Epigenetic and genetic profiling of comorbidity patterns among substance dependence diagnoses.

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 epigenome-wide changes in 886 individuals of African, European, and Admixed-American descents. The LCA identified four latent classes related to SD comorbidities: AD + TD, CoD + TD, AD + CoD + OD + TD (i.e., polysubstance addiction, PSU), and TD. In the epigenome-wide association analysis, SPATA4 cg02833127 was associated with CoD + TD, AD + TD, and PSU latent classes. AD + TD latent class was also associated with CpG sites located on ARID1B, NOTCH1, SERTAD4, and SIN3B, while additional epigenome-wide significant associations with CoD + TD latent class were observed in ANO6 and MOV10 genes. PSU-latent class was also associated with a differentially methylated region in LDB1. We also observed shared polygenic score (PGS) associations for PSU, AD + TD, and CoD + TD latent classes (i.e., attention-deficit hyperactivity disorder, anxiety, educational attainment, and schizophrenia PGS). In contrast, TD-latent class was exclusively associated with posttraumatic stress disorder-PGS. Other specific associations were observed for PSU-latent class (subjective wellbeing-PGS and neuroticism-PGS) and AD + TD-latent class (bipolar disorder-PGS). In conclusion, we identified shared and unique genetic and epigenetic mechanisms underlying SD comorbidity patterns. These findings highlight the importance of modeling the co-occurrence of SD diagnoses when investigating the molecular basis of addiction-related traits.