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

Timmons, James A; Atherton, Philip J; Larsson, Ola; Sood, Sanjana; Blokhin, Ilya O; Brogan, Robert J; Volmar, Claude-Henry; Josse, Andrea R; Slentz, Cris; Wahlestedt, Claes; Phillips, Stuart M; Phillips, Bethan E; Gallagher, Iain J; Kraus, William E

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James A Timmons

Professor of Clinical, metabolic & Molecular Physiology

Ola Larsson

Sanjana Sood

Ilya O Blokhin

Robert J Brogan

Claude-Henry Volmar

Andrea R Josse

Cris Slentz

Claes Wahlestedt

Stuart M Phillips

Professor of Translational Physiology

Iain J Gallagher

William E Kraus


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.


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 Research, 46(15), 7772-7792.

Journal Article Type Article
Acceptance Date Jun 13, 2018
Online Publication Date Jul 9, 2018
Publication Date Sep 6, 2018
Deposit Date Jan 11, 2019
Publicly Available Date Jan 11, 2019
Journal Nucleic Acids Research
Print ISSN 0305-1048
Electronic ISSN 1362-4962
Publisher Oxford University Press
Peer Reviewed Peer Reviewed
Volume 46
Issue 15
Pages 7772-7792
Keywords Genetics
Public URL
Publisher URL


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