Co-expression analysis reveals interpretable gene modules controlled by trans-acting genetic variants
Liis Kolberg, Nurlan Kerimov, Hedi Peterson, Kaur Alasoo
Abstract
Understanding the causal processes that contribute to disease onset and progression is essential for developing novel therapies. Although trans -acting expression quantitative trait loci ( trans -eQTLs) can directly reveal cellular processes modulated by disease variants, detecting trans -eQTLs remains challenging due to their small effect sizes. Here, we analysed gene expression and genotype data from six blood cell types from 226 to 710 individuals. We used co-expression modules inferred from gene expression data with five methods as traits in trans -eQTL analysis to limit multiple testing and improve interpretability. In addition to replicating three established associations, we discovered a novel trans -eQTL near SLC39A8 regulating a module of metallothionein genes in LPS-stimulated monocytes. Interestingly, this effect was mediated by a transient cis -eQTL present only in early LPS response and lost before the trans effect appeared. Our analyses highlight how co-expression combined with functional enrichment analysis improves the identification and prioritisation of trans -eQTLs when applied to emerging cell-type-specific datasets.