A coding and non-coding transcriptomic perspective on the genomics of human metabolic disease

Nucleic Acids Res. 2018 Sep 6;46(15):7772-7792. doi: 10.1093/nar/gky570.

Abstract

Genome-wide association studies (GWAS), relying on hundreds of thousands of individuals, have revealed >200 genomic loci linked to metabolic disease (MD). Loss of insulin sensitivity (IS) is a key component of MD and we hypothesized that discovery of a robust IS transcriptome would help reveal the underlying genomic structure of MD. Using 1,012 human skeletal muscle samples, detailed physiology and a tissue-optimized approach for the quantification of coding (>18,000) and non-coding (>15,000) RNA (ncRNA), we identified 332 fasting IS-related genes (CORE-IS). Over 200 had a proven role in the biochemistry of insulin and/or metabolism or were located at GWAS MD loci. Over 50% of the CORE-IS genes responded to clinical treatment; 16 quantitatively tracking changes in IS across four independent studies (P = 0.0000053: negatively: AGL, G0S2, KPNA2, PGM2, RND3 and TSPAN9 and positively: ALDH6A1, DHTKD1, ECHDC3, MCCC1, OARD1, PCYT2, PRRX1, SGCG, SLC43A1 and SMIM8). A network of ncRNA positively related to IS and interacted with RNA coding for viral response proteins (P < 1 × 10-48), while reduced amino acid catabolic gene expression occurred without a change in expression of oxidative-phosphorylation genes. We illustrate that combining in-depth physiological phenotyping with robust RNA profiling methods, identifies molecular networks which are highly consistent with the genetics and biochemistry of human metabolic disease.

Publication types

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

MeSH terms

  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / therapy
  • Exercise
  • Gene Expression Profiling
  • Genetic Markers / genetics
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study
  • Genomics*
  • Humans
  • Insulin / metabolism
  • Insulin Resistance / genetics*
  • Metabolic Diseases / genetics
  • Models, Molecular
  • Muscle, Skeletal / metabolism*
  • Oxidative Phosphorylation
  • Quantitative Trait Loci
  • RNA / metabolism
  • Transcriptome*

Substances

  • Genetic Markers
  • Insulin
  • RNA