Variations in DNA elucidate molecular networks that cause disease. - Archive ouverte HAL Access content directly
Journal Articles Nature Year : 2008

Variations in DNA elucidate molecular networks that cause disease.

Yanqing Chen
  • Function : Author
Jun Zhu
  • Function : Author
Pek Yee Lum
  • Function : Author
Xia Yang
Shirly Pinto
  • Function : Author
Douglas J Macneil
  • Function : Author
John Lamb
  • Function : Author
Stephen Edwards
  • Function : Author
Solveig K Sieberts
  • Function : Author
Amy Leonardson
  • Function : Author
Lawrence W Castellini
  • Function : Author
Susanna Wang
  • Function : Author
Bin Zhang
  • Function : Author
Valur Emilsson
  • Function : Author
Sudheer Doss
  • Function : Author
Anatole Ghazalpour
  • Function : Author
Steve Horvath
  • Function : Author
Thomas A Drake
  • Function : Author
Aldons J Lusis
  • Function : Author
Eric E Schadt
  • Function : Author

Abstract

Identifying variations in DNA that increase susceptibility to disease is one of the primary aims of genetic studies using a forward genetics approach. However, identification of disease-susceptibility genes by means of such studies provides limited functional information on how genes lead to disease. In fact, in most cases there is an absence of functional information altogether, preventing a definitive identification of the susceptibility gene or genes. Here we develop an alternative to the classic forward genetics approach for dissecting complex disease traits where, instead of identifying susceptibility genes directly affected by variations in DNA, we identify gene networks that are perturbed by susceptibility loci and that in turn lead to disease. Application of this method to liver and adipose gene expression data generated from a segregating mouse population results in the identification of a macrophage-enriched network supported as having a causal relationship with disease traits associated with metabolic syndrome. Three genes in this network, lipoprotein lipase (Lpl), lactamase beta (Lactb) and protein phosphatase 1-like (Ppm1l), are validated as previously unknown obesity genes, strengthening the association between this network and metabolic disease traits. Our analysis provides direct experimental support that complex traits such as obesity are emergent properties of molecular networks that are modulated by complex genetic loci and environmental factors.

Dates and versions

hal-00283069 , version 1 (29-05-2008)

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Yanqing Chen, Jun Zhu, Pek Yee Lum, Xia Yang, Shirly Pinto, et al.. Variations in DNA elucidate molecular networks that cause disease.. Nature, 2008, 452 (7186), pp.429-35. ⟨10.1038/nature06757⟩. ⟨hal-00283069⟩
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