Therefore, here we extend the Gene Recommender with an approach that can systematically identify trans loci controlling gene co-regulation. We broadly refer to the identification of gene co-expression trait loci as 'co-regulatory expression quantitative trait loci' (creQTL) mapping. Unlike trans-eQTL analysis, our method does not consider individual transcripts but rather focuses on multiple co-regulated transcripts. We provide a genome-wide implementation of the Gene Recommender and a statistical framework for association testing. The key steps of the creQTL approach are: gene clustering; calculation of each sample's similarity to each cluster; and statistical testing of how well genotype explains the similarity. We applied creQTL to a study of germline variants and tumor expression in endometrial cancer [27] and identified many loci significantly associated with gene co-regulation. These loci were commonly in noncoding regions closely in cis with genes encoding proteins required for transcription, signaling, cell adhesion, and development. Our results suggest that associating genetic variants with co-regulation via creQTL mapping provides an efficient and agnostic avenue for detecting biological factors important in the coordinate regulation of groups of genes.
