Format

Send to

Choose Destination
See comment in PubMed Commons below
Proc Natl Acad Sci U S A. 2004 Oct 19;101(42):15148-53. Epub 2004 Oct 7.

Molecular triangulation: bridging linkage and molecular-network information for identifying candidate genes in Alzheimer's disease.

Author information

1
Department of Biomedical Informatics, Columbia University, New York, NY 10032, USA.

Abstract

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.

PMID:
15471992
PMCID:
PMC523448
DOI:
10.1073/pnas.0404315101
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center