Does thinner right entorhinal cortex underlie genetic liability to cannabis use?

Background. Although alterations in medial temporal lobe structures have been previously associated with use of cannabis, one of the most widely used illicit drugs, whether such alterations are a cause or effect of cannabis use has been unclear. Methods. In this cross-sectional observational study involving 404 twins/siblings, we have compared cortical thickness and surface area between groups of gender-matched sibling-pairs (concordant cannabis unexposed, concordant exposed and discordant for cannabis exposure) using permutation tests after controlling for potential confounds. Bi-variate polygenic model was used to assess the genetic and environmental contributions underlying cortical morphological phenotypes and frequency of cannabis use. Results. Cortical thickness of the right entorhinal cortex was significantly lower in the concordant exposed siblings compared to both discordant unexposed and discordant exposed groups [false discovery rate (FDR)-corrected, q < 0.05]. The association between the right entorhinal cortex thickness and frequency of cannabis use is due to the contribution of significant shared additive genetic (rho(g) = -0.19 +/- 0.08; p = 0.02) factors but not unique environment (rho(e) = 0.05 +/- 0.09; p = 0.53). Significantly lower surface area of the right entorhinal cortex in discordant exposed group compared with the discordant unexposed group furnishes preliminary evidence in support of causal effect of cannabis use (FDR-corrected, q < 0.05). However, bi-variate polygenic model-based analysis did not show any significant effect. Conclusions. Shared genetic liability may underlie the association between cannabis exposure and thinner right entorhinal cortex. Prospective longitudinal studies are necessary to definitively disentangle the cause-effect relationships of cannabis use.