Monoacylglycerol lipase (MGLL) polymorphism rs604300 interacts with childhood adversity to predict cannabis dependence symptoms and amygdala habituation: Evidence from an endocannabinoid system-level analysis.

Year: 2015

Type: article

Abstract: 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 (ΔR2 = .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; ΔR2 = .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 (ΔR2 = .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.

Source: Journal of Abnormal Psychology

DOI: 10.1037/abn0000079

Authors: Caitlin E. Carey, Arpana Agrawal, Bo Zhang, Emily D. Conley, Louisa Degenhardt, Andrew C. Heath, Daofeng Li, Michael T. Lynskey, Nicholas G. Martin, Grant W. Montgomery, Ting Wang, Laura J. Bierut, Ahmad R. Hariri, Elliot C. Nelson, Ryan Bogdan

Institutions: Washington University in St. Louis, 23andMe (United States), UNSW Sydney, National Drug and Alcohol Research Centre, King's College London, QIMR Berghofer Medical Research Institute, Duke University

Language: English

Topic: Cannabis and Cannabinoid Research

Subfield: Pharmacology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Funders: American Cancer Society, Klingenstein Third Generation Foundation, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, National Institute on Aging, National Institute on Drug Abuse, National Human Genome Research Institute, National Cancer Institute, National Institute of Environmental Health Sciences

OpenAlex ID: W2174513597