A network-based approach to uncover microRNA-mediated disease comorbidities and potential pathobiological implications

Disease–disease relationships (e.g., disease comorbidities) play crucial roles in pathobiological manifestations of diseases and personalized approaches to managing those conditions. In this study, we develop a network-based methodology, termed meta-path-based Disease Network (mpDisNet) capturing algorithm, to infer disease–disease relationships by assembling four biological networks: disease–miRNA, miRNA–gene, disease–gene, and the human protein–protein interactome. mpDisNet is a meta-path-based random walk to reconstruct the heterogeneous neighbors of a given node. mpDisNet uses a heterogeneous skip-gram model to solve the network representation of the nodes. We find that mpDisNet reveals high performance in inferring clinically reported disease–disease relationships, outperforming that of traditional gene/miRNA-overlap approaches. In addition, mpDisNet identifies network-based comorbidities for pulmonary diseases driven by underlying miRNA-mediated pathobiological pathways (i.e., hsa-let-7a- or hsa-let-7b-mediated airway epithelial apoptosis and pro-inflammatory cytokine pathways) as derived from the human interactome network analysis. The mpDisNet offers a powerful tool for network-based identification of disease–disease relationships with miRNA-mediated pathobiological pathways.