Methylomic signature of current cannabis use in two first-episode psychosis cohorts

Abstract

The rising prevalence and legalization of cannabis worldwide have underscored the need for a comprehensive understanding of its biological impact, particularly on mental health. Epigenetic mechanisms, specifically DNA methylation, have gained increasing recognition as vital factors in the interplay between risk factors and mental health. This study aimed to explore the effects of current cannabis use and potency on DNA methylation in two independent cohorts of individuals experiencing first-episode psychosis (FEP) compared to control subjects. The combined sample consisted of 682 participants (cannabis users (n = 188) and never users (n = 494)). DNA methylation profiles were generated on blood-derived DNA samples using the Illumina DNA methylation array platform. Each cohort was analysed individually and then meta-analysed. We identified one CpG site (cg11669285) in the CAVIN1 gene that showed differential methylation with current cannabis use, surpassing the array-wide significance threshold, and independent of the tobacco-related epigenetic signature. Furthermore, a CpG site localized in the MCU gene (cg11669285) achieved array-wide significance in the analysis of high-potency cannabis use. Pathway and regional analyses identified cannabis-related epigenetic deviations in genes linked to immune and mitochondrial function, both of which are known to be influenced by cannabinoids. Notably, the analyses focused on first-onset psychoses identified differential methylation at nominal significance in a CpG site situated in the TRPV2 gene, which is known to be activated by cannabinoids. Overall, these findings contribute to our understanding of the epigenetic consequences of current cannabis use in the general population and in first-episode psychosis and highlight potential molecular pathways affected by cannabis exposure.