Copyright © 2008 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 82, Issue 4, 949-958, 28 March 2008
doi:10.1016/j.ajhg.2008.02.013
Article
Walking the Interactome for Prioritization of Candidate Disease Genes
Sebastian Köhler1, 2, Sebastian Bauer1, 2, Denise Horn1 and Peter N. Robinson1, 
, 
Corresponding author2 These authors contributed equally to this work.
Abstract
The identification of genes associated with hereditary disorders has contributed to improving medical care and to a better understanding of gene functions, interactions, and pathways. However, there are well over 1500 Mendelian disorders whose molecular basis remains unknown. At present, methods such as linkage analysis can identify the chromosomal region in which unknown disease genes are located, but the regions could contain up to hundreds of candidate genes. In this work, we present a method for prioritization of candidate genes by use of a global network distance measure, random walk analysis, for definition of similarities in protein-protein interaction networks. We tested our method on 110 disease-gene families with a total of 783 genes and achieved an area under the ROC curve of up to 98% on simulated linkage intervals of 100 genes surrounding the disease gene, significantly outperforming previous methods based on local distance measures. Our results not only provide an improved tool for positional-cloning projects but also add weight to the assumption that phenotypically similar diseases are associated with disturbances of subnetworks within the larger protein interactome that extend beyond the disease proteins themselves.
Article Information
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