Trex-QTL: A mixture-model for identification of genetic effects with global effects on molecular phenotypes
Year: 2026
Type: preprint
Abstract: 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.
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Awards: Interdisciplinary Stem Cell Training Grant at UCSD III, Center for Genetic Studies of Drug Abuse in Outbred Rats, Center for Genetics, Genomics, and Epigenetics of Substance Use Disorders in Outbred Rats, Characterization of Tandem Repeat and Structural Variants Contributing to Addictive Behaviors in Mice and Rats
OpenAlex ID: W7203481546