A challenge associated with this interpretation is that the functional consequences of rs604300 are not understood. Our examination of gene expression data (publically available at: http://www.braineac.org/) suggest that rs604300 genotype is not associated with global differences in MGLL expression (Hardy, Trabzuni, & Ryten, 2009; Ryten, Trabzuni, & Hardy, 2009). However, if rs604300-related reductions in MGLL expression only occur in the context of childhood adversity, then its main effects may not be observable in curated expression datasets from the general population. Given the exquisite plasticity of eCB signaling in the context of stress, we speculate that the action of rs604300 on cannabis dependence may be epigenetic in nature. While intronic, rs604300 is located just downstream of an enhancer site that is heavily influenced by epigenetic modification (see Supplement). As such, it is possible that rs604300 may result in epigenetically-dependent differences in expression. Future epigenetic research in the context of early life adversity with this locus may be promising.
