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Artigos Científicos

terça-feira, 29 janeiro 2019 17:08

ADGRL3 (LPHN3) variants predict substance use disorder

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Mauricio Arcos-Burgos1,2,3, Jorge I. Vélez1,4, Ariel F. Martinez1, Marta Ribasés 5,6,7, Josep A. Ramos-Quiroga5,6,7,8, Cristina Sánchez-Mora5,6,7, Vanesa Richarte6,7,8, Carlos Roncero6,7,8,9, Bru Cormand10,11,12,13, Noelia Fernández-Castillo10,11,12,13, Miguel Casas5,6,7,8, Francisco Lopera14, David A. Pineda14, Juan D. Palacio14Johan E. Acosta-López15, Martha L. Cervantes-Henriquez4, 15, Manuel G. Sánchez-Rojas15, Pedro J. Puentes-Rozo15,16, Brooke S. G. Molina17, MTA Cooperative Group17, Margaret T. Boden18, Deeann Wallis19, Brett Lidbury20, Saul Newman20, Simon Easteal20, James Swanson21, 22, Hardip Patel23, Nora Volkow24, Maria T. Acosta1, Francisco X. Castellanos25, 26, Jose de Leon18, Claudio A. Mastronardi2, 27, Maximilian Muenke1

Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD USA
INPAC Research Group, Fundación Universitaria Sanitas, Bogotá, Colombia
Instituto de Investigaciones Médicas (IIM), Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
Universidad del Norte, Barranquilla, Colombia
Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
Department of Psychiatry, Hospital Universitari Vall d’Hebron, Barcelona, Spain
Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain
Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
Addiction and Dual Diagnosis Unit, Departament of Psychiatry, Hospital Universitari Vall d’Hebron-Public Health Agency, Barcelona, Spain
Department of Genetics, Microbiology and Statistics, University of Barcelona, Barcelona, CAT Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, CAT Spain
Institut de Recerca Sant Joan de Déu (IRSJD), Esplugues, CAT Spain
Neuroscience Research Group, Universidad de Antioquia, Medellín, Colombia
Grupo de Neurociencias del Caribe, Unidad de Neurociencias Cognitivas, Universidad Simón Bolívar, Barranquilla, Colombia
Grupo de Neurociencias del Caribe, Universidad del Atlántico, Barranquilla, Colombia
Departments of Psychiatry and Psychology, University of Pittsburg, Pittsburg, PA USA
University of Kentucky Mental Health Research Center at Eastern State Hospital, Lexington, KY USA
Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX USA
National Center for Indigenous Genomics, Genome Biology Department, John Curtin School of Medical Research, ANU College of Medicine, Biology and Environment, The Australian National University, Canberra, ACT Australia
Department of Psychiatry, Florida International University, Miami, FL USA
Child Development Center, University of California at Irvine, Irvine, CA USA
Genome Discovery Unit, Genome Biology Department, John Curtin School of Medical Research, ANU College of Medicine, Biology and Environment, The Australian National University, Canberra, ACT Australia
Oasi Institute (IRCCS), Troina, ItalyOffice of the Director, National Institute on Drug Abuse, National Institutes of Health, Rockville, MD USA
Department of Child and Adolescent Psychiatry, Hassenfeld Children’s Hospital at NYU Langone, New York, NY USA
Nathan Kline Institute for Psychiatric Research, Orangeburg, NY USA
Center for Research in Genetics and Genomics, Institute of Translational Medicine, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia

US National Library of Medicine National Institutes of Health

2019 Jan 29


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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