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.
Highlights
Substance use disorders are a growing concern across the world, with an estimated 31 million users worldwide suffering from drug use disorders
A set-based test [32] is utilized to study, at the gene level, the link between the eCB system and alcohol abuse behavior. Through this approach we identify single nucleotide polymorphism (SNP) that are significantly and independently associated to positive alcohol use disorder (AUD) screening, and these SNPs are selected for further study using a case/control analysis and subsequent logistic regression
To test the robustness of these findings after controlling for various relevant covariates, a logistic regression was performed that included only the SNPs that remained significant after correction for multiple tests, sex, the first six ancestry components, parental Alcohol Use Disorder Identification Test (AUDIT) flag, and parental education were included in the logistic model
Summary
Substance use disorders are a growing concern across the world, with an estimated 31 million users worldwide suffering from drug use disorders. Many of the original findings reporting an association between SNPs located in genes of the eCB and various drug abuse behaviors have not been replicated [4, 26], suggesting the possibility of false positive results in these candidate gene approaches. Multiple SNPs in eCB genes that have been previously examined (CNR1, FAAH, MAGL, DAGLA) as well as genes that have not yet been investigated (NAPEPLD) were analyzed in the context of alcohol use disorder (AUD) To understand this relationship, a three-tiered approach was used. A set-based test [32] is utilized to study, at the gene level, the link between the eCB system and alcohol abuse behavior Through this approach we identify SNPs that are significantly and independently associated to positive AUD screening, and these SNPs are selected for further study using a case/control analysis and subsequent logistic regression. Genetic and alcohol use data were used from the Saguenay Youth Study (SYS), a two-generational study comprised of 1,029 French-Canadian adolescents and their parents
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