Abstract

Cannabis use is increasing in the United States, as are its adverse effects. We investigated the genetics of an adverse consequence of cannabis use: cannabis-related aggression (CRA) using a genome-wide association study (GWAS) design. Our GWAS sample included 3269 African Americans (AAs) and 2546 European Americans (EAs). An additional 89 AA subjects from the Grady Trauma Project (GTP) were also examined using a proxy-phenotype replication approach. We identified genome-wide significant risk loci contributing to CRA in AAs at the serotonin receptor 2B receptor gene (HTR2B), and the lead SNP, HTR2B*rs17440378, showed nominal association to aggression in the GTP cohort of cannabis-exposed subjects. A priori evidence linked HTR2B to impulsivity/aggression but not to cannabis response. Human functional data regarding the HTR2B variant further supported our finding. Treating an Htr2b−/− knockout mouse with THC resulted in increased aggressive behavior, whereas wild-type mice following THC administration showed decreased aggression in the resident-intruder paradigm, demonstrating that HTR2B variation moderates the effects of cannabis on aggression. These concordant findings in mice and humans implicate HTR2B as a major locus associated with cannabis-induced aggression.

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Acknowledgements

We appreciate the work in recruitment and assessment provided at Yale University School of Medicine and the APT Foundation by James Poling, Ph.D.; at McLean Hospital by Roger Weiss, M.D., at the Medical University of South Carolina by Kathleen Brady, M.D., Ph.D., and Raymond Anton, M.D.; and at the University of Pennsylvania by David Oslin, M.D. We are grateful to Ann Marie Lacobelle and Christa Robinson for their excellent technical assistance, to the SSADDA interviewers who devoted substantial time and effort to phenotype the study sample, and to John Farrell and Alexan Mardigan for database management assistance. Assistance with data cleaning was provided by the National Center for Biotechnology Information. This study was supported by National Institutes of Health grants RC2 DA028909, R01 DA12690, R01 DA12849, R01 DA18432, R01 AA11330, R01 AA017535, and the VA Connecticut and Philadelphia VA MIRECCs; the Biological Sciences Training Program through Grant Number 5T32 MH14276 and the NARSAD Young Investigator Grant to JLMO. Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the NIH contract “High-throughput genotyping for studying the genetic contributions to human disease” (HHSN268200782096C). LM and ID’A have been supported by funds from the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale, the Université Pierre et Marie Curie, and by grants from the Fondation pour la Recherche Médicale “Equipe FRM DEQ2014039529”, the French Ministry of Research (Agence Nationale pour la Recherche ANR-12-BSV1-0015 and ANR-17-CE16-0008 and the Investissements d’Avenir programme ANR-11-IDEX-0004-02). LM’s team is part of the École des Neurosciences de Paris Ile-de-France network and of the Bio-Psy Labex and as such this work was supported by French state funds managed by the ANR within the Investissements d’Avenir programme under reference ANR-11-IDEX-0004-02.

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Affiliations

  1. Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA

    • Janitza L. Montalvo-Ortiz
    • , Hang Zhou
    • , Yaira Z. Nuñez
    •  & Joel Gelernter
  2. INSERM UMR-S 839, F-75005, Paris, France

    • Ivana D’Andrea
    •  & Luc Maroteaux
  3. Sorbonne Universités, UPMC Univ Paris 6, F-75005, Paris, France

    • Ivana D’Andrea
    •  & Luc Maroteaux
  4. Institut du Fer à Moulin, F-75005, Paris, France

    • Ivana D’Andrea
    •  & Luc Maroteaux
  5. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA

    • Adriana Lori
    •  & Alicia Smith
  6. Department of Psychiatry, Harvard Medical School and McLean Hospital, Belmont, MA, USA

    • Kerry J. Ressler
  7. VA CT Healthcare Center, West Haven, CT, USA

    • Janitza L. Montalvo-Ortiz
    • , Yaira Z. Nuñez
    •  & Joel Gelernter
  8. Departments of Medicine (Biomedical Genetics), Neurology, Ophthalmology, Epidemiology, and Biostatistics, Boston University Schools of Medicine and Public Health, Boston, MA, USA

    • Lindsay A. Farrer
  9. Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA

    • Hongyu Zhao
  10. Department of Genetics, Yale School of Medicine, New Haven, CT, USA

    • Hongyu Zhao
    •  & Joel Gelernter
  11. Department of Psychiatry, Center for Studies of Addiction and Crescenz Veterans Affairs Medical Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    • Henry R. Kranzler
  12. Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA

    • Joel Gelernter

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Conflict of interest

Although unrelated to the current study, HRK has been a consultant, advisory board member, or CME speaker for Indivior and Lundbeck. He is also a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which in the last 3 years was supported by Abbvie, Alkermes, Amygdala Neurosciences, Arbor, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, and Pfizer. The remaining authors declare that they have no conflict of interest.

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Correspondence to Joel Gelernter.

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DOI

https://doi.org/10.1038/s41380-018-0077-6