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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

DOI

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  • 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
  • William N 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
  • Marit E Jørgensen
  • Torben Jørgensen
  • Allan Linneberg
  • DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium
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To characterise 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 cases and 132,532 controls of European ancestry after imputation using the 1000 Genomes multi-ethnic reference panel. Promising association signals were followed-up in additional data sets (of 14,545 or 7,397 T2D cases and 38,994 or 71,604 controls). 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 SNVs. 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.

OriginalsprogEngelsk
TidsskriftDiabetes
Vol/bind66
Udgave nummer11
Sider (fra-til)2888-2902
Antal sider14
ISSN0012-1797
DOI
StatusUdgivet - nov. 2017

ID: 51458319