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

Research output: Contribution to journalArticle

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. © 2017 by the American Diabetes Association.

Details

Authors
  • Robert A. Scott
  • Laura J Scott
  • Reedik Mägi
  • Letizia Marullo
  • Kyle J Gaulton
  • Marika Kaakinen
  • Peter Almgren
  • Valeriya Lyssenko
  • Leif Groop
  • Paul Franks
  • DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium
Organisations
External organisations
  • University of Michigan
  • University of Ferrara
  • Stanford University
  • University of Oxford
  • Imperial College London
  • Umeå University
  • University of Cambridge
  • University of Tartu
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
  • Medical Genetics

Keywords

  • Caucasian, gene expression regulation, genetic variation, genetics, genome-wide association study, human, non insulin dependent diabetes mellitus, physiology, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Gene Expression Regulation, Genetic Variation, Genome-Wide Association Study, Humans
Original languageEnglish
Pages (from-to)2888-2902
Number of pages15
JournalDiabetes
Volume66
Issue number11
Publication statusPublished - 2017
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

Cited By :4 Export Date: 25 January 2018