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

Xia Yang; Joshua L. Deignan; Hongxiu Qi; Jun Zhu; Su Qian; Judy Zhong; Gevork Torosyan; Sana Majid; Brie Falkard; Robert R. Kleinhanz; Jenny Karlsson; Lawrence W. Castellani; Sheena Mumick; Kai Wang; Tao Xie; Michael Coon; Chunsheng Zhang; Daria Estrada-Smith; Charles R. Farber; Susanna S. Wang; Atila Van Nas; Anatole Ghazalpour; Bin Zhang; Douglas J. Macneil; John R. Lamb; Katrina M. Dipple; Marc L. Reitman; Margarete Mehrabian; Pek Y. Lum; Eric E. Schadt; Aldons J. Lusis; Thomas A. Drake

doi:10.1038/ng.325

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

Xia Yang, Joshua L. Deignan, Hongxiu Qi, Jun Zhu, Su Qian, Judy Zhong, Gevork Torosyan, Sana Majid, Brie Falkard, Robert R. Kleinhanz, Jenny Karlsson, Lawrence W. Castellani, Sheena Mumick, Kai Wang, Tao Xie, Michael Coon, Chunsheng Zhang, Daria Estrada-Smith, Charles R. Farber, Susanna S. WangAtila Van Nas, Anatole Ghazalpour, Bin Zhang, Douglas J. Macneil, John R. Lamb, Katrina M. Dipple, Marc L. Reitman, Margarete Mehrabian, Pek Y. Lum, Eric E. Schadt, Aldons J. Lusis, Thomas A. Drake

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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.

Original language	English
Pages (from-to)	415-423
Number of pages	9
Journal	Nature Genetics
Volume	41
Issue number	4
DOIs	https://doi.org/10.1038/ng.325
State	Published - Apr 2009
Externally published	Yes

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Yang, X., Deignan, J. L., Qi, H., Zhu, J., Qian, S., Zhong, J., Torosyan, G., Majid, S., Falkard, B., Kleinhanz, R. R., Karlsson, J., Castellani, L. W., Mumick, S., Wang, K., Xie, T., Coon, M., Zhang, C., Estrada-Smith, D., Farber, C. R., ... Drake, T. A. (2009). Validation of candidate causal genes for obesity that affect shared metabolic pathways and networks. Nature Genetics, 41(4), 415-423. https://doi.org/10.1038/ng.325

@article{36098d36378649149cd3914653e9c2ca,

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.",

author = "Xia Yang and Deignan, {Joshua L.} and Hongxiu Qi and Jun Zhu and Su Qian and Judy Zhong and Gevork Torosyan and Sana Majid and Brie Falkard and Kleinhanz, {Robert R.} and Jenny Karlsson and Castellani, {Lawrence W.} and Sheena Mumick and Kai Wang and Tao Xie and Michael Coon and Chunsheng Zhang and Daria Estrada-Smith and Farber, {Charles R.} and Wang, {Susanna S.} and {Van Nas}, Atila and Anatole Ghazalpour and Bin Zhang and Macneil, {Douglas J.} and Lamb, {John R.} and Dipple, {Katrina M.} and Reitman, {Marc L.} and Margarete Mehrabian and Lum, {Pek Y.} and Schadt, {Eric E.} and Lusis, {Aldons J.} and Drake, {Thomas A.}",

note = "Funding Information: The authors thank R. Davis, P. Wen, M. Rosales, X. Wu, K. Ranola and X. Xia for helping with the tissue collection. We would also like to thank L. Ingram-Drake and S. Charugundla for technical support and O. Mirochnitchenko and I. Goldberg for providing mouse models. The study was funded by US National Institutes of Health grants DK072206, HL28481 and HL30568.",

year = "2009",

month = apr,

doi = "10.1038/ng.325",

language = "English",

volume = "41",

pages = "415--423",

journal = "Nature Genetics",

issn = "1061-4036",

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Yang, X, Deignan, JL, Qi, H, Zhu, J, Qian, S, Zhong, J, Torosyan, G, Majid, S, Falkard, B, Kleinhanz, RR, Karlsson, J, Castellani, LW, Mumick, S, Wang, K, Xie, T, Coon, M, Zhang, C, Estrada-Smith, D, Farber, CR, Wang, SS, Van Nas, A, Ghazalpour, A, Zhang, B, Macneil, DJ, Lamb, JR, Dipple, KM, Reitman, ML, Mehrabian, M, Lum, PY, Schadt, EE, Lusis, AJ & Drake, TA 2009, 'Validation of candidate causal genes for obesity that affect shared metabolic pathways and networks', Nature Genetics, vol. 41, no. 4, pp. 415-423. https://doi.org/10.1038/ng.325

TY - JOUR

T1 - Validation of candidate causal genes for obesity that affect shared metabolic pathways and networks

AU - Yang, Xia

AU - Deignan, Joshua L.

AU - Qi, Hongxiu

AU - Zhu, Jun

AU - Qian, Su

AU - Zhong, Judy

AU - Torosyan, Gevork

AU - Majid, Sana

AU - Falkard, Brie

AU - Kleinhanz, Robert R.

AU - Karlsson, Jenny

AU - Castellani, Lawrence W.

AU - Mumick, Sheena

AU - Wang, Kai

AU - Xie, Tao

AU - Coon, Michael

AU - Zhang, Chunsheng

AU - Estrada-Smith, Daria

AU - Farber, Charles R.

AU - Wang, Susanna S.

AU - Van Nas, Atila

AU - Ghazalpour, Anatole

AU - Zhang, Bin

AU - Macneil, Douglas J.

AU - Lamb, John R.

AU - Dipple, Katrina M.

AU - Reitman, Marc L.

AU - Mehrabian, Margarete

AU - Lum, Pek Y.

AU - Schadt, Eric E.

AU - Lusis, Aldons J.

AU - Drake, Thomas A.

N1 - Funding Information: The authors thank R. Davis, P. Wen, M. Rosales, X. Wu, K. Ranola and X. Xia for helping with the tissue collection. We would also like to thank L. Ingram-Drake and S. Charugundla for technical support and O. Mirochnitchenko and I. Goldberg for providing mouse models. The study was funded by US National Institutes of Health grants DK072206, HL28481 and HL30568.

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

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