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

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

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Authors

  • 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
  • Roman Wennauer
  • Johan G. Eriksson
  • Satu Mannisto
  • Leena Peltonen
  • Emmi Tikkanen
  • Guillaume Charpentier
  • Elodie Eury
  • Stephane Lobbens
  • Bruna Gigante
  • Karin Leander
  • Olga McLeod
  • Erwin P. Bottinger
  • Omri Gottesman
  • Douglas Ruderfer
  • Matthias Blueher
  • Peter Kovacs
  • Anke Tonjes
  • Nisa M. Maruthur
  • Chiara Scapoli
  • Raimund Erbel
  • Karl-Heinz Joeckel
  • 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
  • Ines 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
  • Josee Dupuis
  • Andrew P. Morris
  • Michael Boehnke (Lead / Corresponding author)
  • Mark I. McCarthy (Lead / Corresponding author)
  • Inga Prokopenko (Lead / Corresponding author)
  • for the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium

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Info

Original languageEnglish
Pages (from-to)2888-2902
Number of pages15
JournalDiabetes
Volume66
Issue number11
Early online date31 May 2017
DOIs
StatePublished - Nov 2017

Abstract

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 × 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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