Nature Genetics
37, 243 - 253 (2005)
Published online: 13 February 2005; | doi:10.1038/ng1522
Integrated transcriptional profiling and linkage analysis for identification of genes underlying diseaseNorbert Hubner1, Caroline A Wallace2, 7, Heike Zimdahl1, 7, Enrico Petretto2, 7, Herbert Schulz1, Fiona Maciver2, Michael Mueller2, Oliver Hummel1, Jan Monti1, Vaclav Zidek3, Alena Musilova3, Vladimir Kren3, 4, Helen Causton2, Laurence Game2, Gabriele Born1, Sabine Schmidt1, Anita Müller1, Stuart A Cook2, Theodore W Kurtz5, John Whittaker6, Michal Pravenec3, 4
& Timothy J Aitman21
Max-Delbrück-Center for Molecular Medicine, Berlin-Buch 13125, Germany. 2
MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, London W12 0NN, UK. 3
Institute of Physiology, Czech Academy of Sciences and Centre for Applied Genomics, 142 20 Prague 4, Czech Republic. 4
Institute of Biology and Medical Genetics, Charles University, 120 00 Prague 2, Czech Republic. 5
University of California, San Francisco, California 94143-0134, USA. 6
Department of Epidemiology and Public Health, Imperial College, London W2 1PG, UK. 7
These authors contributed equally to this work.
Correspondence should be addressed to Michal Pravenec pravenec@biomed.cas.cz or Timothy J Aitman t.aitman@csc.mrc.ac.ukIntegration of genome-wide expression profiling with linkage analysis is a new approach to identifying genes underlying complex traits. We applied this approach to the regulation of gene expression in the BXH/HXB panel of rat recombinant inbred strains, one of the largest available rodent recombinant inbred panels and a leading resource for genetic analysis of the highly prevalent metabolic syndrome. In two tissues important to the pathogenesis of the metabolic syndrome, we mapped cis- and trans-regulatory control elements for expression of thousands of genes across the genome. Many of the most highly linked expression quantitative trait loci are regulated in cis, are inherited essentially as monogenic traits and are good candidate genes for previously mapped physiological quantitative trait loci in the rat. By comparative mapping we generated a data set of 73 candidate genes for hypertension that merit testing in human populations. Mining of this publicly available data set is expected to lead to new insights into the genes and regulatory pathways underlying the extensive range of metabolic and cardiovascular disease phenotypes that segregate in these recombinant inbred strains.
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