volumes (depicted as smaller volumes for exposed vs. unexposed individuals in Figure 1a). Siblings share 50% of their genes and much of their rearing environment. Therefore, within-pair volumetric differences would be preliminary evidence for causation, pending replication in MZ pairs. Contrast 2 and 3 both hypothesize no volumetric differences between the exposed and unexposed members of the discordant pairs and thus tested facets of the hypothesis that cannabis use and brain volumes share predispositional factors. This would suggest that differences in volume likely pre-date (or co-occur with) cannabis use and that other variables, like genetic liability or rearing environment, may lead to both neural differences and liability to cannabis use. Alternatively, these other factors could contribute to neural differences, in turn increasing liability to cannabis use. Contrast 2 compared brain volumes from concordant exposed pairs to both members of discordant pairs to test exposure-related differences by concordance/discordance (Figure 1b). A significant effect might indicate that concordantly exposed pairs are at greater liability for cannabis use and altered brain volumes (because both siblings have used cannabis) than discordant pairs, i.e. graded liability. Contrast 3 compared volumes from concordant unexposed pairs to all other groups to test whether altered brain volumes and
