2007). This vertical pleiotropy does not violate the assumptions of MR, but simply means there are intermediate mechanisms operating between the exposure and the outcome. However, the strong effects we observe for lifetime smoking suggest that any mediating influence of cannabis use is likely to only partially account for these effects, given the relatively low prevalence of cannabis use [e.g. annual prevalence in the UK of ~7% in 2010 (United Nations Office on Drugs and Crime (UNODC), 2011)]. Multivariable MR analysis of tobacco and cannabis use would help resolve this question.
