RT Journal Article
SR Electronic
T1 Integration of human pancreatic islet genomic data refines regulatory mechanisms at Type 2 Diabetes susceptibility loci
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 190892
DO 10.1101/190892
A1 Matthias Thurner
A1 Martijn van de Bunt
A1 Jason M Torres
A1 Anubha Mahajan
A1 Vibe Nylander
A1 Amanda J Bennett
A1 Kyle Gaulton
A1 Amy Barrett
A1 Carla Burrows
A1 Christopher G Bell
A1 Robert Lowe
A1 Stephan Beck
A1 Vardhman K Rakyan
A1 Anna L Gloyn
A1 Mark I McCarthy
YR 2018
UL http://biorxiv.org/content/early/2018/02/03/190892.abstract
AB 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.