Monoacylglycerol lipase (MGLL) polymorphism rs604300 interacts with childhood adversity to predict cannabis dependence symptoms and amygdala habituation: Evidence from an endocannabinoid system-level analysis.
- Authors
- Carey, Caitlin E; Agrawal, Arpana; Zhang, Bo; Conley, Emily D; Degenhardt, Louisa; Heath, Andrew C; Li, Daofeng; Lynskey, Michael T; Martin, Nicholas G; Montgomery, Grant W; Wang, Ting; Bierut, Laura J; Hariri, Ahmad R; Nelson, Elliot C; Bogdan, Ryan
- Year
- 2015
- Journal
- Journal of abnormal psychology
- PMID
- 26595473
- DOI
- 10.1037/abn0000079
- PMCID
- PMC4700831
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.
Interaction of rs604300 with childhood sexual abuse to predict cannabis dependence symptoms in CATS. X-axis denotes the log of a participant's CSA score, while y-axis indicates the residualized number of DSM-IV cannabis dependence symptoms endorsed by a participant. Shaded area indicates Johnson-Neyman region of significance. For raw data, see Figure S2. CSA = childhood sexual abuse.* p < .05. ** p < .01. *** p < .001.
Interaction of rs604300 with childhood abuse to predict cannabis dependence symptoms in SAGE. X-axis denotes whether or not a participant experienced abuse before the age of 16, while y-axis indicates residualized number of DSM-IV cannabis dependence symptoms endorsed by that participant. Error bars represent the SEM. For raw data, see Figure S3. CA = childhood abuse.* p < .05. ** p < .01. *** p < .001.
Main effects of fMRI task and interactions with rs604300 to predict threat-related amygdala habituation. A) Bilateral threat-related basolateral amygdala habituation (block 1 > block 2 > block 3 > block 4) across all participants. Right hemisphere: Montreal Neurological Institute (MNI) coordinates = 24, -8, and -16 (t = 9.25, P < .05 FWE), cluster size = 103 voxels. Left hemisphere: MNI coordinates = -22, -8, and -16 (t = 9.00, P < .05 FWE), cluster size = 161 voxels. B) Graph of the interaction between the most significant SNP from the Comorbidity and Trauma Study (CATS), rs604300 in MGLL, with childhood adversity to predict habituation to threat-related stimuli in the right basolateral amygdala in the Duke Neurogenetics Study (DNS). X-axis denotes the log of a participant's score on the Childhood Trauma Questionnaire—Short Form (CTQ), while y-axis indicates amount of neural reactivity to socially-relevant stimuli early in the course of the task relative to later in the task. Shaded area indicates Johnson-Neyman region of significance. For raw data, see Figure S4. R BL = right basolateral.* p < .05. ** p < .01. *** p < .001.
Full structural equation model predicting the effect of childhood sexual abuse (CSA) on cannabis dependence symptoms through using cannabis to control mood, as moderated by rs604300 genotype. The dashed lines represent the indirect effects of CSA on dependence symptoms through the mediator for each genotype group.* p < .05. ** p < .01. *** p < .001.
Methylation and histone-mediated epigenetic signatures and MGLL mRNA expression in brain and blood samples. A) There is little methylation in neurospheres in this region accompanied by H3k4me1 and H3K27ac enrichment. Such enrichment, would serve to enhance MGLL gene expression. In contrast, in blood cells, this region is heavily methylated with no H3k4me1 and H3K27ac enrichment. B) These epigenetic markers of methylation and histone-modification-related enhancement may serve to drive MGLL expression in the brain while suppressing it in blood. Additional details may be found in the Supplement.
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