Marijuana is the most commonly used illicit drug (Substance Abuse and Mental Health Services Administration 2007), and the proportion of users who meet DSM-IV (American Psychiatric Association 1994) diagnostic criteria for cannabis dependence (CD) is increasing (Compton et al., 2004). However, marijuana users are not equally likely to progress to CD. Genetic variance exerts a significant influence on the liability for substance use disorders (SUD; e.g., Gynther et al. 1995; van den Bree et al. 1998; Rhee et al. 2003). Yet, candidate gene association studies of SUD have proved difficult to replicate, in part, because they have often attempted to associate a genetic variant with a dichotomous diagnostic variable (see Hutchison et al. 2004). A better approach, and one that is more reflective of the underlying pathology of SUD, is the use of an intermediate phenotype (Gottesman and Gould 2003), whereby a narrowly defined phenotype that is associated with the clinical presentation of SUD and represents an underlying biological mechanism is substituted for the dichotomous variable. However, intermediate phenotypes of CD remain unexplored.
