Canna~Fangled Abstracts

Endocannabinoid Gene × Gene Interaction Association to Alcohol Use Disorder in Two Adolescent Cohorts

By April 20, 2021May 9th, 2021No Comments

Abstract

Genetic markers of the endocannabinoid system have been linked to a variety of addiction-related behaviors that extend beyond cannabis use. In the current study we investigate the relationship between endocannabinoid (eCB) genetic markers and alcohol use disorder (AUD) in European adolescents (14-18 years old) followed in the IMAGEN study (n = 2,051) and explore replication in a cohort of North American adolescents from Canadian Saguenay Youth Study (SYS) (n = 772). Case-control status is represented by a score of more than 7 on the Alcohol Use Disorder Identification Test (AUDIT). First a set-based test method was used to examine if a relationship between the eCB system and AUDIT case/control status exists at the gene level. Using only SNPs that are both independent and significantly associated to case-control status, we perform Fisher’s exact test to determine SNP level odds ratios in relation to case-control status and then perform logistic regressions as post-hoc analysis, while considering various covariates. Generalized multifactor dimensionality reduction (GMDR) was used to analyze the most robust SNP×SNP interaction of the five eCB genes with positive AUDIT screen. While no gene-sets were significantly associated to AUDIT scores after correction for multiple tests, in the case/control analysis, 7 SNPs were significantly associated with AUDIT scores of > 7 (p < 0.05; OR<1). Two SNPs remain significant after correction by false discovery rate (FDR): rs9343525 in CNR1 (pcorrected =0.042, OR = 0.73) and rs507961 in MGLL (pcorrected = 0.043, OR = 0.78). Logistic regression showed that both rs9353525 (CNR1) and rs507961 (MGLL) remained significantly associated with positive AUDIT screens (p < 0.01; OR < 1) after correction for multiple covariables and interaction of covariable × SNP. This result was not replicated in the SYS cohort. The GMDR model revealed a significant three-SNP interaction (p = 0.006) involving rs484061 (MGLL), rs4963307 (DAGLA), and rs7766029 (CNR1) predicted case-control status, after correcting for multiple covariables in the IMAGEN sample. A binomial logistic regression of the combination of these three SNPs by phenotype in the SYS cohort showed a result in the same direction as seen in the IMAGEN cohort (BETA = 0.501, p = 0.06). While preliminary, the present study suggests that the eCB system may play a role in the development of AUD in adolescents.

 

Keywords: CNR1, DAGL, MGLL, alcohol use disorder, cannabinoid receptor 1, endocannabinoid system

Conflict of interest statement

TB served in an advisory or consultancy role for Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Shire. TB received conference support or speaker’s fee by Lilly, Medice, Novartis and Shire. TB has been involved in clinical trials conducted by Shire & Viforpharma. TB received royalties from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press. The present work is unrelated to the above grants and relationships. LP served in an advisory or consultancy role for Roche and Viforpharm and received speaker’s fee by Shire. LP received royalties from Hogrefe, Kohlhammer and Schattauer. The present work is unrelated to the above grants and relationships. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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