PGC-1a Responsive Genes Involved in Oxidative Phosphorylation are Coordinately Downregulated in Human Diabetes

Nature Nature Genet. 15 June 2003, vol. 34 no. 3 pp 267 ? 273.. Published: 2003.06.14

Vamsi K. Mootha, Cecilia M. Lindgren, Karl-Fredrik Eriksson, Aravind Subramanian, Smita Sihag, Joseph Lehar, Pere Puigserver, Emma Carlsson, Martin Ridderstr?le, 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, and Leif C. Groop

Read Manuscript

Abstract

DNA microarrays can be used to discover 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-1a, 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.

Keywords: bioinformatics diabetes gene set enrichment analysis mitochondria oxidative phosphorylation physiology

Supplemental Data

Description	Link/Filename
Human diabetes expression data	reannotate_select_cal.eis.gz
Phenotype data	Phenotype_Data.xls
Probe sets corresponding to gene sets	all_pathways.tar.gz
GSEA results for NGT versus DM2	GSEA_results_NGT_vs_DM2.xls
OXPHOS homolog expression in mouse	mouse_expression.tar.gz