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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 7772-7792 |
| Number of pages | 21 |
| Journal | Nucleic Acids Research |
| Volume | 46 |
| Issue number | 15 |
| DOIs | |
| State | Published - Jan 1 2018 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Genetics
Cite this
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 R; Phillips, Stuart M.; Phillips, Bethan E.; Gallagher, Iain J.; Kraus, William E.
In: Nucleic Acids Research, Vol. 46, No. 15, 01.01.2018, p. 7772-7792.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A coding and non-coding transcriptomic perspective on the genomics of human metabolic disease
AU - Timmons, James A.
AU - Atherton, Philip J.
AU - Larsson, Ola
AU - Sood, Sanjana
AU - Blokhin, Ilya O.
AU - Brogan, Robert J.
AU - Volmar, Claude Henry
AU - Josse, Andrea R.
AU - Slentz, Cris
AU - Wahlestedt, Claes R
AU - Phillips, Stuart M.
AU - Phillips, Bethan E.
AU - Gallagher, Iain J.
AU - Kraus, William E.
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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.
AB - 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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U2 - 10.1093/nar/gky570
DO - 10.1093/nar/gky570
M3 - Article
VL - 46
SP - 7772
EP - 7792
JO - Nucleic Acids Research
JF - Nucleic Acids Research
SN - 0305-1048
IS - 15
ER -