EnrichNet: network-based gene set enrichment analysis

Motivation: Assessing functional associations between an experimentally derived gene or protein set of interest and a database of known gene/protein sets is a common task in the analysis of large-scale functional genomics data. For this purpose, a frequently used approach is to apply an over-representation-based enrichment analysis. However, this approach has four drawbacks: (i) it can only score functional associations of overlapping gene/proteins sets; (ii) it disregards genes with missing annotations; (iii) it does not take into account the network structure of physical interactions between the gene/protein sets of interest and (iv) tissue-specific gene/protein set associations cannot be recognized. Results: To address these limitations, we introduce an integrative analysis approach and web-application called EnrichNet. It combines a novel graph-based statistic with an interactive sub-network visualization to accomplish two complementary goals: improving the prioritization of putative functional gene/protein set associations by exploiting information from molecular interaction networks and tissue-specific gene expression data and enabling a direct biological interpretation of the results. By using the approach to analyse sets of genes with known involvement in human diseases, new pathway associations are identified, reflecting a dense sub-network of interactions between their corresponding proteins.