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Mol Psychiatry. 2018 Dec;23(12):2277-2286. doi: 10.1038/s41380-018-0077-6. Epub 2018 Jun 6.

Translational studies support a role for serotonin 2B receptor (HTR2B) gene in aggression-related cannabis response.

Author information

1
Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.
2
VA CT Healthcare Center, West Haven, CT, USA.
3
INSERM UMR-S 839, F-75005, Paris, France.
4
Sorbonne Universités, UPMC Univ Paris 6, F-75005, Paris, France.
5
Institut du Fer à Moulin, F-75005, Paris, France.
6
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
7
Department of Psychiatry, Harvard Medical School and McLean Hospital, Belmont, MA, USA.
8
Departments of Medicine (Biomedical Genetics), Neurology, Ophthalmology, Epidemiology, and Biostatistics, Boston University Schools of Medicine and Public Health, Boston, MA, USA.
9
Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.
10
Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
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.
12
Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA. joel.gelernter@yale.edu.
13
VA CT Healthcare Center, West Haven, CT, USA. joel.gelernter@yale.edu.
14
Department of Genetics, Yale School of Medicine, New Haven, CT, USA. joel.gelernter@yale.edu.
15
Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA. joel.gelernter@yale.edu.

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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