The genetic regulatory signature of type 2 diabetes in human skeletal muscle

Nat Commun. 2016 Jun 29;7:11764. doi: 10.1038/ncomms11764.

Abstract

Type 2 diabetes (T2D) results from the combined effects of genetic and environmental factors on multiple tissues over time. Of the >100 variants associated with T2D and related traits in genome-wide association studies (GWAS), >90% occur in non-coding regions, suggesting a strong regulatory component to T2D risk. Here to understand how T2D status, metabolic traits and genetic variation influence gene expression, we analyse skeletal muscle biopsies from 271 well-phenotyped Finnish participants with glucose tolerance ranging from normal to newly diagnosed T2D. We perform high-depth strand-specific mRNA-sequencing and dense genotyping. Computational integration of these data with epigenome data, including ATAC-seq on skeletal muscle, and transcriptome data across diverse tissues reveals that the tissue-specific genetic regulatory architecture of skeletal muscle is highly enriched in muscle stretch/super enhancers, including some that overlap T2D GWAS variants. In one such example, T2D risk alleles residing in a muscle stretch/super enhancer are linked to increased expression and alternative splicing of muscle-specific isoforms of ANK1.

Publication types

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

MeSH terms

  • Alleles
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / metabolism*
  • Epigenomics
  • Female
  • Gene Expression Regulation
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study*
  • Humans
  • Male
  • Muscle, Skeletal / metabolism*
  • Polymorphism, Single Nucleotide
  • RNA, Messenger
  • Sequence Analysis, RNA

Substances

  • RNA, Messenger