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Variants in the <jats:italic>ADGRL3<\/jats:italic> (<jats:italic>LPHN3<\/jats:italic>) gene predispose to ADHD and predict ADHD severity, disruptive behaviors comorbidity, long-term outcome, and response to treatment. In this study, we investigated whether variants within <jats:italic>ADGRL3<\/jats:italic> are associated with SUD, a disorder that is frequently co-morbid with ADHD. Using family-based, case-control, and longitudinal samples from disparate regions of the world (<jats:italic>n<\/jats:italic>\u2009=\u20092698), recruited either for clinical, genetic epidemiological or pharmacogenomic studies of ADHD, we assembled recursive-partitioning frameworks (classification tree analyses) with clinical, demographic, and <jats:italic>ADGRL3<\/jats:italic> genetic information to predict SUD susceptibility. Our results indicate that SUD can be efficiently and robustly predicted in ADHD participants. The genetic models used remained highly efficient in predicting SUD in a large sample of individuals with severe SUD from a psychiatric institution that were not ascertained on the basis of ADHD diagnosis, thus identifying <jats:italic>ADGRL3<\/jats:italic> as a risk gene for SUD. Recursive-partitioning analyses revealed that rs4860437 was the predominant predictive variant. This new methodological approach offers novel insights into higher order predictive interactions and offers a unique opportunity for translational application in the clinical assessment of patients at high risk for SUD.<\/jats:p>","DOI":"10.1038\/s41398-019-0396-7","type":"journal-article","created":{"date-parts":[[2019,1,29]],"date-time":"2019-01-29T18:04:17Z","timestamp":1548785057000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["ADGRL3 (LPHN3) variants predict substance use disorder"],"prefix":"10.1038","volume":"9","author":[{"given":"Mauricio","family":"Arcos-Burgos","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3146-7899","authenticated-orcid":false,"given":"Jorge I.","family":"V\u00e9lez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4109-1928","authenticated-orcid":false,"given":"Ariel F.","family":"Martinez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1039-1116","authenticated-orcid":false,"given":"Marta","family":"Ribas\u00e9s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josep A.","family":"Ramos-Quiroga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"S\u00e1nchez-Mora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanesa","family":"Richarte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1421-7385","authenticated-orcid":false,"given":"Carlos","family":"Roncero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5318-4382","authenticated-orcid":false,"given":"Bru","family":"Cormand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noelia","family":"Fern\u00e1ndez-Castillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Casas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Lopera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Pineda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan D.","family":"Palacio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan E.","family":"Acosta-L\u00f3pez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha L.","family":"Cervantes-Henriquez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel G.","family":"S\u00e1nchez-Rojas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro J.","family":"Puentes-Rozo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brooke S. 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He has received travel awards from Eli Lilly and Co., Janssen-Cilag, and Shire for participating in psychiatric meetings. The ADHD Program chaired by J.A.R.-Q. has received unrestricted educational and research support from Eli Lilly and Co., Janssen-Cilag, Shire, Rovi, Ferrer and Laboratorios Rubi\u00f3 in the past two years. The remaining authors declare that they have no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"42"}}