chheda - Institute for Molecular Medicine Finland
Lewin Eisele - Institut für Medizinische Informatik, Biometrie und Epidemiologie
Stefan Gustafsson - Science for Life Laboratory
Mattias Franberg - Karolinska Institutet
Rona J. Strawbridge - Karolinska Institutet
Rafn Benediktsson - University of Iceland
Astradur B. Hreidarsson - Landspitali Univ Hosp, Reykjavik, Iceland
Augustine Kong - deCODE Genetics
Gunnar Sigurdsson - Landspitali Univ Hosp, Reykjavik, Iceland
Nicola D. Kerrison - MRC Epidemiology Unit
Jian'an Luan - University of Cambridge
Liming Liang - Harvard University
Thomas Meitinger - Helmholtz Zentrum München
Michael Roden - Deutsches Diabetes-Zentrum e.V.
Barbara Thorand - Deutsches Diabetes-Zentrum e.V.
Tonu Esko - University of Tartu
Evelin Mihailov - University of Tartu
Caroline Fox - Brigham and Women's Hospital
Ching-Ti Liu - Boston University
Denis Rybin - Boston University
Bo Isomaa - Folkhalsan Res Ctr, Helsinki, Finland
Valeriya Lyssenko - Lund University
Tiinamaija Tuomi - Folkhalsan Res Ctr, Helsinki, Finland
David J. Couper - University of North Carolina at Chapel Hill
James S. Pankow - University of Minnesota
Niels Grarup - Novo Nordisk Foundation
Christian T. Have - University of Copenhagen
Marit E. Jorgensen - Steno Diabet Ctr, Gentofte, Denmark
Torben Jorgensen - Capital Region of Denmark
Allan Linneberg - Capital Region of Denmark
Marilyn C. Cornelis - Northwestern University
Rob M. Van Dam - National University Health System
David J. Hunter - Supreme Council Of Health
Peter Kraft - Harvard University
Qi Sun - Harvard University
Sarah Edkins - Wellcome Sanger Institute
Katharine R. Owen - University of Oxford
John R. B. Perry - University of Cambridge
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 Human Genome Research Institute
Peter S. Chines - National Human Genome Research Institute
Heather M. Stringham - University of Michigan–Ann Arbor
Heikki A. Koistinen - Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland
Leena Kinnunen - Finnish Institute for Health and Welfare
Bengt Sennblad - Karolinska Institutet
Thomas W. Muehleisen - University of Bonn
Markus M. Noethen - University of Bonn
Sonali Pechlivanis - Institut für Medizinische Informatik, Biometrie und Epidemiologie
Damiano Baldassarre - Centro Cardiologico Monzino
Karl Gertow - Karolinska Institutet
Steve E. Humphries - University College London
Elena Tremoli - Centro Cardiologico Monzino
Norman Klopp - Medizinische Hochschule Hannover
Julia Meyer - Helmholtz Zentrum München
Gerald Steinbach - Universität Ulm
Diabetes Genetics Replicat
Inga Prokopenko - School of Biosciences
Publication Details: Diabetes (New York, N.Y.), Vol.66(11), pp.2888-2902
Publisher: Amer Diabetes Assoc
Number of pages: 15
Date published: 01/11/2017
Grant note: MR/M501633/1; MC_PC_13046; MC_PC_13048; MC_UU_12015/2; MC_UU_12015/1; G0601261; MR/K007017/1; MR/M501633/2 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) UL1RR025005 / NIH and NIH Roadmap for Medical Research; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA HHSN268201100005C; HHSN268201100006C; HHSN268201100007C; HHSN268201100008C; HHSN268201100009C; HHSN268201100010C; HHSN268201100011C; HHSN268201100012C; R01HL087641; R01HL59367; R01HL086694 / National Heart, Lung, and Blood Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) HHSN268200625226C / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA U01HG004402 / National Human Genome Research Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI)
Identifiers: 99929047002346
Academic Unit: School of Biosciences
Language: English
Resource Type: Journal article

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

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