Cannabis use alters DNA methylation, with implications beyond smoking effects

In a recent study published in the journal Dr Molecular PsychiatryA team of researchers conducted a large-scale meta-analysis consisting of an epigenome-wide association study to determine whether lifetime marijuana use was associated with deoxyribonucleic acid (DNA) methylation observed in peripheral blood.

Study: Meta-analysis of trans-ancestry epigenome-wide association of DNA methylation with lifetime cannabis use. Image credit: Juan Gaertner/Shutterstock

Background

With an increasing number of states in the United States as well as countries around the world legalizing the medical use of marijuana, the use of marijuana has become extremely common. However, while the therapeutic benefits of cannabis through medicinal use have been well studied, its recreational use also raises many concerns, particularly addiction, cognitive deficits and mental health disorders such as depression, anxiety, psychosis, mania and schizophrenia.

DNA methylation is an indicator of the influence of environmental factors on health, and some types of DNA methylation due to environmental factors are long-lasting, while others are transient. It occurs when a methyl group is attached to the fifth carbon of cytosine in a region with repeats of cytosine and guanine (CpG). Studies have shown that cigarette smoking causes both permanent and transient DNA methylation at CpG sites throughout the genome. DNA methylation patterns have also been observed in specific genes such as adolescents who frequently use cannabis and patients who are dependent on cannabis.

About the study

In the current study, the team built on the methodology of their previous study, in which they conducted the first epigenome-wide association study using peripheral blood samples and investigated a large population study consisting of seven cohorts of different ancestries. They examined the relationship between lifetime marijuana use and DNA methylation patterns while adjusting for factors such as age, gender, technical covariates, blood cell ratios, and cigarette smoking behavior.

Data were obtained from seven cohorts participating in the study, spanning different study groups such as twins, older adults, parents and children, and adult twins. The final study population included 4,190 individuals who reported using marijuana in their lifetime and 5,246 individuals who had never used marijuana in their lifetime, for a total of 9,436 participants. Cannabis use was identified based on participant or parent report, and an individual had at least one episode of cannabis use before peripheral blood sampling was defined as minimal-user.

DNA methylation was measured in peripheral blood samples and β-values, which are the percentage of methylated DNA at targeted CpG sites, were calculated. The association between lifetime cannabis use and DNA methylation levels was tested using linear models or a general estimating equation model where participants were related. Epigenome-wide association study analyzes were stratified by European-American and African-American genetic ancestry groups, and analyzes were adjusted for sex, age, cigarette smoking, and blood cell type estimates.

The meta-analysis summarized ancestry- and cohort-specific results from epigenome-wide association studies and statistical analysis was performed for evaluation. The methylation score, which is the weighted sum of CpG sites significantly associated with cannabis use, was also calculated. Additionally, DNA methylation correlations between whole blood and brain regions such as prefrontal cortex, cerebellum, superior temporal gyrus, and entorhinal cortex were examined.

result

The results reported that four CpG sites showed significant association with cannabis use, and among them disintegrin and metalloprotease 12 (ADAM12) and alpha-actinin 1 (ACTN1) gene and adhesion near G protein-coupled receptor F1 (ADGRF1) genes and long noncoding ribonucleic acid (RNA). LINC01132.

The basic model of the epigenome-wide association study indicated that cannabis use was associated with DNA methylation at CpG sites that largely overlapped with those involved in cigarette smoking. However, apolipoprotein B receptor adjusted for cigarette smoking behavior (APOBR) genes.

Five genes containing DNA-methylated CpG sites associated with cannabis use play important roles in various health outcomes. LINC01132 It acts as an oncogene and is associated with the malignancy of hepatocellular carcinoma and ovarian cancer, although cannabis use has been reported to reduce the incidence of hepatocellular carcinomas. Genetic variation in this ACTN1 The gene, which encodes a cytoskeletal protein that anchors actin fibers to the cell membrane, has been linked to diseases such as Bowen’s disease, Angelman syndrome, lupus erythematosus and congenital macrothrombocytopenia, as well as to coronavirus disease 2019 (COVID-19).

Conclusion

Overall, the results revealed significant DNA methylation changes at CpG sites across five genes that play important roles in health and disease. Although four of these CpG sites overlap with those associated with cigarette smoking, cannabis use is independently associated with DNA methylation at a gene. The findings highlight the utility of DNA methylation as a tool for understanding the interaction between environmental factors and genetics and emphasize the need for further research into the effects of cannabis use on health outcomes.