1. Genetics and Genomics
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Integration of human pancreatic islet genomic data refines regulatory mechanisms at Type 2 Diabetes susceptibility loci

  1. Matthias Thurner
  2. Martijn van de Bunt
  3. Jason M Torres
  4. Anubha Mahajan
  5. Vibe Nylander
  6. Amanda J Bennett
  7. Kyle J Gaulton
  8. Amy Barrett
  9. Carla Burrows
  10. Christopher G Bell
  11. Robert Lowe
  12. Stephan Beck
  13. Vardhman K Rakyan
  14. Anna L Gloyn
  15. Mark I McCarthy  Is a corresponding author
  1. University of Oxford, United Kingdom
  2. University of California, San Diego, United States
  3. Kings College London, United Kingdom
  4. Barts and The London School of Medicine and Dentistry, United Kingdom
  5. University College London, United Kingdom
Research Article
  • Cited 39
  • Views 3,490
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Cite this article as: eLife 2018;7:e31977 doi: 10.7554/eLife.31977

Abstract

Human genetic studies have emphasised the dominant contribution of pancreatic islet dysfunction to development of Type 2 Diabetes (T2D). However, limited annotation of the islet epigenome has constrained efforts to define the molecular mechanisms mediating the, largely regulatory, signals revealed by Genome-Wide Association Studies (GWAS). We characterised patterns of chromatin accessibility (ATAC-seq, n=17) and DNA methylation (whole-genome bisulphite sequencing, n=10) in human islets, generating high-resolution chromatin state maps through integration with established ChIP-seq marks. We found enrichment of GWAS signals for T2D and fasting glucose was concentrated in subsets of islet enhancers characterised by open chromatin and hypomethylation, with the former annotation predominant. At several loci (including CDC123, ADCY5, KLHDC5) the combination of fine-mapping genetic data and chromatin state enrichment maps, supplemented by allelic imbalance in chromatin accessibility pinpointed likely causal variants. The combination of increasingly-precise genetic and islet epigenomic information accelerates definition of causal mechanisms implicated in T2D pathogenesis.

Article and author information

Author details

  1. Matthias Thurner

    The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7329-9769
  2. Martijn van de Bunt

    The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6744-6125
  3. Jason M Torres

    The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  4. Anubha Mahajan

    The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  5. Vibe Nylander

    Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  6. Amanda J Bennett

    Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  7. Kyle J Gaulton

    Department of Pediatrics, University of California, San Diego, San Diego, United States
    Competing interests
    No competing interests declared.
  8. Amy Barrett

    Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  9. Carla Burrows

    Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  10. Christopher G Bell

    Department of Twin Research and Genetic Epidemiology, Kings College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  11. Robert Lowe

    Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, United Kingdom
    Competing interests
    No competing interests declared.
  12. Stephan Beck

    Department of Cancer Biology, UCL Cancer Institute, University College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  13. Vardhman K Rakyan

    Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, United Kingdom
    Competing interests
    No competing interests declared.
  14. Anna L Gloyn

    The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1205-1844
  15. Mark I McCarthy

    The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
    For correspondence
    mark.mccarthy@drl.ox.ac.uk
    Competing interests
    Mark I McCarthy, Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4393-0510

Funding

Wellcome (90367)

  • Matthias Thurner
  • Jason M Torres
  • Anna L Gloyn
  • Mark I McCarthy

Wellcome (90532)

  • Matthias Thurner
  • Jason M Torres
  • Anna L Gloyn
  • Mark I McCarthy

Wellcome (106130)

  • Matthias Thurner
  • Jason M Torres
  • Anna L Gloyn
  • Mark I McCarthy

Wellcome (98381)

  • Matthias Thurner
  • Jason M Torres
  • Anna L Gloyn
  • Mark I McCarthy

Wellcome (095101/Z/10/Z)

  • Matthias Thurner
  • Jason M Torres
  • Anna L Gloyn
  • Mark I McCarthy

Wellcome (200837/Z/16/Z)

  • Matthias Thurner
  • Jason M Torres
  • Anna L Gloyn
  • Mark I McCarthy

Wellcome (099673/Z/12/Z)

  • Matthias Thurner
  • Jason M Torres
  • Anna L Gloyn
  • Mark I McCarthy

Novo Nordisk

  • Martijn van de Bunt

Horizon 2020 Framework Programme (HEALTH-F4-2007-201413)

  • Vibe Nylander
  • Anna L Gloyn

Royal Society

  • Stephan Beck

National Institute for Health Research

  • Anna L Gloyn
  • Mark I McCarthy

National Institutes of Health (U01-DK105535)

  • Anna L Gloyn
  • Mark I McCarthy

National Institutes of Health (U01-DK085545)

  • Anna L Gloyn
  • Mark I McCarthy

National Institutes of Health (R01-DK098032)

  • Anna L Gloyn
  • Mark I McCarthy

National Institutes of Health (R01-MH090941)

  • Anna L Gloyn
  • Mark I McCarthy

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: The Human Research Ethics Board at the University of Alberta (Pro00001754), the University of Oxford's Oxford Tropical Research Ethics Committee (OxTREC Reference: 2-15), or the Oxfordshire Regional Ethics Committee B (REC reference: 09/H0605/2) approved the studies. All organ donors provided informed consent for use of pancreatic tissue in research.

Reviewing Editor

  1. Marcelo Nobrega, University of Chicago, United States

Publication history

  1. Received: September 13, 2017
  2. Accepted: February 6, 2018
  3. Accepted Manuscript published: February 7, 2018 (version 1)
  4. Version of Record published: February 27, 2018 (version 2)

Copyright

© 2018, Thurner et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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