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

Publication ,  Journal Article
Timmons, JA; Atherton, PJ; Larsson, O; Sood, S; Blokhin, IO; Brogan, RJ; Volmar, C-H; Josse, AR; Slentz, C; Wahlestedt, C; Phillips, SM ...
Published in: Nucleic Acids Res
September 6, 2018

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.

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Published In

Nucleic Acids Res

DOI

EISSN

1362-4962

Publication Date

September 6, 2018

Volume

46

Issue

15

Start / End Page

7772 / 7792

Location

England

Related Subject Headings

  • Transcriptome
  • RNA
  • Quantitative Trait Loci
  • Oxidative Phosphorylation
  • Muscle, Skeletal
  • Models, Molecular
  • Metabolic Diseases
  • Insulin Resistance
  • Insulin
  • Humans
 

Citation

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Chicago
ICMJE
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Timmons, J. A., Atherton, P. J., Larsson, O., Sood, S., Blokhin, I. O., Brogan, R. J., … Kraus, W. E. (2018). A coding and non-coding transcriptomic perspective on the genomics of human metabolic disease. Nucleic Acids Res, 46(15), 7772–7792. https://doi.org/10.1093/nar/gky570
Timmons, James A., Philip J. Atherton, Ola Larsson, Sanjana Sood, Ilya O. Blokhin, Robert J. Brogan, Claude-Henry Volmar, et al. “A coding and non-coding transcriptomic perspective on the genomics of human metabolic disease.Nucleic Acids Res 46, no. 15 (September 6, 2018): 7772–92. https://doi.org/10.1093/nar/gky570.
Timmons JA, Atherton PJ, Larsson O, Sood S, Blokhin IO, Brogan RJ, et al. A coding and non-coding transcriptomic perspective on the genomics of human metabolic disease. Nucleic Acids Res. 2018 Sep 6;46(15):7772–92.
Timmons, James A., et al. “A coding and non-coding transcriptomic perspective on the genomics of human metabolic disease.Nucleic Acids Res, vol. 46, no. 15, Sept. 2018, pp. 7772–92. Pubmed, doi:10.1093/nar/gky570.
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. A coding and non-coding transcriptomic perspective on the genomics of human metabolic disease. Nucleic Acids Res. 2018 Sep 6;46(15):7772–7792.
Journal cover image

Published In

Nucleic Acids Res

DOI

EISSN

1362-4962

Publication Date

September 6, 2018

Volume

46

Issue

15

Start / End Page

7772 / 7792

Location

England

Related Subject Headings

  • Transcriptome
  • RNA
  • Quantitative Trait Loci
  • Oxidative Phosphorylation
  • Muscle, Skeletal
  • Models, Molecular
  • Metabolic Diseases
  • Insulin Resistance
  • Insulin
  • Humans