Variations in DNA elucidate molecular networks that cause disease

Yanqing Chen, Jun Zhu, Pek Yee Lum, Xia Yang, Shirly Pinto, Douglas J. MacNeil, Chunsheng Zhang, John Lamb, Stephen Edwards, Solveig K. Sieberts, Amy Leonardson, Lawrence W. Castellini, Susanna Wang, Marie-France Champy, Bin Zhang, Valur Emilsson, Sudheer Doss, Anatole Ghazalpour, Steve Horvath, Thomas A. Drake, Aldons J. Lusis and Eric E. Schadt ()
Additional contact information
Yanqing Chen: Rosetta Inpharmatics, LLC, Merck & Co., Inc., 401 Terry Avenue North, Seattle, Washington 98109, USA
Jun Zhu: Rosetta Inpharmatics, LLC, Merck & Co., Inc., 401 Terry Avenue North, Seattle, Washington 98109, USA
Pek Yee Lum: Rosetta Inpharmatics, LLC, Merck & Co., Inc., 401 Terry Avenue North, Seattle, Washington 98109, USA
Xia Yang: Rosetta Inpharmatics, LLC, Merck & Co., Inc., 401 Terry Avenue North, Seattle, Washington 98109, USA
Shirly Pinto: Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, New Jersey 07065, USA
Douglas J. MacNeil: Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, New Jersey 07065, USA
Chunsheng Zhang: Rosetta Inpharmatics, LLC, Merck & Co., Inc., 401 Terry Avenue North, Seattle, Washington 98109, USA
John Lamb: Rosetta Inpharmatics, LLC, Merck & Co., Inc., 401 Terry Avenue North, Seattle, Washington 98109, USA
Stephen Edwards: Rosetta Inpharmatics, LLC, Merck & Co., Inc., 401 Terry Avenue North, Seattle, Washington 98109, USA
Solveig K. Sieberts: Rosetta Inpharmatics, LLC, Merck & Co., Inc., 401 Terry Avenue North, Seattle, Washington 98109, USA
Amy Leonardson: Rosetta Inpharmatics, LLC, Merck & Co., Inc., 401 Terry Avenue North, Seattle, Washington 98109, USA
Lawrence W. Castellini: Molecular Genetics, and Immunology
Susanna Wang: Molecular Genetics, and Immunology
Marie-France Champy: Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS/INSERM/ULP, 67404 Illkirch, France
Bin Zhang: Rosetta Inpharmatics, LLC, Merck & Co., Inc., 401 Terry Avenue North, Seattle, Washington 98109, USA
Valur Emilsson: Rosetta Inpharmatics, LLC, Merck & Co., Inc., 401 Terry Avenue North, Seattle, Washington 98109, USA
Sudheer Doss: Molecular Genetics, and Immunology
Anatole Ghazalpour: Molecular Genetics, and Immunology
Steve Horvath: and
Thomas A. Drake: UCLA, 650 Young Drive South, Los Angeles, California 90095, USA
Aldons J. Lusis: Molecular Genetics, and Immunology
Eric E. Schadt: Rosetta Inpharmatics, LLC, Merck & Co., Inc., 401 Terry Avenue North, Seattle, Washington 98109, USA

Nature, 2008, vol. 452, issue 7186, 429-435

Abstract: 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 β (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.

Date: 2008
References: Add references at CitEc
Citations: View citations in EconPapers (16)

Downloads: (external link)
https://www.nature.com/articles/nature06757 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:452:y:2008:i:7186:d:10.1038_nature06757

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/nature06757

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().