In this first cross-ancestry GWAS of DSM-NicDep (N = 61,861), we replicated the well-known CHRNA5 risk locus. DSM-NicDep was genetically correlated with other substance use disorders, smoking-related phenotypes, and psychiatric disorders. DSM-NicDep was more closely related to the genetic underpinnings of other DSM- or ICD-defined substance use disorders than was PTU (problematic tobacco use, a phenotype that combined FTND and cigarettes per day).