title: Monoacylglycerol lipase (MGLL) polymorphism rs604300 interacts with childhood adversity to predict cannabis dependence symptoms and amygdala habituation: Evidence from an endocannabinoid system-level analysis.
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.
authors.affiliation: Department of Psychology, Washington University in St. Louis.
authors.forename: Caitlin E
authors.initials: CE
authors.lastname: Carey
authors.affiliation: Department of Psychiatry, Washington University in St. Louis.
authors.forename: Arpana
authors.initials: A
authors.lastname: Agrawal
authors.affiliation: Department of Genetics, Washington University in St. Louis.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: 23andMe.
authors.forename: Emily D
authors.initials: ED
authors.lastname: Conley
authors.affiliation: National Drug and Alcohol Research Centre, University of New South Wales.
authors.forename: Louisa
authors.initials: L
authors.lastname: Degenhardt
authors.affiliation: Department of Psychiatry, Washington University in St. Louis.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Heath
authors.affiliation: Department of Genetics, Washington University in St. Louis.
authors.forename: Daofeng
authors.initials: D
authors.lastname: Li
authors.affiliation: Institute of Psychiatry, Kings College London.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lynskey
authors.affiliation: Berghofer Medical Research Institute.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: Berghofer Medical Research Institute.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.affiliation: Department of Genetics, Washington University in St. Louis.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, Washington University in St. Louis.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Bierut
authors.affiliation: Department of Psychology and Neuroscience, Duke University.
authors.forename: Ahmad R
authors.initials: AR
authors.lastname: Hariri
authors.affiliation: Department of Psychiatry, Washington University in St. Louis.
authors.forename: Elliot C
authors.initials: EC
authors.lastname: Nelson
authors.affiliation: Department of Psychology, Washington University in St. Louis.
authors.forename: Ryan
authors.initials: R
authors.lastname: Bogdan
mesh_terms: D000293:Adolescent; D000328:Adult; D054523:Adult Survivors of Child Abuse / Q000523:psychology*; D000581:Amidohydrolases / Q000235:genetics; D000679:Amygdala / Q000503:physiopathology*; D063388:Endocannabinoids / Q000235:genetics; D005260:Female; D059647:Gene-Environment Interaction; D005838:Genotype; D006801:Humans; D008016:Life Change Events; D008071:Lipoprotein Lipase / Q000235:genetics; D008297:Male; D002189:Marijuana Abuse / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology / Q000523:psychology; D008875:Middle Aged; D008994:Monoacylglycerol Lipases / Q000235:genetics*; D010739:Phospholipase D / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics; D055815:Young Adult; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D063388:Endocannabinoids; D008071:Lipoprotein Lipase; D008994:Monoacylglycerol Lipases; D010739:Phospholipase D; D043884:Receptor, Cannabinoid, CB1; D000099252:Fatty Acid Amide Hydrolases; C571130:CNR1 protein, human; C480280:DAGLA protein, human; C480281:DAGLB protein, human; C581518:NAPEPLD protein, human