Genetic factors are strongly implicated in the susceptibility to develop externalizing syndromes such as attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder, conduct disorder, and substance use disorder (SUD). Variants in the ADGRL3 (LPHN3) 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 ADGRL3 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 (n = 2698), recruited either for clinical, genetic epidemiological or pharmacogenomic studies of ADHD, we assembled recursive-partitioning frameworks (classification tree analyses) with clinical, demographic, and ADGRL3 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 ADGRL3 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.
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This study was supported by the National Human Genome Research Institute intramural funds (to M.M.) for the ascertainment of patients from the Paisa population. The Kentucky sample was ascertained using funds from the Eli Lilly Research Foundation (to J.d.L.), a National Alliance for Research on Schizophrenia and Depression (NARSAD) Independent Award (to J.d.L.), University of Kentucky internal funding (to J.d.L.), and Roche Molecular Systems, Inc., who provided free genotyping and laboratory supplies (to J.d.L.). J.I.V. is partially supported by research grant FOFICO 32101-511035-PE0031 from Universidad del Norte, Barranquilla, Colombia. The Multimodal Treatment Study of Children with ADHD (MTA) was a National Institute of Mental Health (NIMH) cooperative agreement randomized clinical trial, continued under an NIMH contract as a follow-up study and finally under a National Institute on Drug Abuse (NIDA) contract followed by a data analysis grant (DA039881). The Spanish sample was recruited, assessed and genotyped using funds from the Instituto de Salud Carlos III, Spain (PI12/01139, PI14/01700, PI15/01789, PI16/01505), and co-financed by the European Regional Development Fund (ERDF); Agència de Gestió d’Ajuts Universitaris i de Recerca-AGAUR, Generalitat de Catalunya (2014SGR1357, 2014SGR0932); Departament de Salut, Generalitat de Catalunya; Ministerio de Economía, Industria y Competitividad, Spain (SAF2015-68341-R); the European College of Neuropsychopharmacology (ECNP network: ‘ADHD across the lifespan’) and a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation. This project has also received funding from the European Union’s Horizon 2020 research and innovation programme (CoCA under grant agreement 667302). C.S.-M. is recipient of a Sara Borrell contract from the Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad, Spain (CD15/00199). M.R. is a recipient of a Miguel de Servet contract from the Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad, Spain (CP09/00119 and CPII15/00023). N.F.-C. was supported by a contract of the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER).
Supplementary information accompanies this paper at: https://doi.org/ 10.1038/s41398-019-0396-7
Arcos-Burgos, Mauricio; Vélez, Jorge I.; Martinez, Ariel F.; Ribasés, Marta; Ramos-Quiroga, Josep A.; Sánchez-Mora, Cristina; Richarte, Vanesa; Roncero, Carlos; Cormand, Bru; Fernández-Castillo, Noelia; Casas, Miguel; Lopera, Francisco; Pineda, David A.; Palacio, Juan D.; Acosta-López, Johan E.; Cervantes-Henriquez, Martha L.; Sánchez-Rojas, Manuel G.; Puentes-Rozo, Pedro J.; Molina, Brooke S. G.; MTA Cooperative Group; Boden, Margaret T.; Wallis, Deeann; Lidbury, Brett; Newman, Saul; Easteal, Simon; Swanson, James; Patel, Hardip; Volkow, Nora; Acosta, Maria T.; Castellanos, Francisco X.; and de Leon, Jose, "ADGRL3 (LPHN3) Variants Predict Substance Use Disorder" (2019). Psychiatry Faculty Publications. 52.