Methylomic Investigation of Problematic Adolescent Cannabis Use and Its Negative Mental Health Consequences.

Abstract Objective The impact of adolescent cannabis use is a pressing public health question due to the high rates of use and links to negative outcomes. Here we consider the association between problematic adolescent cannabis use and methylation. Method Using an enrichment-based sequencing approach, we performed a methylome-wide association study (MWAS) of problematic adolescent cannabis use in 703 adolescent samples from the Great Smoky Mountain Study. Using epigenomic deconvolution, we performed MWASs for the main cell types in blood: granulocytes, T-cells, B-cells and monocytes. Enrichment testing was conducted to establish overlap between cannabis-associated methylation differences and variants associated with negative mental health effects of adolescent cannabis use. Results Whole blood identified 45 significant CpGs, and cell-type specific analyses yielded 32 additional CpGs not identified in the whole blood MWAS. We observed significant overlap between the B-cell MWAS and genetic studies of education attainment and intelligence. Furthermore, the results from both T-cells and monocytes overlapped with findings from a MWAS of psychosis conducted in brain tissue. Conclusion In one of the first methylome-wide studies of adolescent cannabis use, we identified several methylation sites located in genes of importance for potentially relevant brain functions. Our findings resulted in several testable hypotheses by which cannabis-associated methylation can impact neurological development, inflammation response, as well as potential mechanisms linking cannabis-associated methylation to potential downstream mental health effects.