Discovery of protein interaction networks shared by diseases

Abstract

The study of protein-protein interactions is essential to define the molecular networks that contribute to maintain homeostasis of an organism's body functions. Disruptions in protein interaction networks have been shown to result in diseases in both humans and animals. Monogenic diseases disrupting biochemical pathways such as hereditary coagulopathies (e.g. hemophilia), provided a deep insight in the biochemical pathways of acquired coagulopathies of complex diseases. Indeed, a variety of complex liver diseases can lead to decreased synthesis of the same set of coagulation factors as in hemophilia. Similarly, more complex diseases such as different cancers have been shown to result from malfunctions of common proteins pathways. In order to discover, in high throughput, the molecular underpinnings of poorly characterized diseases, we present a statistical method to identify shared protein interaction network(s) between diseases. Integrating (i) a protein interaction network with (ii) disease to protein relationships derived from mining Gene Ontology annotations and the biomedical literature with natural language understanding (PhenoGO), we identified protein-protein interactions that were associated with pairs of diseases and calculated the statistical significance of the occurrence of interactions in the protein interaction knowledgebase. Significant correlations between diseases and shared protein networks were identified and evaluated in this study, demonstrating the high precision of the approach and correct non-trivial predictions, signifying the potential for discovery. In conclusion, we demonstrate that the associations between diseases are directly correlated to their underlying protein-protein interaction networks, possibly providing insight into the underlying molecular mechanisms of phenotypes and biological processes disrupted in related diseases.

Figure 1. Method to correlate human diseases based on their underlying protein interactions. M and m refer to parameters of the hypergeometric calculations as described in equation 1

Figure 2. Distribution of the number of disease pairs from PhenoGO according to the number of possible protein interactions observed between their proteins in the Reactome

Figure 3. Protein interactions between Xeroderma Pigmentosum and Cockayne Syndrome

Shared proteins between the two diseases are represented (top), proteins in the Cockayne syndrome (right), and those in the Xeroderma Pigmentosum (left). Protein interactions between the two diseases are linked by lines.