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 journalArticlepeer-review

4846 Scopus citations


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 languageEnglish (US)
Pages (from-to)267-273
Number of pages7
JournalNature Genetics
Issue number3
StatePublished - Jul 1 2003
Externally publishedYes

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics


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