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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Timmons, JA; Atherton, PJ; Larsson, O; Sood, S; Blokhin, IO; Brogan, RJ; Volmar, C-H; Josse, AR; Slentz, C; Wahlestedt, C; Phillips, SM; Phillips, BE; Gallagher, IJ; Kraus, WE

Published Date

  • September 6, 2018

Published In

Volume / Issue

  • 46 / 15

Start / End Page

  • 7772 - 7792

PubMed ID

  • 29986096

Pubmed Central ID

  • PMC6125682

Electronic International Standard Serial Number (EISSN)

  • 1362-4962

Digital Object Identifier (DOI)

  • 10.1093/nar/gky570


  • eng

Conference Location

  • England