Genetic variant effects on gene expression in human pancreatic islets and their implications for T2D

Nat Commun. 2020 Sep 30;11(1):4912. doi: 10.1038/s41467-020-18581-8.

Abstract

Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, key tissues and cell-types required for functional inference are absent from large-scale resources. Here we explore the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using data from 420 donors. We find: (a) 7741 cis-eQTLs in islets with a replication rate across 44 GTEx tissues between 40% and 73%; (b) marked overlap between islet cis-eQTL signals and active regulatory sequences in islets, with reduced eQTL effect size observed in the stretch enhancers most strongly implicated in GWAS signal location; (c) enrichment of islet cis-eQTL signals with T2D risk variants identified in genome-wide association studies; and (d) colocalization between 47 islet cis-eQTLs and variants influencing T2D or glycemic traits, including DGKB and TCF7L2. Our findings illustrate the advantages of performing functional and regulatory studies in disease relevant tissues.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Blood Glucose / genetics*
  • Blood Glucose / metabolism
  • Cell Line, Tumor
  • Cohort Studies
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / genetics*
  • Diacylglycerol Kinase / genetics
  • Diacylglycerol Kinase / metabolism
  • Enhancer Elements, Genetic
  • Female
  • Gene Expression Regulation
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Humans
  • Islets of Langerhans / metabolism*
  • Male
  • Mice
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci*
  • RNA-Seq
  • Sequence Analysis, DNA
  • Transcription Factor 7-Like 2 Protein / genetics
  • Transcription Factor 7-Like 2 Protein / metabolism
  • Young Adult

Substances

  • Blood Glucose
  • TCF7L2 protein, human
  • Transcription Factor 7-Like 2 Protein
  • DGKD protein, human
  • Diacylglycerol Kinase