Trans-ancestry epigenome-wide association meta-analysis of DNA methylation with lifetime cannabis use

• Published in: Molecular psychiatry 2024-01, Vol.29 (1), p.124-133
• Main Authors: Fang, Fang, Quach, Bryan, Lawrence, Kaitlyn G., van Dongen, Jenny, Marks, Jesse A., Lundgren, Sara, Lin, Mingkuan, Odintsova, Veronika V., Costeira, Ricardo, Xu, Zongli, Zhou, Linran, Mandal, Meisha, Xia, Yujing, Vink, Jacqueline M., Bierut, Laura J., Ollikainen, Miina, Taylor, Jack A., Bell, Jordana T., Kaprio, Jaakko, Boomsma, Dorret I., Xu, Ke, Sandler, Dale P., Hancock, Dana B., Johnson, Eric O.
• Format: Article
• Language: English
• Subjects: 45/43; 631/337; 692/53/2423; Adult; Behavioral Sciences; Biological Psychology; Black People; Cannabis; Cannabis - genetics; Cigarette smoking; Cigarette Smoking - genetics; CpG islands; CpG Islands - genetics; DNA methylation; DNA Methylation - genetics; Epigenesis, Genetic - genetics; Epigenome - genetics; Epigenomics - methods; Female; Genome-Wide Association Study - methods; Humans; Male; Marijuana; Marijuana Smoking - genetics; Marijuana Use - genetics; Medicine; Medicine & Public Health; Meta-analysis; Middle Aged; Neurosciences; Peripheral blood; Pharmacotherapy; Psychiatry; White People - genetics
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/s41380-023-02310-w

Cannabis is widely used worldwide, yet its links to health outcomes are not fully understood. DNA methylation can serve as a mediator to link environmental exposures to health outcomes. We conducted an epigenome-wide association study (EWAS) of peripheral blood-based DNA methylation and lifetime cannabis use (ever vs. never) in a meta-analysis including 9436 participants (7795 European and 1641 African ancestry) from seven cohorts. Accounting for effects of cigarette smoking, our trans-ancestry EWAS meta-analysis revealed four CpG sites significantly associated with lifetime cannabis use at a false discovery rate of 0.05 ( p < 5.85 × 10 − 7 ) : cg22572071 near gene ADGRF1 , cg15280358 in ADAM12 , cg00813162 in ACTN1 , and cg01101459 near LINC01132 . Additionally, our EWAS analysis in participants who never smoked cigarettes identified another epigenome-wide significant CpG site, cg14237301 annotated to APOBR . We used a leave-one-out approach to evaluate methylation scores constructed as a weighted sum of the significant CpGs. The best model can explain 3.79% of the variance in lifetime cannabis use. These findings unravel the DNA methylation changes associated with lifetime cannabis use that are independent of cigarette smoking and may serve as a starting point for further research on the mechanisms through which cannabis exposure impacts health outcomes.