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

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.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

3 Datasets 3 Publications

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD00001003946	DNA from 10 human pancreatic islet samples was processed for Whole-genome Bisulphite Sequencing. The resulting libraries were sequenced on an Illumina Hiseq 2000 to generate 100bp paired-end read data. The resulting fastq.gz and mapped bam files were deposited.	Illumina HiSeq 2000	10
EGAD00001003947	18 human pancreatic islet preparations derived from 17 donors were processed for ATAC-seq. The data was generated on an Illumina Hiseq 2500 sequencing machine to generate 50bp paired end read data. The resulting fastq.gz and mapped bam files were deposited.	Illumina HiSeq 2500	18
EGAD00010001695	Islet_HumanMethylation450K_ThurnerEtAl	HumanMethylation450K	41

Publications	Citations
Integration of human pancreatic islet genomic data refines regulatory mechanisms at Type 2 Diabetes susceptibility loci. Thurner M, van de Bunt M, Torres JM, Mahajan A, Nylander V, Bennett AJ, Gaulton KJ, Barrett A, Burrows C, Bell CG, Lowe R, Beck S, Rakyan VK, Gloyn AL, McCarthy MI. Elife 7: 2018 e31977	58
Deep learning models predict regulatory variants in pancreatic islets and refine type 2 diabetes association signals. Wesolowska-Andersen A, Zhuo Yu G, Nylander V, Abaitua F, Thurner M, Torres JM, Mahajan A, Gloyn AL, McCarthy MI. Elife 9: 2020 e51503	14
TIGER: The gene expression regulatory variation landscape of human pancreatic islets. Alonso L, Piron A, Morán I, Guindo-Martínez M, Bonàs-Guarch S, Atla G, Miguel-Escalada I, Royo R, Puiggròs M, Garcia-Hurtado X, Suleiman M, Marselli L, Esguerra JLS, Turatsinze JV, Torres JM, Nylander V, Chen J, Eliasson L, Defrance M, Amela R, MAGIC, Mulder H, Gloyn AL, Groop L, Marchetti P, Eizirik DL, Ferrer J, Mercader JM, Cnop M, Torrents D. Cell Rep 37: 2021 109807	31