Abstract

Genetic and sociodemographic risk factors potentially associated with cannabis use (CU) were investigated in 40 cannabis users and 96 control subjects. DNA methylation analyses were also performed to explore the possibility of epigenetic changes related to CU. We conducted a candidate gene association study that included variants involved in the dopaminergic (ANKK1, NCAM1 genes) and endocannabinoid (CNR1, CNR2 gene) pathways. Sociodemographic data included gender, marital status, level of education, and body mass index. We used MeDIP-qPCR to test whether variations in DNA methylation might be associated with CU. We found a significant association between SNP rs1049353 of CNR1 gene (p = 0.01) and CU. Differences were also observed related to rs2501431 of CNR2 gene (p = 0.058). A higher education level appears to decrease the risk of CU. Interestingly, females were less likely to use cannabis than males. There was a significantly higher level of DNA methylation in cannabis users compared to controls in two of the genes tested: hypermethylation at exon 8 of DRD2 gene (p = 0.034) and at the CpG-rich region in the NCAM1 gene (p = 0.0004). Both genetic variants and educational attainment were also related to CU. The higher rate of DNA methylation, evidenced among cannabis users, may be either a marker of CU or a consequence of long-term exposure to cannabis. The identified genetic variants and the differentially methylated regions may represent biomarkers and/or potential targets for designs of pharmacological therapeutic agents. Our observations also suggest that educational programs may be useful strategies for CU prevention.

Highlights

  • Marijuana is the most common drug used illicitly throughout the world

  • Male participants had 6.6 times higher risk to be cannabis users compared to females (p = 0.001)

  • All the levels of educational attainment higher than the reference category seem to decrease the risk of cannabis use (CU)

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Summary

Introduction

Marijuana is the most common drug used illicitly throughout the world. 9% of those exposed to cannabis become addicted (cannabis use disorder, DSM-5). The number increases to 16% when cannabis use (CU) is initiated during adolescence and to 50% when cannabis is used daily[1]. Because of the gateway hypothesis of early CU2 and because of potential negative effects of the drug[3], genetic risk factors for CU have been investigated using a diversity of methods. Twin studies have suggested that genetic markers may explain about 50% of the variance in CU disorders[4,5,6,7]. Association studies have provided evidence of genetic risks that include differential changes at Taq1A allele (rs1800497, ANKK1) that influences the function of dopamine receptors[8]. Changes at rs1049353, rs806380, rs2180619, rs806379, rs12720071, rs2023239 and the haplotype rs6454674-rs806380-rs806377-

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