Eric E. Schadt*†, Stephanie A. Monks*†‡, Thomas A. Drake§, Aldons J. Lusis, Nam Che, Veronica Colinayo, Thomas G. Ruff¶, Stephen B. Milligan*, John R. Lamb*, Guy Cavet*, Peter S. Linsley*, Mao Mao*, Roland B. Stoughton* & Stephen H. Friend*#

Treating messenger RNA transcript abundances as quantitative traits and mapping gene expression quantitative trait loci for these traits has been pursued in gene-specific ways. Transcript abundances often serve as a surrogate for classical quantitative traits in that the levels of expression are significantly correlated with the classical traits across members of a segregating population. The correlation structure between transcript abundances and classical traits has been used to identify susceptibility loci for complex diseases such as diabetes and allergic asthma. One study recently completed the first comprehensive dissection of transcriptional regulation in budding yeast, giving a detailed glimpse of a genome-wide survey of the genetics of gene expression. Unlike classical quantitative traits, which often represent gross clinical measurements that may be far removed from the biological processes giving rise to them, the genetic linkages associated with transcript abundance affords a closer look at cellular biochemical processes. Here we describe comprehensive genetic screens of mouse, plant and human transcriptomes by considering gene expression values as quantitative traits. We identify a gene expression pattern strongly associated with obesity in a murine cross, and observe two distinct obesity subtypes. Furthermore, we find that these obesity subtypes are under the control of different loci.

* Rosetta Inpharmatics, LLC, 12040 115th Avenue N.E., Kirkland, Washington 98034, USA
‡ Department of Biostatistics, University of Washington, Seattle, Washington 98195, USA
§ Department of Pathology and Laboratory Medicine, Molecular Genetics and Immunology, Department of Medicine, and Department of Human Genetics, UCLA, Los Angeles, California 90095, USA
Department of Microbiology, Molecular Genetics and Immunology, Department of Medicine, and Department of Human Genetics, UCLA, Los Angeles, California 90095, USA
¶ Monsanto Company, St Louis, Missouri 63167, USA
# Merck Research Laboratories, Merck & Co., Inc., POB 4, WP14-2500, West Point, Pennsylvania 19486, USA
† These authors contributed equally to this work

Correspondence and requests for materials should be addressed to E.E.S. (e-mail: eric_schadt@merck.com) or S.H.F. (e-mail: stephen_friend@merck.com).