PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes

Vamsi K. Mootha; Cecilia M. Lindgren; Karl Fredrik Eriksson; Aravind Subramanian; Smita Sihag; Joseph Lehar; Pere Puigserver; Emma Carlsson; Martin Ridderstråle; Esa Laurila; Nicholas Houstis; Mark J. Daly; Nick Patterson; Jill P. Mesirov; Todd R. Golub; Pablo Tamayo; Bruce Spiegelman; Eric S. Lander; Joel N. Hirschhorn; David Altshuler; Leif C. Groop

doi:10.1038/ng1180

PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes

Vamsi K. Mootha, Cecilia M. Lindgren, Karl Fredrik Eriksson, Aravind Subramanian, Smita Sihag, Joseph Lehar, Pere Puigserver, Emma Carlsson, Martin Ridderstråle, Esa Laurila, Nicholas Houstis, Mark J. Daly, Nick Patterson, Jill P. Mesirov, Todd R. Golub, Pablo Tamayo, Bruce Spiegelman, Eric S. Lander, Joel N. Hirschhorn, David AltshulerLeif C. Groop

Research output: Contribution to journal › Article › peer-review

4846 Scopus citations

Abstract

DNA microarrays can be used to identify gene expression changes characteristic of human disease. This is challenging, however, when relevant differences are subtle at the level of individual genes. We introduce an analytical strategy, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes. Using this approach, we identify a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle. Expression of these genes is high at sites of insulin-mediated glucose disposal, activated by PGC-1α and correlated with total-body aerobic capacity. Our results associate this gene set with clinically important variation in human metabolism and illustrate the value of pathway relationships in the analysis of genomic profiling experiments.

Original language	English (US)
Pages (from-to)	267-273
Number of pages	7
Journal	Nature Genetics
Volume	34
Issue number	3
DOIs	https://doi.org/10.1038/ng1180
State	Published - Jul 1 2003
Externally published	Yes

ASJC Scopus subject areas

Genetics(clinical)
Genetics

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10.1038/ng1180

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Mootha, V. K., Lindgren, C. M., Eriksson, K. F., Subramanian, A., Sihag, S., Lehar, J., Puigserver, P., Carlsson, E., Ridderstråle, M., Laurila, E., Houstis, N., Daly, M. J., Patterson, N., Mesirov, J. P., Golub, T. R., Tamayo, P., Spiegelman, B., Lander, E. S., Hirschhorn, J. N., ... Groop, L. C. (2003). PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nature Genetics, 34(3), 267-273. https://doi.org/10.1038/ng1180

Mootha, VK, Lindgren, CM, Eriksson, KF, Subramanian, A, Sihag, S, Lehar, J, Puigserver, P, Carlsson, E, Ridderstråle, M, Laurila, E, Houstis, N, Daly, MJ, Patterson, N, Mesirov, JP, Golub, TR, Tamayo, P, Spiegelman, B, Lander, ES, Hirschhorn, JN, Altshuler, D & Groop, LC 2003, 'PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes', Nature Genetics, vol. 34, no. 3, pp. 267-273. https://doi.org/10.1038/ng1180

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abstract = "DNA microarrays can be used to identify gene expression changes characteristic of human disease. This is challenging, however, when relevant differences are subtle at the level of individual genes. We introduce an analytical strategy, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes. Using this approach, we identify a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle. Expression of these genes is high at sites of insulin-mediated glucose disposal, activated by PGC-1α and correlated with total-body aerobic capacity. Our results associate this gene set with clinically important variation in human metabolism and illustrate the value of pathway relationships in the analysis of genomic profiling experiments.",

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AU - Sihag, Smita

AU - Lehar, Joseph

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AU - Ridderstråle, Martin

AU - Laurila, Esa

AU - Houstis, Nicholas

AU - Daly, Mark J.

AU - Patterson, Nick

AU - Mesirov, Jill P.

AU - Golub, Todd R.

AU - Tamayo, Pablo

AU - Spiegelman, Bruce

AU - Lander, Eric S.

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PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes

Abstract

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