Integration of human pancreatic islet genomic data refines regulatory mechanisms at Type 2 Diabetes susceptibility loci
- University of Oxford, United Kingdom
- University of California, San Diego, United States
- Kings College London, United Kingdom
- Barts and The London School of Medicine and Dentistry, United Kingdom
- University College London, United Kingdom
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
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Islet open chromatin dataAvailable through controlled access at the EGA website (study accession no: EGAS00001002592).
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Islet DNA methylation dataAvailable through controlled access at the EGA website (study accession no: EGAS00001002592).
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Transcription profiling by high throughput sequencing of human and mouse pancreatic islet-cellsAvailable from Array Express (accession no: E-MTAB-1294).
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Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variantsAvailable from NCBI GEO (accession no: GSE51312).
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Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variantsAvailable from Array Express (accession no: E-MTAB-1919).
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Integrative analysis of 111 reference human epigenomesAvailable from Epigenome Roadmap website.
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Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density ImputationAvailable from the Engage consortium website.
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Transcript Expression Data from Human Islets Links Regulatory Signals from Genome-Wide Association Studies for Type 2 Diabetes and Glycemic Traits to Their Downstream EffectorsAvailable from the EGA website (study accession no: EGAS00001002592).
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An Expanded Genome-Wide Association Study of Type 2 Diabetes in EuropeansAvailable from the Diagram Consortium website.
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Whole-genome Bisulfite Sequencing of Human Pancreatic Islets Reveals Novel Differentially Methylated Regions in Type 2 Diabetes PathogenesisAvailable through links in the Supplementary Data information.
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A high-resolution map of human evolutionary constraint using 29 mammalsAvailable through the institutional website.
Article and author information
Author details
Martijn van de Bunt
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.
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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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
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