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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We thank C. Ladd, M. Gaasenbeek and G. Ahlqvist for technical assistance; L. Gaffney for preparing illustrations; D. Stram and R. Heinrich for discussions; M. Patti and colleagues for sharing their manuscript before publication; B. Gewurz, E. Rosen, members of D.A. and E.S.L.'s labs for comments on the manuscript; and the individuals who volunteered for this study. V.K.M. is supported by a Howard Hughes Medical Institute physician postdoctoral fellowship. C.M.L. was supported by the Foundation for Strategic Research, the Royal Physiographic Society, the Sven Lundgrens Foundation and the Albert Pahlssons Foundation. T.R.G. is an Investigator of the Howard Hughes Medical Institute. J.N.H. is the recipient of a Career Development Award of the Burroughs Welcome Fund. D.A. is a Clinical Scholar in Translational Research of the Burroughs Welcome Fund and a Charles E. Culpeper Scholar of the Rockefeller Brothers Fund. This work was supported in part by grants from Affymetrix, Millennium Pharmaceuticals and Bristol-Myers Squibb to E.S.L. and from the Sigrid Juselius Foundation, the Juvenile Diabetes Foundation-Wallenberg Foundation, the Swedish Medical Research Council, the Novo-Nordisk Foundation and a European Community Genomics Integrated Force for Type 2 Diabetes grant to L.C.G.

Author information

Author notes

    • Vamsi K Mootha
    •  & Cecilia M Lindgren

    These authors contributed equally to this work.

    • David Altshuler
    •  & Leif C Groop

    These two authors contributed equally to this work.


  1. Whitehead Institute/MIT Center for Genome Research, Cambridge, Massachusetts, USA.

    • Vamsi K Mootha
    • , Cecilia M Lindgren
    • , Aravind Subramanian
    • , Smita Sihag
    • , Joseph Lehar
    • , Nicholas Houstis
    • , Mark J Daly
    • , Nick Patterson
    • , Jill P Mesirov
    • , Todd R Golub
    • , Pablo Tamayo
    • , Eric S Lander
    • , Joel N Hirschhorn
    •  & David Altshuler
  2. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • Vamsi K Mootha
    •  & David Altshuler
  3. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Vamsi K Mootha
  4. Department of Endocrinology, Wallenberg Laboratory, University Hospital MAS, Lund University, S-205 02 Malmo, Sweden.

    • Cecilia M Lindgren
    • , Karl-Fredrik Eriksson
    • , Emma Carlsson
    • , Martin Ridderstråle
    • , Esa Laurila
    •  & Leif C Groop
  5. Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.

    • Pere Puigserver
    • , Todd R Golub
    •  & Bruce Spiegelman
  6. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Eric S Lander
  7. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • Joel N Hirschhorn
    •  & David Altshuler
  8. Divisions of Pediatrics and Endocrinology, Children's Hospital, Boston, Massachusetts, USA.

    • Joel N Hirschhorn
  9. Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • David Altshuler


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The authors declare no competing financial interests.

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Correspondence to David Altshuler or Leif C Groop.

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