ADGRL3 (LPHN3) variants predict substance use disorder

doi:10.1038/s41398-019-0396-7

ADGRL3 (LPHN3) variants predict substance use disorder

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Abstract

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.

Original language	English
Article number	42
Journal	Translational Psychiatry
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41398-019-0396-7
State	Published - Dec 1 2019

Bibliographical note

Funding Information:
First and foremost, we thank all the patients who participated in this study. 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).

Publisher Copyright:
© 2019, The Author(s).

ASJC Scopus subject areas

Psychiatry and Mental health
Cellular and Molecular Neuroscience
Biological Psychiatry

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10.1038/s41398-019-0396-7

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@article{16cfba6cd37142c2b3b4a350bd0b32a4,

title = "ADGRL3 (LPHN3) variants predict substance use disorder",

abstract = "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.",

author = "Mauricio Arcos-Burgos and V{\'e}lez, {Jorge I.} and Martinez, {Ariel F.} and Marta Ribas{\'e}s and Ramos-Quiroga, {Josep A.} and Cristina S{\'a}nchez-Mora and Vanesa Richarte and Carlos Roncero and Bru Cormand and Noelia Fern{\'a}ndez-Castillo and Miguel Casas and Francisco Lopera and Pineda, {David A.} and Palacio, {Juan D.} and Acosta-L{\'o}pez, {Johan E.} and Cervantes-Henriquez, {Martha L.} and S{\'a}nchez-Rojas, {Manuel G.} and Puentes-Rozo, {Pedro J.} and Molina, {Brooke S.G.} and Boden, {Margaret T.} and Deeann Wallis and Brett Lidbury and Saul Newman and Simon Easteal and James Swanson and Hardip Patel and Nora Volkow and Acosta, {Maria T.} and Castellanos, {Francisco X.} and {de Leon}, Jose and Mastronardi, {Claudio A.} and Maximilian Muenke",

note = "Funding Information: First and foremost, we thank all the patients who participated in this study. 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); Ag{\`e}ncia de Gesti{\'o} d{\textquoteright}Ajuts Universitaris i de Recerca-AGAUR, Generalitat de Catalunya (2014SGR1357, 2014SGR0932); Departament de Salut, Generalitat de Catalunya; Ministerio de Econom{\'i}a, Industria y Competitividad, Spain (SAF2015-68341-R); the European College of Neuropsychopharmacology (ECNP network: {\textquoteleft}ADHD across the lifespan{\textquoteright}) and a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation. This project has also received funding from the European Union{\textquoteright}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 Econom{\'i}a, 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 Econom{\'i}a, Industria y Competitividad, Spain (CP09/00119 and CPII15/00023). N.F.-C. was supported by a contract of the Centro de Investigaci{\'o}n Biom{\'e}dica en Red de Enfermedades Raras (CIBERER). Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41398-019-0396-7",

language = "English",

volume = "9",

number = "1",

}

TY - JOUR

T1 - ADGRL3 (LPHN3) variants predict substance use disorder

AU - Arcos-Burgos, Mauricio

AU - Vélez, Jorge I.

AU - Martinez, Ariel F.

AU - Ribasés, Marta

AU - Ramos-Quiroga, Josep A.

AU - Sánchez-Mora, Cristina

AU - Richarte, Vanesa

AU - Roncero, Carlos

AU - Cormand, Bru

AU - Fernández-Castillo, Noelia

AU - Casas, Miguel

AU - Lopera, Francisco

AU - Pineda, David A.

AU - Palacio, Juan D.

AU - Acosta-López, Johan E.

AU - Cervantes-Henriquez, Martha L.

AU - Sánchez-Rojas, Manuel G.

AU - Puentes-Rozo, Pedro J.

AU - Molina, Brooke S.G.

AU - Boden, Margaret T.

AU - Wallis, Deeann

AU - Lidbury, Brett

AU - Newman, Saul

AU - Easteal, Simon

AU - Swanson, James

AU - Patel, Hardip

AU - Volkow, Nora

AU - Acosta, Maria T.

AU - Castellanos, Francisco X.

AU - de Leon, Jose

AU - Mastronardi, Claudio A.

AU - Muenke, Maximilian

N1 - Funding Information: First and foremost, we thank all the patients who participated in this study. 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). Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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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ER -

ADGRL3 (LPHN3) variants predict substance use disorder

Abstract

Bibliographical note

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UN SDGs

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