The junction of the 3′ ends of ANKK1 and DRD2 was globally associated with all three phenotypes involving AD (Figure 1), but harbored specific risk variants only for AD+DD. The global significance might be due to a few weak or moderate variants in this region but the individual effect was not strong enough to meet the criterion for statistical significance. A larger sample size for AD-only would be helpful to examine this hypothesis and to detect smaller specific effects from this region. On the other hand, the heterogeneity of AD-all statistically may well have diluted the association signal in this region. Thus, it appears that those strong effects depend on the presence of comorbidity, which might reflect a different neurobiological mechanism or more severe form of substance dependence. This result underscores the importance of the phenotype definition, and possible effects of comorbidity, in studies of complex traits such as substance dependence.
