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Elife. 2018 Feb 7;7. pii: e31977. doi: 10.7554/eLife.31977.

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

Author information

The Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom.
Department of Pediatrics, University of California, San Diego, San Diego, United States.
Department of Twin Research and Genetic Epidemiology, Kings College London, London, United Kingdom.
MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, United Kingdom.
Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, United Kingdom.
Department of Cancer Biology, UCL Cancer Institute, University College London, London, United Kingdom.
Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, United Kingdom.


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.


GWAS; Type 2 Diabetes; epigenetics; evolutionary biology; genomics; human; human biology; human pancreatic islets; medicine

[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

MT, Mv, JT, AM, VN, AB, KG, AB, CB, CB, RL, SB, VR, AG No competing interests declared, MM Senior editor, <italic>eLife</italic>

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