James A Timmons
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
Authors
PHILIP ATHERTON philip.atherton@nottingham.ac.uk
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
BETH PHILLIPS beth.phillips@nottingham.ac.uk
Professor of Translational Physiology
Iain J Gallagher
William E Kraus
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.
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 |
DOI | https://doi.org/10.1093/nar/gky570 |
Keywords | Genetics |
Public URL | https://nottingham-repository.worktribe.com/output/1465637 |
Publisher URL | https://academic.oup.com/nar/article/46/15/7772/5050628 |
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Publisher Licence URL
https://creativecommons.org/licenses/by/4.0/
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