The minor allele of rs1409568, which was more common in cannabis dependent cases in the meta-analysis, was associated with increased hippocampal volume. This finding is also inconsistent with the hypothesis that liability to heavy cannabis use should relate to decreased hippocampal volume. There are, at least, two plausible explanations for our observation of the opposite association. First, it is possible that the association between rs1409568 and hippocampal volume is independent of its association with cannabis dependence in the meta-analysis. While such a pleiotropic effect adds encouraging evidence favoring a role of rs1409568 in neural regions typically associated with addiction, and augments its functional plausibility, it does not help reconcile the mechanism by which rs1409568 might influence liability to cannabis dependence. Second, the association between rs1409568 and hippocampal volume did not replicate in the large ENIGMA meta-analysis. This raises the possibility that the association is a false positive in DNS and suggests that caution is warranted in its interpretation.
