Genome-wide DNA methylation analysis of cannabis use disorder in a veteran cohort enriched for posttraumatic stress disorder.

Cannabis use has been increasing over the past decade, not only in the general US population, but particularly among military veterans. With this rise in use has come a concomitant increase in cannabis use disorder (CUD) among veterans. Here, we performed an epigenome-wide association study for lifetime CUD in an Iraq/Afghanistan era veteran cohort enriched for posttraumatic stress disorder (PTSD) comprising 2,310 total subjects (1,109 non-Hispanic black and 1,201 non-Hispanic white). We also investigated CUD interactions with current PTSD status and examined potential indirect effects of DNA methylation (DNAm) on the relationship between CUD and psychiatric diagnoses. Four CpGs were associated with lifetime CUD, even after controlling for the effects of current smoking (AHRR cg05575921, LINC00299 cg23079012, VWA7 cg22112841, and FAM70A cg08760398). Importantly, cg05575921, a CpG strongly linked to smoking, remained associated with lifetime CUD even when restricting the analysis to veterans who reported never smoking cigarettes. Moreover, CUD interacted with current PTSD to affect cg05575921 and cg23079012 such that those with both CUD and PTSD displayed significantly lower DNAm compared to the other groups. Finally, we provide preliminary evidence that AHRR cg05575921 helps explain the association between CUD and any psychiatric diagnoses, specifically mood disorders.