The effects of CYP2C19 metaboliser status on DNA methylation

Background CYP2C19 enzyme is crucial in the metabolism of drugs and wider environmental exposures. CYP2C19 metaboliser status is determined by variation within the CYP2C19 gene and has been linked to the efficacy of drug treatment and side effects. Studies of the effects of CYP2C19 metaboliser status on DNA methylation could reveal mechanistic pathways underlying the effect of CYP2C19 metaboliser status on drug response and health consequences. Methods A methylome-wide association study was conducted in the Generation Scotland cohort of 18,413 individuals to investigate the association between CYP2C19 metaboliser status and genome-wide DNA methylation, including its interaction with CYP2C19-metabolised medication use. Pathway enrichment analysis was conducted for the cytosine-guanine dinucleotide (CpG) probes significantly associated with CYP2C19 metaboliser status. We then conducted a phenome-wide association analysis (PheWAS) in the UK Biobank (n=2,408 to 370,419) to examine the effects of CYP2C19 metaboliser status on behavioural, cognitive and neuroimaging traits. Results 48 CpG probes were significantly associated with CYP2C19 metaboliser status (PBonferroni < 0.05), annotated to genes involving drug metabolism, liver function, and lipid profile. There was no interaction with CYP2C19-metabolised medication use. Pathway enrichment analysis showed enrichment in biological processes involving metabolic activities and the P450 pathway. PheWAS showed CYP2C19 metaboliser status associated with the structure of brain regions in relation to physical conditions (such as pain) that are comorbid with depression. Conclusions This research suggests that CYP2C19 metaboliser status may impact DNA methylation and metabolic pathways that do not depend on the prescription of drugs metabolised by this enzyme. DNA methylation may provide an alternative means of assessing CYP2C19 activity in future studies. ### Competing Interest Statement The authors have declared no competing interest.