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

被引：214

作者：

Yang, Xia ^{[2
]}

Deignan, Joshua L. ^{[2
]}

Qi, Hongxiu ^{[2
]}

Zhu, Jun ^{[3
]}

Qian, Su ^{[4
]}

Zhong, Judy ^{[3
]}

Torosyan, Gevork ^{[5
]}

Majid, Sana ^{[5
]}

Falkard, Brie ^{[5
]}

Kleinhanz, Robert R. ^{[3
]}

Karlsson, Jenny ^{[1
]}

Castellani, Lawrence W. ^{[2
]}

Mumick, Sheena ^{[4
]}

Wang, Kai ^{[3
]}

Xie, Tao ^{[3
]}

Coon, Michael ^{[3
]}

Zhang, Chunsheng ^{[3
]}

Estrada-Smith, Daria ^{[5
]}

Farber, Charles R. ^{[2
]}

Wang, Susanna S. ^{[5
]}

Van Nas, Atila ^{[5
]}

Ghazalpour, Anatole ^{[5
]}

Zhang, Bin ^{[3
]}

MacNeil, Douglas J. ^{[4
]}

Lamb, John R. ^{[3
]}

Dipple, Katrina M. ^{[5
]}

Reitman, Marc L. ^{[6
]}

Mehrabian, Margarete ^{[2
]}

Lum, Pek Y. ^{[3
]}

Schadt, Eric E. ^{[3
]}

Lusis, Aldons J. ^{[2
,5
]}

Drake, Thomas A. ^{[1
]}

机构：

[1] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA

[3] Rosetta Inphamat LLC, Seattle, WA USA

[4] Merck & Co Inc, Dept Metab Disorders, Rahway, NJ 07065 USA

[5] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA

[6] Merck & Co Inc, Dept Clin Pharmacol, Rahway, NJ 07065 USA

来源：

NATURE GENETICS | 2009年 / 41卷 / 04期

基金：

美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; HUMAN GLUTATHIONE PEROXIDASES; GLYCEROL KINASE-DEFICIENCY; INSULIN-RESISTANCE; EXPRESSION; MICE; DISEASE; LOCI; GENETICS; PROTEIN;

D O I：

10.1038/ng.325

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：415 / 423

页数：9

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