Trex-QTL: A mixture-model for identification of genetic effects with global effects on molecular phenotypes.

While thousands of cis expression quantitative trait loci ( cis -eQTLs) have been reliably identified, detecting trans -eQTL effects has proven to be challenging due to insufficient statistical power, lack of comparable tissues and cohorts, and low reproducibility across studies. Here, we present Trex-QTL, a novel trans -eQTL detection method that models eQTL summary statistics as a mixture consisting of both target gene and null associations. Compared to other recently developed methods, Trex-QTL has improved power for trans -eQTL detection and employs a simplified framework, requiring only eQTL association summary statistics as input. We performed extensive simulations to characterize the conditions under which trans -eQTLs are detectable by Trex-QTL across a range of effect sizes and numbers of target genes. We applied Trex-QTL to the Depression Genes and Networks (DGN) dataset and replicated two well-established trans -eQTLs at ARHGEF3 and IKZF1 . We then applied Trex-QTL to the deeply characterized heterogeneous stock (HS) rat cohort with matched brain transcriptomic and genomic data, identifying 7 top-scoring, linkage disequilibrium-independent trans -eQTLs. One previously unreported trans -eQTL is at the locus harboring Jag2 , a critical ligand for the Notch signaling pathway, which is associated with decreased Jag2 expression and decreased expression of multiple downstream genes including known Notch targets. A second example is a strong trans -eQTL overlapping a cluster of interferon genes associated with interferon-response genes including C4a and Parp14 . We show evidence that this signal is mediated by a cis -eQTL for a cluster of interferon ligand genes that operate upstream of interferon receptor signaling. Both of these signals co-localize with association signals for a range of other phenotypes measured in this cohort. Overall, we demonstrate that Trex-QTL represents a powerful method to identify trans -eQTLs with global effects on molecular phenotypes and identify novel biologically compelling examples of such loci.