This study investigated the genetic and epigenetic mechanisms underlying the comorbidity of five substance dependence diagnoses (SDs; alcohol, AD; cannabis, CaD; cocaine, CoD; opioid, OD; tobacco, TD). A latent class analysis (LCA) was performed on 22,668 individuals from six cohorts to identify comorbid DSM-IV SD patterns. In subsets of this sample, we tested SD-latent classes with respect to polygenic overlap of psychiatric and psychosocial traits in 7659 individuals of European descent and…