Enhancing the prioritization of disease-causing genes through tissue specific protein interaction networks

PLoS Comput Biol. 2012;8(9):e1002690. doi: 10.1371/journal.pcbi.1002690. Epub 2012 Sep 27.

Abstract

The prioritization of candidate disease-causing genes is a fundamental challenge in the post-genomic era. Current state of the art methods exploit a protein-protein interaction (PPI) network for this task. They are based on the observation that genes causing phenotypically-similar diseases tend to lie close to one another in a PPI network. However, to date, these methods have used a static picture of human PPIs, while diseases impact specific tissues in which the PPI networks may be dramatically different. Here, for the first time, we perform a large-scale assessment of the contribution of tissue-specific information to gene prioritization. By integrating tissue-specific gene expression data with PPI information, we construct tissue-specific PPI networks for 60 tissues and investigate their prioritization power. We find that tissue-specific PPI networks considerably improve the prioritization results compared to those obtained using a generic PPI network. Furthermore, they allow predicting novel disease-tissue associations, pointing to sub-clinical tissue effects that may escape early detection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Computer Simulation
  • Genetic Predisposition to Disease / genetics*
  • Humans
  • Models, Biological*
  • Protein Interaction Mapping / methods*
  • Proteome / genetics*
  • Proteome / metabolism*
  • Signal Transduction / genetics*
  • Tissue Distribution

Substances

  • Proteome

Grants and funding

OM and YYW were supported in part by a fellowship from the Edmond J. Safra Bioinformatics program at Tel Aviv University. YYW was also supported by Eshkol Fellowship from the Israeli Ministry of Science and Technology. ER and RS were supported by a Bikura grant from the Israel Science Foundation and a James Mcdonnel Foundation grant. RS was further supported by a research grant from the Israeli Science Foundation (grant no. 241/11). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.