{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T13:27:47Z","timestamp":1768570067298,"version":"3.49.0"},"posted":{"date-parts":[[2025,9,29]]},"group-title":"Genetic and Genomic Medicine","reference-count":86,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T00:00:00Z","timestamp":1759104000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,9,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Epistasis causes an individual\u2019s genetic background to modulate a DNA variant\u2019s effect on trait [1\u20136]. Epistatic interactions among different loci in human complex traits are expected to be widespread but have not been found [7]. This could be due to small interaction effect sizes, the statistical complexity of estimating interactions that is higher than marginal variant effects, and a substantial multiple testing burden in a genome-wide scan [8\u201311]. Targeting interacting variants that contribute to the same biological pathway could lighten this burden. Here we combined Targeted Machine Learning [12, 13] with experimentally verified differential binding variants across 9 nuclear hormone receptors (NHR) to identify 535 two-point DNA variant-variant and 185 three-point variant-variant-sex NHR interactions among 768 traits in the UK Biobank (UKB) at a false discovery rate per trait of less than 0.05. Significance testing combined k allele-specific components into a Hotelling\u2019s\n                  <jats:italic>T<\/jats:italic>\n                  <jats:sup>2<\/jats:sup>\n                  test of Average Interaction Effect estimates at pairs\/triples of loci (\n                  <jats:italic>k<\/jats:italic>\n                  \u2264 4 or\n                  <jats:italic>k<\/jats:italic>\n                  \u2264 8 for 2- or 3-point interactions, respectively). Nearly a third of 2-point interactions replicated, as they involved the same DNA-binding site and human trait but different trans-acting DNA variants. These epistatic mechanisms of altered transcription factor binding provide both plausible molecular mechanisms of action, and insight into sex-biased genetic risk, for diverse human traits and diseases.\n                <\/jats:p>","DOI":"10.1101\/2025.09.28.25336826","type":"posted-content","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T22:55:16Z","timestamp":1759186516000},"source":"Crossref","is-referenced-by-count":0,"title":["Epistatic contributions to human traits via transcription factor mechanisms"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1119-2576","authenticated-orcid":false,"given":"Breeshey","family":"Roskams-Hieter","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3708-3706","authenticated-orcid":false,"given":"Olivier","family":"Labayle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelsey","family":"Tetley-Campbell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1432-5511","authenticated-orcid":false,"given":"Mark J.","family":"van der Laan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0202-7816","authenticated-orcid":false,"given":"Chris P.","family":"Ponting","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7998-4262","authenticated-orcid":false,"given":"Sjoerd V.","family":"Beentjes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5203-2205","authenticated-orcid":false,"given":"Ava","family":"Khamseh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025100101501071000_2025.09.28.25336826v1.1","doi-asserted-by":"crossref","unstructured":"Mackay, T. & Moore, J. 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