{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T22:25:10Z","timestamp":1787005510482,"version":"build-2736575974"},"posted":{"date-parts":[[2026,8,13]]},"group-title":"Genomics","reference-count":50,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R56HG013535"],"award-info":[{"award-number":["R56HG013535"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U01DA051234"],"award-info":[{"award-number":["U01DA051234"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P50DA037844"],"award-info":[{"award-number":["P50DA037844"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P30DA060810"],"award-info":[{"award-number":["P30DA060810"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000900","name":"California Institute for Regenerative Medicine","doi-asserted-by":"crossref","award":["EDUC4-12804"],"award-info":[{"award-number":["EDUC4-12804"]}],"id":[{"id":"10.13039\/100000900","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  While thousands of\n                  <jats:italic>cis<\/jats:italic>\n                  expression quantitative trait loci (\n                  <jats:italic>cis<\/jats:italic>\n                  -eQTLs) have been reliably identified, detecting\n                  <jats:italic>trans<\/jats:italic>\n                  -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\n                  <jats:italic>trans<\/jats:italic>\n                  -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\n                  <jats:italic>trans<\/jats:italic>\n                  -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\n                  <jats:italic>trans<\/jats:italic>\n                  -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\n                  <jats:italic>trans<\/jats:italic>\n                  -eQTLs at\n                  <jats:italic>ARHGEF3<\/jats:italic>\n                  and\n                  <jats:italic>IKZF1<\/jats:italic>\n                  . 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\n                  <jats:italic>trans<\/jats:italic>\n                  -eQTLs. One previously unreported\n                  <jats:italic>trans<\/jats:italic>\n                  -eQTL is at the locus harboring\n                  <jats:italic>Jag2<\/jats:italic>\n                  , a critical ligand for the Notch signaling pathway, which is associated with decreased\n                  <jats:italic>Jag2<\/jats:italic>\n                  expression and decreased expression of multiple downstream genes including known Notch targets. A second example is a strong\n                  <jats:italic>trans<\/jats:italic>\n                  -eQTL overlapping a cluster of interferon genes associated with interferon-response genes including\n                  <jats:italic>C4a<\/jats:italic>\n                  and\n                  <jats:italic>Parp14<\/jats:italic>\n                  . We show evidence that this signal is mediated by a\n                  <jats:italic>cis<\/jats:italic>\n                  -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\n                  <jats:italic>trans<\/jats:italic>\n                  -eQTLs with global effects on molecular phenotypes and identify novel biologically compelling examples of such loci.\n                <\/jats:p>","DOI":"10.64898\/2026.08.07.743622","type":"posted-content","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T05:05:10Z","timestamp":1786683910000},"source":"Crossref","is-referenced-by-count":0,"title":["Trex-QTL: A mixture-model for identification of genetic effects with global effects on molecular phenotypes"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3687-2199","authenticated-orcid":false,"given":"Cynthia","family":"Wu","sequence":"first","affiliation":[{"name":"Bioinformatics and Systems Biology Program, UC San Diego, La Jolla, CA, USA"},{"name":"Department of Medicine, UC San Diego, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7928-7950","authenticated-orcid":false,"given":"Andrey","family":"Bzikadze","sequence":"additional","affiliation":[{"name":"Bioinformatics and Systems Biology Program, UC San Diego, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2934-7679","authenticated-orcid":false,"given":"Tianyao","family":"Xu","sequence":"additional","affiliation":[{"name":"Bioinformatics and Systems Biology Program, UC San Diego, La Jolla, CA, USA"},{"name":"Department of Medicine, UC San Diego, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7395-6295","authenticated-orcid":false,"given":"Eric M.","family":"Mendenhall","sequence":"additional","affiliation":[{"name":"Mendex Bio, Huntsville, Alabama, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2680-6921","authenticated-orcid":false,"given":"Hao","family":"Chen","sequence":"additional","affiliation":[{"name":"University of Tennessee Health Science Center, Department of Pharmacology, Addiction Science and Toxicology, Memphis, TN 38103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3877-0628","authenticated-orcid":false,"given":"Francesca","family":"Telese","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, UC San Diego, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3024-114X","authenticated-orcid":false,"given":"Oksana","family":"Polesskaya","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, UC San Diego, La Jolla, CA, 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