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

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