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
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
Jason M Torres
The Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
Anubha Mahajan
The Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
Vibe Nylander
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
Amanda J Bennett
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
Kyle J Gaulton
Department of Pediatrics, University of California, San Diego, San Diego, United States
Amy Barrett
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
Carla Burrows
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
Christopher G Bell
Department of Twin Research and Genetic Epidemiology, Kings College London, London, United Kingdom; MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, United Kingdom
Robert Lowe
Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, United Kingdom
Stephan Beck
Department of Cancer Biology, UCL Cancer Institute, University College London, London, United Kingdom
Vardhman K Rakyan
Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, United Kingdom
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; Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, United Kingdom
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; 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.
