In this linkage scan we identified several loci predisposing to comorbid dependence on multiple substances using a fuzzy clustering approach to derive a measure of common factors among the SD disorder phenotypes. This general measure of substance dependence was derived from five substance dependence traits including alcohol, cocaine, cannabis, opioid and nicotine, and explained about 60% of the total variability among the MSDs in the two US populations under study. We identified an autosome-wide significant linkage peak in EAs on chromosome 4q12 and obtained suggestive evidence for linkage with loci on chromosomes 3, 9 and 10 in AAs and on chromosome 21 in EAs. The two suggestive linkage peaks (peak locations at 147.6 and 96.7 cM) identified on chromosome 10 for the common component of MSD in AAs in the current study approximate our previously reported linkage signals for alcohol dependence on chromosome 10 at 117.2 cM in AAs [Gelernter et al., 2009] and at 137.7 cM in EAs [Panhuysen et al., 2010].