[Molecular triangulation: Bridging linkage and molecular-network information for identifying candidate genes]
>>Published online before print October 7, 2004
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0404315101
Genetics
Molecular triangulation: Bridging linkage and molecular-network information for identifying candidate genes in Alzheimer's disease
Michael Krauthammer a,b,c, Charles A. Kaufmann d, T. Conrad Gilliam b,d,e, and Andrey Rzhetsky a,b,f,g
aDepartment of Biomedical Informatics, bColumbia Genome Center, Departments of dPsychiatry and eGenetics and Development, and fCenter for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032
Edited by Michael H. Wigler, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, and approved September 7, 2004 (received for review June 16, 2004)
A major challenge in human genetics is identifying the molecular basis of common heritable disorders. In contrast to rare single-gene diseases, multifactorial disorders are thought to arise from the combined effect of multiple gene variants, such that any single variant may have only a modest effect on disease susceptibility. We present a method to identify genes that may harbor a significant proportion of the genetic variation that predisposes individuals to a given multifactorial disorder. First, we perform an automated literature analysis that predicts physical interactions (edges) among candidate disease genes (seed nodes, selected on the basis of prior information) and other molecular entities. We derive models of molecular networks from this analysis and map the seed nodes to them. We then compute the graph-theoretic distance (the minimum number of edges that must be traversed) between the seed nodes and all other nodes in the network. We assume that nodes that are found in close proximity to multiple seed nodes are the best disease-related candidate genes. To evaluate this approach, we selected four seed genes, each with a proven role in Alzheimer's disease (AD). The method performed well in predicting additional network nodes that match AD gene candidates identified manually by an expert. We also show that the method prioritizes among the seed nodes themselves, rejecting false-positive seeds that are derived from (noisy) whole-genome genetic-linkage scans. We propose that this strategy will provide a valuable means to bridge genetic and genomic knowledge in the search for genetic determinants of multifactorial disorders.<<
Open access freebie (pdf): pnas.org
Cheers, Tuck, Posting something before the thread goes bye-bye |
