1. Genetics and Genomics

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
https://doi.org/10.7554/eLife.31977
Share this article
Cite this article
  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
(2018)
Integration of human pancreatic islet genomic data refines regulatory mechanisms at Type 2 Diabetes susceptibility loci
eLife 7:e31977.
https://doi.org/10.7554/eLife.31977
  2. Download BibTeX
  3. Download .RIS

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.

Data availability

The following data sets were generated
    1. M Thurner et al
    (2017) Islet open chromatin data
    Available through controlled access at the EGA website (study accession no: EGAS00001002592).
    http://www.ebi.ac.uk/ega/
    1. M Thurner et al
    (2017) Islet DNA methylation data
    Available through controlled access at the EGA website (study accession no: EGAS00001002592).
    http://www.ebi.ac.uk/ega/
The following previously published data sets were used

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.

Reviewing Editor

  1. Marcelo Nobrega, University of Chicago, United States

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.

Version 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.

Metrics

  • 4,404
    Page views
  • 647
    Downloads
  • 77
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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
(2018)
Integration of human pancreatic islet genomic data refines regulatory mechanisms at Type 2 Diabetes susceptibility loci
eLife 7:e31977.
https://doi.org/10.7554/eLife.31977

Share this article

https://doi.org/10.7554/eLife.31977

Categories and tags

Research organism

Further reading

    1. Genetics and Genomics
    2. Immunology and Inflammation

    Transposable elements regulate thymus development and function

    Jean-David Larouche, Céline M Laumont ... Claude Perreault
    Research Article

    Transposable elements (TEs) are repetitive sequences representing ~45% of the human and mouse genomes and are highly expressed by medullary thymic epithelial cells (mTECs). In this study, we investigated the role of TEs on T-cell development in the thymus. We performed multiomic analyses of TEs in human and mouse thymic cells to elucidate their role in T-cell development. We report that TE expression in the human thymus is high and shows extensive age- and cell lineage-related variations. TE expression correlates with multiple transcription factors in all cell types of the human thymus. Two cell types express particularly broad TE repertoires: mTECs and plasmacytoid dendritic cells (pDCs). In mTECs, transcriptomic data suggest that TEs interact with transcription factors essential for mTEC development and function (e.g., PAX1 and REL), and immunopeptidomic data showed that TEs generate MHC-I-associated peptides implicated in thymocyte education. Notably, AIRE, FEZF2, and CHD4 regulate small yet non-redundant sets of TEs in murine mTECs. Human thymic pDCs homogenously express large numbers of TEs that likely form dsRNA, which can activate innate immune receptors, potentially explaining why thymic pDCs constitutively secrete IFN ɑ/β. This study highlights the diversity of interactions between TEs and the adaptive immune system. TEs are genetic parasites, and the two thymic cell types most affected by TEs (mTEcs and pDCs) are essential to establishing central T-cell tolerance. Therefore, we propose that orchestrating TE expression in thymic cells is critical to prevent autoimmunity in vertebrates.

    1. Genetics and Genomics

    Deciphering the complex relationship between type 2 diabetes and fracture risk with both genetic and observational evidence

    Pianpian Zhao, Zhifeng Sheng ... Hou-Feng Zheng
    Research Article

    The ‘diabetic bone paradox’ suggested that type 2 diabetes (T2D) patients would have higher areal bone mineral density (BMD) but higher fracture risk than individuals without T2D. In this study, we found that the genetically predicted T2D was associated with higher BMD and lower risk of fracture in both weighted genetic risk score (wGRS) and two-sample Mendelian randomization (MR) analyses. We also identified ten genomic loci shared between T2D and fracture, with the top signal at SNP rs4580892 in the intron of gene RSPO3. And the higher expression in adipose subcutaneous and higher protein level in plasma of RSPO3 were associated with increased risk of T2D, but decreased risk of fracture. In the prospective study, T2D was observed to be associated with higher risk of fracture, but BMI mediated 30.2% of the protective effect. However, when stratified by the T2D-related risk factors for fracture, we observed that the effect of T2D on the risk of fracture decreased when the number of T2D-related risk factors decreased, and the association became non-significant if the T2D patients carried none of the risk factors. In conclusion, the genetically determined T2D might not be associated with higher risk of fracture. And the shared genetic architecture between T2D and fracture suggested a top signal around RSPO3 gene. The observed effect size of T2D on fracture risk decreased if the T2D-related risk factors could be eliminated. Therefore, it is important to manage the complications of T2D to prevent the risk of fracture.

    1. Genetics and Genomics

    The BTB-ZF gene Bm-mamo regulates pigmentation in silkworm caterpillars

    Songyuan Wu, Xiaoling Tong ... Fangyin Dai
    Research Article

    The color pattern of insects is one of the most diverse adaptive evolutionary phenotypes. However, the molecular regulation of this color pattern is not fully understood. In this study, we found that the transcription factor Bm-mamo is responsible for black dilute (bd) allele mutations in the silkworm. Bm-mamo belongs to the BTB zinc finger family and is orthologous to mamo in Drosophila melanogaster. This gene has a conserved function in gamete production in Drosophila and silkworms and has evolved a pleiotropic function in the regulation of color patterns in caterpillars. Using RNAi and clustered regularly interspaced short palindromic repeats (CRISPR) technology, we showed that Bm-mamo is a repressor of dark melanin patterns in the larval epidermis. Using in vitro binding assays and gene expression profiling in wild-type and mutant larvae, we also showed that Bm-mamo likely regulates the expression of related pigment synthesis and cuticular protein genes in a coordinated manner to mediate its role in color pattern formation. This mechanism is consistent with the dual role of this transcription factor in regulating both the structure and shape of the cuticle and the pigments that are embedded within it. This study provides new insight into the regulation of color patterns as well as into the construction of more complex epidermal features in some insects.