TIGER: The gene expression regulatory variation landscape of human pancreatic islets

Cell Rep. 2021 Oct 12;37(2):109807. doi: 10.1016/j.celrep.2021.109807.

Abstract

Genome-wide association studies (GWASs) identified hundreds of signals associated with type 2 diabetes (T2D). To gain insight into their underlying molecular mechanisms, we have created the translational human pancreatic islet genotype tissue-expression resource (TIGER), aggregating >500 human islet genomic datasets from five cohorts in the Horizon 2020 consortium T2DSystems. We impute genotypes using four reference panels and meta-analyze cohorts to improve the coverage of expression quantitative trait loci (eQTL) and develop a method to combine allele-specific expression across samples (cASE). We identify >1 million islet eQTLs, 53 of which colocalize with T2D signals. Among them, a low-frequency allele that reduces T2D risk by half increases CCND2 expression. We identify eight cASE colocalizations, among which we found a T2D-associated SLC30A8 variant. We make all data available through the TIGER portal (http://tiger.bsc.es), which represents a comprehensive human islet genomic data resource to elucidate how genetic variation affects islet function and translates into therapeutic insight and precision medicine for T2D.

Keywords: RNA-seq; allele-specific expression; beta cell; epigenomics; expression quantitative trait locus (eQTL); genome-wide association study (GWAS); pancreatic islets; regulatory variation; transcriptome; type 2 diabetes.

Publication types

  • Meta-Analysis
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cyclin D2 / genetics
  • Cyclin D2 / metabolism
  • Databases, Genetic
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / metabolism
  • Epigenome
  • Europe
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genetic Variation*
  • Genome-Wide Association Study
  • Genomics*
  • Humans
  • Islets of Langerhans / metabolism*
  • Phenotype
  • Quantitative Trait Loci
  • Transcriptome
  • Zinc Transporter 8 / genetics
  • Zinc Transporter 8 / metabolism

Substances

  • CCND2 protein, human
  • Cyclin D2
  • SLC30A8 protein, human
  • Zinc Transporter 8