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

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Abstract
Thomas Drake and colleagues report the results of knockout or transgene introduction for nine obesity candidate genes in mice. Eight of the nine mutations result in significant changes in obesity-related traits, validating their previously developed approach for identifying candidate genes involved in particular phenotypes. They further identify related metabolic pathways that are altered by manipulation of the eight genes. 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.