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We used a cluster analytic method to differentiate homogeneous, highly heritable subtypes of CRBs and to compare their utility with that of the DSM\u2010IV CD as traits for genetic association analysis. Clinical features of CRBs and co\u2010occurring disorders were obtained via a poly\u2010diagnostic interview administered to 9,965 participants in genetic studies of substance dependence. A subsample of subjects (N\u2009=\u20093,443) were genotyped for 1,350 single nucleotide polymorphisms (SNPs) selected from 130 candidate genes related to addiction. Cluster analysis of clinical features of the sample yielded five subgroups, two of which were characterized by heavy cocaine use and high heritability: a<jats:italic>heavy cocaine use, infrequent intravenous injection group<\/jats:italic>and an<jats:italic>early\u2010onset, heavy cocaine use, high comorbidity group<\/jats:italic>. The utility of these traits was compared with the CD diagnosis through association testing of 2,320 affected subjects and 480 cocaine\u2010exposed controls. Analyses examined both single SNP (main) and SNP\u2013SNP interaction (epistatic) effects, separately for African\u2010Americans and European\u2010Americans. The two derived subtypes showed more significant<jats:italic>P<\/jats:italic>values for 6 of 8 main effects and 7 of 8 epistatic effects. Variants in the<jats:italic>CLOCK<\/jats:italic>gene were significantly associated with the<jats:italic>heavy cocaine use, infrequent intravenous injection group<\/jats:italic>, but not with the DSM\u2010IV diagnosis of CD. 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