GeneCOCOA: Detecting context-specific functions of individual genes using co-expression data

Extraction of meaningful biological insight from gene expression profiling often focuses on the identification of statistically enriched terms or pathways. These methods typically use gene sets as input data, and subsequently return overrepresented terms along with associated statistics describing their enrichment. This approach does not cater to analyses focused on a single gene-of-interest, particularly when the gene lacks prior functional characterization. To address this, we formulated GeneCOCOA, a method which utilizes context-specific gene co-expression and curated functional gene sets, but focuses on a user-supplied gene-of-interest (GOI). The co-expression between the GOI and subsets of genes from functional groups (e.g. pathways, GO terms) is derived using linear regression, and resulting root-mean-square error values are compared against background values obtained from randomly selected genes. The resulting p values provide a statistical ranking of functional gene sets from any collection, along with their associated terms, based on their co-expression with the gene of interest in a manner specific to the context and experiment. GeneCOCOA thereby provides biological insight into both gene function, and putative regulatory mechanisms by which the expression of the GOI is controlled. Despite its relative simplicity, GeneCOCOA outperforms similar methods in the accurate recall of known gene-disease associations. We furthermore include a differential GeneCOCOA mode, thus presenting the first implementation of a gene-focused approach to experiment-specific gene set enrichment analysis. GeneCOCOA is formulated as an R package for ease-of-use, available at https://github.com/si-ze/geneCOCOA.