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However, relatively little has been done to examine genes associated with orexin signaling and specific behavioral phenotypes in humans. Here, we tested for association of twenty-seven genes involved in orexin signaling with behavioral phenotypes in humans. We tested the full gene set, functional subsets, and individual genes involved in orexin signaling. Our primary phenotype of interest was Externalizing, a composite factor comprised of behaviors and disorders associated with reward-seeking, motivation, and behavioral regulation. We also tested for association with additional phenotypes that have been related to orexin regulation in model organism studies, including alcohol consumption, problematic alcohol use, daytime sleepiness, insomnia, cigarettes per day, smoking initiation, and body mass index. The composite set of 27 genes corresponding to orexin function was highly associated with Externalizing, as well as with alcohol consumption, insomnia, cigarettes per day, smoking initiation and BMI. In addition, all gene subsets (except the <jats:italic>OXR2\/HCRTR2<\/jats:italic> subset) were associated with Externalizing. BMI was significantly associated with all gene subsets. The \u201cvalidated factors for <jats:italic>PPOX<\/jats:italic>\/<jats:italic>HCRT<\/jats:italic>\u201d and \u201c<jats:italic>PPOX<\/jats:italic>\/<jats:italic>HCRT<\/jats:italic> upregulation\u201d gene subsets also were associated with alcohol consumption. Individually, 8 genes showed a strong association with Externalizing, 12 with BMI, 7 with smoking initiation, 3 with alcohol consumption, and 2 with problematic alcohol use, after correction for multiple testing. This study indicates that orexin genes are associated with multiple behaviors and disorders related to self-regulation in humans. This is consistent with prior work in animals that implicated orexin signaling in motivational activation induced by salient stimuli, and supports the hypothesis that orexin signaling is an important potential therapeutic target for numerous behavioral disorders.<\/jats:p>","DOI":"10.1038\/s41380-025-02895-4","type":"journal-article","created":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T20:00:51Z","timestamp":1738180851000},"page":"2922-2930","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Genetic associations between orexin genes and phenotypes related to behavioral regulation in humans, including substance use"],"prefix":"10.1038","volume":"30","author":[{"given":"Fazil","family":"Aliev","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"De Sa Nogueira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"Aston-Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1636-893X","authenticated-orcid":false,"given":"Danielle M.","family":"Dick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,29]]},"reference":[{"key":"2895_CR1","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/S0092-8674(00)80949-6","volume":"92","author":"T Sakurai","year":"1998","unstructured":"Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, et al. 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