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.
Yang
Xia
X
Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Deignan
Joshua L
JL
Qi
Hongxiu
H
Zhu
Jun
J
Qian
Su
S
Zhong
Judy
J
Torosyan
Gevork
G
Majid
Sana
S
Falkard
Brie
B
Kleinhanz
Robert R
RR
Karlsson
Jenny
J
Castellani
Lawrence W
LW
Mumick
Sheena
S
Wang
Kai
K
Xie
Tao
T
Coon
Michael
M
Zhang
Chunsheng
C
Estrada-Smith
Daria
D
Farber
Charles R
CR
Wang
Susanna S
SS
van Nas
Atila
A
Ghazalpour
Anatole
A
Zhang
Bin
B
Macneil
Douglas J
DJ
Lamb
John R
JR
Dipple
Katrina M
KM
Reitman
Marc L
ML
Mehrabian
Margarete
M
Lum
Pek Y
PY
Schadt
Eric E
EE
Lusis
Aldons J
AJ
Drake
Thomas A
TA
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
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