Evidence of familial confounding of the association between cannabis use and cerebellar-cortical functional connectivity using a twin study.

Cerebellar-cortical resting-state functional connectivity (rsFC) has been reported to be altered in cannabis users. However, this association may be due to genetic and environmental confounding rather than a causal relationship between cannabis use and changes in rsFC. In this co-twin control study, linear mixed models were used to assess relationships between the number of lifetime cannabis uses (NLCU) and age of cannabis onset (ACO) with cerebellar-cortical rsFC. The rsFC with seven functional networks was evaluated in 147 monozygotic and 82 dizygotic twin pairs. Importantly, the use of genetically informed models in this twin sample facilitated examining whether shared genetic or environmental effects underlie crude associations between cannabis measures and connectivity. Individual-level phenotypic analyses (i.e., accounting for twin-pair non-independence) showed that individuals in the full sample with earlier ACO and higher NLCU had lower cerebellar rsFC within the VA, DA, and FP networks. Yet, there were no significant differences in cerebellar-cortical rsFC between monozygotic twins who were discordant for cannabis measures. These findings suggest shared genetic or environmental confounds contribute to associations between cannabis use and altered cerebellar-cortical rsFC, rather than unique causal impacts of cannabis use on cerebellar-cortical rsFC.