Large-scale trans-eQTLs affect hundreds of transcripts and mediate patterns of transcriptional co-regulation

Abstract

Genetic variation affecting gene regulation is a driver of phenotypic differences between individuals and can be used to uncover how biological processes are organized in a cell. Although detecting cis-eQTLs is now routine, trans-eQTLs have proven more challenging to find due to the modest variance explained and the multiple testing burden when comparing millions of SNPs for association to thousands of transcripts. Here, we provide evidence for the existence of trans-eQTLs by looking for SNPs associated with the expression of multiple genes simultaneously. We find substantial evidence of trans-eQTLs, with an 1.8-fold enrichment in nominally significant markers in all three populations and significant overlap between results across the populations. These trans-eQTLs target the same genes and show the same direction of effect across populations. We define a high-confidence set of eight independent trans-eQTLs which are associated to multiple transcripts in all three populations, and affect the same targets in all three populations with the same direction of effect. We then show that target transcripts of trans-eQTLs encode proteins that interact more frequently than expected by chance, and are enriched for pathway annotations indicative of roles in basic cell homeostasis. Thus, we have demonstrated that trans-eQTLs can be accurately identified even in studies of limited sample size.