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Mol Psychiatry. 2018 May;23(5):1293-1302. doi: 10.1038/mp.2017.200. Epub 2017 Nov 7.

Genome-wide association study identifies a novel locus for cannabis dependence.

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Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
Department of Psychological and Brain Sciences, Washington University in St. Louis, St Louis, MO, USA.
Department of Developmental Biology, Washington University School of Medicine, St Louis, MO, USA.
Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Psychiatry, University of Connecticut Health, Farmington, CT, USA.
Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
King's College London, Addictions Department, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
Downstate Medical Center, Department of Psychiatry, State University of New York, Brooklyn, NY, USA.
Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.
Stark Neuroscience Center, Indiana University School of Medicine, Indianapolis, IN, USA.
Rutgers, Department of Genetics, The State University of New Jersey, New Brunswick, NJ, USA.
National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW, Australia.
Yale University School of Medicine, Department of Psychiatry, New Haven, CT, USA.
US Department of Veterans Affairs, West Haven, CT, USA.
Department of Psychology and Neuroscience, Duke University, Durham, NC, USA.
Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, VISN 4 MIRECC, Crescenz VAMC, Philadelphia, PA, USA.
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.
Department of Genetics, Washington University School of Medicine, St Louis, MO, USA.
Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, IN, USA.


Despite moderate heritability, only one study has identified genome-wide significant loci for cannabis-related phenotypes. We conducted meta-analyses of genome-wide association study data on 2080 cannabis-dependent cases and 6435 cannabis-exposed controls of European descent. A cluster of correlated single-nucleotide polymorphisms (SNPs) in a novel region on chromosome 10 was genome-wide significant (lowest P=1.3E-8). Among the SNPs, rs1409568 showed enrichment for H3K4me1 and H3K427ac marks, suggesting its role as an enhancer in addiction-relevant brain regions, such as the dorsolateral prefrontal cortex and the angular and cingulate gyri. This SNP is also predicted to modify binding scores for several transcription factors. We found modest evidence for replication for rs1409568 in an independent cohort of African American (896 cases and 1591 controls; P=0.03) but not European American (EA; 781 cases and 1905 controls) participants. The combined meta-analysis (3757 cases and 9931 controls) indicated trend-level significance for rs1409568 (P=2.85E-7). No genome-wide significant loci emerged for cannabis dependence criterion count (n=8050). There was also evidence that the minor allele of rs1409568 was associated with a 2.1% increase in right hippocampal volume in an independent sample of 430 EA college students (fwe-P=0.008). The identification and characterization of genome-wide significant loci for cannabis dependence is among the first steps toward understanding the biological contributions to the etiology of this psychiatric disorder, which appears to be rising in some developed nations.

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