Journal
JOURNAL OF ABNORMAL PSYCHOLOGY
Volume 124, Issue 4, Pages 860-877Publisher
AMER PSYCHOLOGICAL ASSOC
DOI: 10.1037/abn0000079
Keywords
cannabis; endocannabinoid; childhood abuse; MGLL; amygdala
Funding
- National Science Foundation [DGE-1143954]
- American Cancer Society [RSG-14-049-01-DMC]
- NIH [R01HG007354, R01HG007175, R01ES024992, HHSN268200782096C]
- Australian National Health and Medical Research Council (NHMRC) [1041472]
- National Institute on Drug Abuse [DA033369, DA031579, R01 DA17305]
- Klingenstein Third Generation Foundation
- National Institutes of Health [NIA R01-AG045231, N01-HG-65403]
- Australian Government under the Substance Misuse Prevention and Service Improvements Grants Fund
- NIH Genes, Environment and Health Initiative [GEI] [U01 HG004422]
- Gene Environment Association Studies (GENEVA) under GEI
- Collaborative Study on the Genetics of Alcoholism (COGA) [U10 AA008401]
- Collaborative Genetic Study of Nicotine Dependence (COGEND) [P01 CA089392]
- Family Study of Cocaine Dependence (FSCD) [R01 DA013423, R01 DA019963]
- NIH GEI [U01HG004438]
- National Institute on Alcohol Abuse and Alcoholism
- Duke University
- [R01DA23668]
- [K02DA32573]
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Despite evidence for heritable variation in cannabis involvement and the discovery of cannabinoid receptors and their endogenous ligands, no consistent patterns have emerged from candidate endocannabinoid (eCB) genetic association studies of cannabis involvement. Given interactions between eCB and stress systems and associations between childhood stress and cannabis involvement, it may be important to consider childhood adversity in the context of eCB-related genetic variation. We employed a system-level gene-based analysis of data from the Comorbidity and Trauma Study N = 1,558) to examine whether genetic variation in six eCB genes anabolism: DAGLA, DAGLB, NAPEPLD; catabolism: MGLL, FAAH; binding: CNR1; SNPs N = 65) and childhood sexual abuse CSA) predict cannabis dependence symptoms. Significant interactions with CSA emerged for MGLL at the gene level p = .009), and for rs604300 within MGLL (Delta R-2 = .007, p = .001), the latter of which survived SNP-level Bonferroni correction and was significant in an additional sample with similar directional effects N = 859; Delta R-2 = .005, p = .026). Furthermore, in a third sample N = 312), there was evidence that rs604300 genotype interacts with early life adversity to predict threat-related basolateral amygdala habituation, a neural phenotype linked to the eCB system and addiction (Delta R-2 = .013, p = .047). Rs604300 may be related to epigenetic modulation of MGLL expression. These results are consistent with rodent models implicating 2-arachidonoylglycerol 2-AG), an endogenous cannabinoid metabolized by the enzyme encoded by MGLL, in the etiology of stress adaptation related to cannabis dependence, but require further replication.
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