Article abstract
Nature Genetics 41, 415 - 423 (2009)
Published online: 8 March 2009 | Corrected online: 22 March 2009 | doi:10.1038/ng.325
Validation of candidate causal genes for obesity that affect shared metabolic pathways and networks
Xia Yang1, Joshua L Deignan1, Hongxiu Qi1, Jun Zhu2, Su Qian3, Judy Zhong2, Gevork Torosyan4, Sana Majid4, Brie Falkard4, Robert R Kleinhanz2, Jenny Karlsson5, Lawrence W Castellani1, Sheena Mumick3, Kai Wang2, Tao Xie2, Michael Coon2, Chunsheng Zhang2, Daria Estrada-Smith4, Charles R Farber1, Susanna S Wang4, Atila van Nas4, Anatole Ghazalpour4, Bin Zhang2, Douglas J MacNeil3, John R Lamb2, Katrina M Dipple4, Marc L Reitman6, Margarete Mehrabian1, Pek Y Lum2, Eric E Schadt2, Aldons J Lusis1,4 & Thomas A Drake5
Abstract
A principal task in dissecting the genetics of complex traits is to identify causal genes for disease phenotypes. We previously developed a method to infer causal relationships among genes through the integration of DNA variation, gene transcription and phenotypic information. Here we have validated our method through the characterization of transgenic and knockout mouse models of genes predicted to be causal for abdominal obesity. Perturbation of eight out of the nine genes, with Gas7, Me1 and Gpx3 being newly confirmed, resulted in significant changes in obesity-related traits. Liver expression signatures revealed alterations in common metabolic pathways and networks contributing to abdominal obesity and overlapped with a macrophage-enriched metabolic network module that is highly associated with metabolic traits in mice and humans. Integration of gene expression in the design and analysis of traditional F2 intercross studies allows high-confidence prediction of causal genes and identification of pathways and networks involved.
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
- Rosetta Inpharmatics, LLC, a wholly owned subsidiary of Merck & Co. Inc., Seattle, Washington, USA.
- Department of Metabolic Disorders, Merck & Co. Inc., Rahway, New Jersey, USA.
- Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
- Department of Clinical Pharmacology, Merck & Co. Inc., Rahway, New Jersey, USA.
Correspondence to: Thomas A Drake5 e-mail: tdrake@mednet.ucla.edu
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