substance that is unexplained by the latent dimension of risk. Notably, this study utilized structured missingness to exclude dependence information from non-substance users and experimenters, who might have been scored as “non-dependent/asymptomatic” using a diagnostic phenotype, thereby improving our ability to detect genetic and environmental factors specific to the development of DSM-IV dependence symptoms amongst drug users. Comorbid alcohol, tobacco, and cannabis dependence was best characterized as alternate manifestations of an underlying trait, referred to Substance Dependence Vulnerability (SDV). We labeled the latent factor in Figure 1b and Table 6 as Substance Dependence Vulnerability (SDV), to imply that the common mechanism behind endorsing dependence symptoms across these substances was the loss-of-control and repeated use of the substances. This was based upon the biochemical adaptation that takes place in the brain as a result of repeated drug administration and psychosocial problems that comprise the DSM-IV dependence symptom count. Biochemical adaptations in the brain center on the mesolimbic dopamine reward pathway and the changes in the reward cascade that take place with repeated drug exposure, ultimately leading to a downregulated dopamine response (Koob and Le Moal, 2001); thus genetic effects on the latent trait may be indicative of system wide genetic polymorphisms
