{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T22:09:59Z","timestamp":1793138999337,"version":"4.5.0"},"posted":{"date-parts":[[2026,2,9]]},"group-title":"Genetic and Genomic Medicine","reference-count":80,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T00:00:00Z","timestamp":1770595200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Externalizing spectrum disorders\u2014spanning attention-deficit\/hyperactivity disorder, conduct disorder, substance use disorders, and other disorders characterized by disinhibition\u2014frequently co-occur within individuals due, in part, to shared genetic etiology. To advance understanding of this genetic architecture, we conducted a multi-ancestry, multivariate genome-wide association analysis of more than 4 million individuals, identifying 1,294 genomic regions linked to an externalizing factor. Fine-mapping and gene prioritization efforts identified 961 effector genes, with the putative causal variant associations showing robust replication in the All of Us Research Program sample. Bioinformatic analyses revealed a broadly distributed neural architecture with early and sustained involvement of GABAergic and glutamatergic neurons. Drug repurposing analyses further highlighted the role of GABA\n                  <jats:sub>A<\/jats:sub>\n                  receptors, as well as dopaminergic signaling, excitatory-inhibitory balance, and neurosteroid pathways. A genome-wide polygenic index predicted \u223c12% of the variance in externalizing in independent cohorts of individuals with European-like ancestry, compared to \u223c3% in individuals with African-like ancestry, and was associated with myriad health and life outcomes. Together, these findings map the shared genetic etiology of externalizing psychopathology and identify neurodevelopmental and synaptic mechanisms with translational relevance.\n                <\/jats:p>","DOI":"10.64898\/2026.02.09.26344198","type":"posted-content","created":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T02:45:26Z","timestamp":1770691526000},"source":"Crossref","is-referenced-by-count":3,"title":["Genomic insights into substance use and disinhibitory disorders"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1471-6566","authenticated-orcid":false,"given":"Camille M.","family":"Williams","sequence":"first","affiliation":[{"name":"Laboratoire de Sciences Cognitives et Psycholinguistique, D\u00e9partement d\u2032\u00c9tudes Cognitives, \u00c9cole Normale Sup\u00e9rieure, EHESS, CNRS, PSL University, Paris, France"},{"name":"Department of Psychology, University of Texas at Austin, Austin, TX, USA"},{"name":"Population Research Center, University of Texas at Austin, Austin, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly E.","family":"Poore","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, USA"},{"name":"Rutgers Addiction Research Center, Brain Health Institute, Rutgers Health, Piscataway, NJ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Londono-Correa","sequence":"additional","affiliation":[{"name":"Department of Psychology, University of Texas at Austin, Austin, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuchen","family":"Ning","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Academic Medical Center, Amsterdam, The Netherlands"},{"name":"Department of Economics, School of Business and Economics, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasia S.","family":"Courchesne-Krak","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of California, San Diego, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maia","family":"Choi","sequence":"additional","affiliation":[{"name":"Rutgers Addiction Research Center, Brain Health Institute, Rutgers Health, Piscataway, NJ, USA"},{"name":"Department of Psychology, School of Arts and Sciences, Rutgers University, NJ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6671-6816","authenticated-orcid":false,"given":"Justin D.","family":"Tubbs","sequence":"additional","affiliation":[{"name":"Center for Precision Psychiatry, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA"},{"name":"Department of Psychiatry, Harvard Medical School, Massachusetts General Hospital, Boston, MA, 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