In addition, we found that CLOCK variation was associated with the CD subtype characterized by heavy cocaine use with infrequent intravenous injection. Because the finding was limited to that CD subtype, if replicated, it confirms the important role of phenotype refinement through multivariate cluster analysis in the identification of genetic factors for CD [Gelernter et al., 2005b; Kranzler et al., 2008; Sun et al., 2012]. The phenotypic heterogeneity in CD may partially explain why there has been no significant replicated association implicating circadian system regulation of cocaine sensitization and the reward system in animal models [Andretic et al., 1999; Abarca et al., 2002; Yuferov et al., 2005; Perreau-Lenz et al., 2007]. Of specific interest in this regard is the finding of increased cocaine reward and excitability of midbrain dopamine neurons in mice lacking a functional CLOCK gene [McClung et al., 2005]. In addition to the SNP in the CLOCK gene that reached significance (Table V), three other CLOCK variants were strongly associated with the CD subtype of heavy cocaine use with infrequent intravenous injection (Table V), consistent with a contribution
