Co-regulatory expression quantitative trait loci mapping: method and application to endometrial cancer

Background: Expression quantitative trait loci (eQTL) studies have helped identify the genetic determinants of gene expression. Understanding the potential interacting mechanisms underlying such findings, however, is challenging. Methods: We describe a method to identify the trans-acting drivers of multiple gene co-expression, which reflects the action of regulatory molecules. This method-termed co-regulatory expression quantitative trait locus (creQTL) mapping-allows for evaluation of a more focused set of phenotypes within a clear biological context than conventional eQTL mapping. Results: Applying this method to a study of endometrial cancer revealed regulatory mechanisms supported by the literature: a creQTL between a locus upstream of STARD13/DLC2 and a group of seven IFN beta-induced genes. This suggests that the Rho-GTPase encoded by STARD13 regulates IFN beta-induced genes and the DNA damage response. Conclusions: Because of the importance of IFN beta in cancer, our results suggest that creQTL may provide a finer picture of gene regulation and may reveal additional molecular targets for intervention. An open source R implementation of the method is available at http://sites.google.com/site/kenkompass/.