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Attention-deficit/hyperactivity disorder and lifetime cannabis use: genetic overlap and causality

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Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a severely impairing neurodevelopmental disorder with a prevalence of 5% in children and adolescents and of 2.5% in adults. Comorbid conditions in ADHD play a key role in symptom progression, disorder course and outcome. ADHD is associated with a significantly increased risk for substance use, abuse and dependence. ADHD and cannabis use are partly determined by genetic factors; the heritability of ADHD is estimated at 70–80% and of cannabis use initiation at 40–48%. In this study, we used summary statistics from the largest available meta-analyses of genome-wide association studies (GWAS) of ADHD (n = 53,293) and lifetime cannabis use (n = 32,330) to gain insights into the genetic overlap and causal relationship of these two traits. We estimated their genetic correlation to be r2 = 0.29 (P = 1.63 × 10−5) and identified four new genome-wide significant loci in a cross-trait analysis: two in a single variant association analysis (rs145108385, P = 3.30 × 10−8 and rs4259397, P = 4.52 × 10−8) and two in a gene-based association analysis (WDPCP, P = 9.67 × 10−7 and ZNF251, P = 1.62 × 10−6). Using a two-sample Mendelian randomization approach we found support that ADHD is causal for lifetime cannabis use, with an odds ratio of 7.9 for cannabis use in individuals with ADHD in comparison to individuals without ADHD (95% CI (3.72, 15.51), P = 5.88 × 10−5). These results substantiate the temporal relationship between ADHD and future cannabis use and reinforce the need to consider substance misuse in the context of ADHD in clinical interventions.

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Acknowledgements

We are grateful to patients from the Hospital Universitari Vall d’Hebron who kindly participated in this research. Genotyping was performed at the Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and financially supported by the Netherlands Scientific Organization (NWO 480-05-003 PI: Posthuma) along with a supplement from the Dutch Brain Foundation and the VU University Amsterdam. S.V.F. is supported by the K.G. Jebsen Center for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway, the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no 602805, the European Union’s Horizon 2020 research and innovation programme under grant agreements No 667302 & 728018 and NIMH grants 5R01MH101519 and U01 MH109536-01. B.F.‘s research is supported by a personal grant from the Netherlands Organization for Scientific Research (NWO) Vici Innovation Program (grant 016-130-669). Additional support is received from the European Community’s Seventh Framework Programme (FP7/2007-13) under grant agreement n° 602805 (Aggressotype), and from the European Community’s Horizon 2020 Programme (H2020/2014-20) under grant agreements n° 643051 (MiND), and n° 667302 (CoCA). I.G.M. is a recipient of a contract from the 7th Framework Programme for Research, Technological Development and Demonstration, European Commission (AGGRESSOTYPE_FP7HEALTH2013/602805). B.M.N. was supported by the National Institutes of Health (1R01MH094469). Over the course of this investigation, M.P. has been a recipient of a pre-doctoral fellowship from the Vall d’Hebron Research Institute (PRED-VHIR-2013) and a research grant from the Deutscher Akademischer Austauschdienst (DAAD), Germany (Research Grants - Short-Term Grants, 2017). M.R. is a recipient of a Miguel de Servet contract from the Instituto de Salud Carlos III, Spain (CP09/00119 and CPII15/00023). P.R. is a recipient of a pre-doctoral fellowship from the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR), Generalitat de Catalunya, Spain (2016FI_B 00899). C.S.M. is a recipient of a Sara Borrell contract and a mobility grant from the Spanish Ministerio de Economía y Competitividad, Instituto de Salud Carlos III (CD15/00199 and MV16/00039). M.S.A. is a recipient of a contract from the Biomedical Network Research Center on Mental Health (CIBERSAM), Madrid, Spain. J.M.V. was supported by the European Research Council (ERC-284167). This work was funded by Instituto de Salud Carlos III (PI14/01700, PI15/01789, PI16/01505, PI17/00289), and co-financed by the European Regional Development Fund (ERDF), Agència de Gestió d’Ajuts Universitaris i de Recerca-AGAUR, Generalitat de Catalunya, Spain (2014SGR1357, 2017SGR1461), the Health Research and Innovation Strategy Plan (PERIS SLT006/17/287), Generalitat de Catalunya, Spain, the European College of Neuropsychopharmacology (ECNP network: ‘ADHD across the lifespan’), Departament de Salut, Generalitat de Catalunya, Spain, and a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation. The research leading to these results has received funding from the European Union Seventh Framework Program (FP72007-2013) under grant agreement No 602805 and from the European Union H2020 Programme (H2020/2014-20) under grant agreements Nos. 667302 (CoCA) and 643051 (MiND) and 728018 (Eat2BeNICE). The iPSYCH project is funded by the Lundbeck Foundation (grant numbers R102-A9118 and R155-2014-1724) and the universities and university hospitals of Aarhus and Copenhagen. The European Community’s Horizon 2020 Programme (H2020/2014-20) under Grant No. 667302 (CoCA). Analyses of the iPSYCH data was done using the high-performance computer capacity on the GenomeDK HPC facility provided by the Center for Integrative Sequencing, iSEQ, Aarhus Genome Center, Aarhus University, Denmark, funded by grants from Aarhus University and Aarhus University Hospital.

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Conflict of interest

M.C. has received travel grants and research support from Eli Lilly and Co., Janssen-Cilag, Shire, and Laboratorios Rubió. He has been on the advisory board and served as a consultant for Eli Lilly and Co., Janssen-Cilag, Shire, and Laboratorios Rubió. In the past year, S.V.F. received income, potential income, travel expenses continuing education support and/or research support from Otsuka, Arbor, Ironshore, Shire, Akili Interactive Labs, CogCubed, Alcobra, VAYA, Ironshore, Sunovion, and Genomind. With his institution, he has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. B.F. has received educational speaking fees from Shire and Medice. J.A.R.Q. has served on the speakers’ bureau and acted as a consultant for Eli Lilly and Co., Janssen-Cilag, Novartis, Lundbeck, Shire, Ferrer, and Laboratorios Rubió. 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, and Laboratorios Rubió in the past two years. The remaining authors declare that they have no conflict of interest.

Correspondence to María Soler Artigas or Marta Ribasés.

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