Validation of candidate causal genes for obesity that affect shared metabolic pathways and networks.


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 F(2) intercross studies allows high-confidence prediction of causal genes and identification of pathways and networks involved.

DOI: 10.1038/ng.325

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@article{Yang2009ValidationOC, title={Validation of candidate causal genes for obesity that affect shared metabolic pathways and networks.}, author={Xia Yang and Joshua L Deignan and Hongxiu Qi and Jun Zhu and Su Qian and Judy Zhong and Gevork Torosyan and Sana Majid and Brie Falkard and Robert Kleinhanz and Jenny Karlsson and Lawrence W. Castellani and Sheena Mumick and Kai Wang and Tao Xie and Michael Coon and Chunsheng Zhang and Daria Estrada-Smith and Charles R. Farber and Susanna S. Wang and Atila van Nas and Anatole Ghazalpour and Bin Zhang and Douglas J Macneil and John R. Lamb and Katrina M . Dipple and Marc L Reitman and Margarete Mehrabian and Pek Y. Lum and Eric E. Schadt and Aldons J. Lusis and Thomas Drake}, journal={Nature genetics}, year={2009}, volume={41 4}, pages={415-23} }