Variations in DNA elucidate molecular networks that cause disease |
| |
Authors: | Chen Yanqing Zhu Jun Lum Pek Yee Yang Xia Pinto Shirly MacNeil Douglas J Zhang Chunsheng Lamb John Edwards Stephen Sieberts Solveig K Leonardson Amy Castellini Lawrence W Wang Susanna Champy Marie-France Zhang Bin Emilsson Valur Doss Sudheer Ghazalpour Anatole Horvath Steve Drake Thomas A Lusis Aldons J Schadt Eric E |
| |
Institution: | Rosetta Inpharmatics, LLC, Merck & Co., Inc., 401 Terry Avenue North, Seattle, Washington 98109, USA. |
| |
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. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|