title: Validation of candidate causal genes for obesity that affect shared metabolic pathways and networks.
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 F(2) intercross studies allows high-confidence prediction of causal genes and identification of pathways and networks involved.
authors.affiliation: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Yang
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Deignan
authors.forename: Hongxiu
authors.initials: H
authors.lastname: Qi
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.forename: Su
authors.initials: S
authors.lastname: Qian
authors.forename: Judy
authors.initials: J
authors.lastname: Zhong
authors.forename: Gevork
authors.initials: G
authors.lastname: Torosyan
authors.forename: Sana
authors.initials: S
authors.lastname: Majid
authors.forename: Brie
authors.initials: B
authors.lastname: Falkard
authors.forename: Robert R
authors.initials: RR
authors.lastname: Kleinhanz
authors.forename: Jenny
authors.initials: J
authors.lastname: Karlsson
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Castellani
authors.forename: Sheena
authors.initials: S
authors.lastname: Mumick
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Tao
authors.initials: T
authors.lastname: Xie
authors.forename: Michael
authors.initials: M
authors.lastname: Coon
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Zhang
authors.forename: Daria
authors.initials: D
authors.lastname: Estrada-Smith
authors.forename: Charles R
authors.initials: CR
authors.lastname: Farber
authors.forename: Susanna S
authors.initials: SS
authors.lastname: Wang
authors.forename: Atila
authors.initials: A
authors.lastname: van Nas
authors.forename: Anatole
authors.initials: A
authors.lastname: Ghazalpour
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Macneil
authors.forename: John R
authors.initials: JR
authors.lastname: Lamb
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Dipple
authors.forename: Marc L
authors.initials: ML
authors.lastname: Reitman
authors.forename: Margarete
authors.initials: M
authors.lastname: Mehrabian
authors.forename: Pek Y
authors.initials: PY
authors.lastname: Lum
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Drake
mesh_terms: D000005:Abdomen / Q000033:anatomy & histology; D000273:Adipose Tissue / Q000033:anatomy & histology; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D014644:Genetic Variation; D005979:Glutathione Peroxidase / Q000235:genetics*; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000033:anatomy & histology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009765:Obesity / Q000235:genetics*; D010641:Phenotype; D015203:Reproducibility of Results; D014158:Transcription, Genetic; D033921:Vesicular Transport Proteins
chemical_list: D002352:Carrier Proteins; C114909:GAS7 protein, human; D006023:Glycoproteins; C104585:NPC2 protein, human; D009419:Nerve Tissue Proteins; D033921:Vesicular Transport Proteins; C486484:GPX3 protein, human; D005979:Glutathione Peroxidase