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Endocannabinoid Gene x Gene Interaction Association to Alcohol Use Disorder in two Adolescent Cohorts

Elkrief, Laurent; Spinney, Sean; Vosberg, Daniel E; Banaschewski, Tobias; Bokde, Arun; Quinlan, Erin B; Desrivi�res, Sylvane; Flor, Herta; Garavan, Hugh; Gowland, Penny; Heinz, Andreas; Br�hl, R�diger; Martinot, Jean -Luc; Martinot, Marie-Laure Paill�re; Nees, Frauke; Orfanos, Dimitri Papadopoulos; Poustka, Luise; Hohmann, Sarah; Millenet, Sabina K; Fr�hner, Juliane H; Smolka, Michael N; Walter, Henrik; Whelan, Robert; Schumann, Gunter; Pausova, Zdenka; Paus, Tom�; Huguet, Guillaume; Conrod, Patricia

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Authors

Laurent Elkrief

Sean Spinney

Daniel E Vosberg

Tobias Banaschewski

Arun Bokde

Erin B Quinlan

Sylvane Desrivi�res

Herta Flor

Hugh Garavan

Andreas Heinz

R�diger Br�hl

Jean -Luc Martinot

Marie-Laure Paill�re Martinot

Frauke Nees

Dimitri Papadopoulos Orfanos

Luise Poustka

Sarah Hohmann

Sabina K Millenet

Juliane H Fr�hner

Michael N Smolka

Henrik Walter

Robert Whelan

Gunter Schumann

Zdenka Pausova

Tom� Paus

Guillaume Huguet

Patricia Conrod



Abstract

Genetic markers of endocannabinoid system have been linked to a variety of addiction-related behaviours that extend beyond cannabis use. In the current study we investigate the relationship between eCB genetic markers and AUDs in European adolescents (14-18 years old), followed in the IMAGEN study (n=2051) 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 x SNP interaction of the 5 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 [less than] 0.05; OR [less than] 1). Two SNPs remain significant after correction by false discovery rate (FDR); rs9343525 in CNR1 (pcorrected=0.04273, OR=0.729) and rs507961 in MGLL (pcorrected=0.04273, OR=0.784). Logistic regression showed that both rs9353525 (CNR1) and rs507961 (MGLL) remained significantly associated with positive AUDIT screens (p [less than] 0.01; OR[less than] 1), after correction for multiple covariables and interaction of covariable x 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.

Citation

Elkrief, L., Spinney, S., Vosberg, D. E., Banaschewski, T., Bokde, A., Quinlan, E. B., Desrivières, S., Flor, H., Garavan, H., Gowland, P., Heinz, A., Brühl, R., Martinot, J. .-L., Martinot, M.-L. P., Nees, F., Orfanos, D. P., Poustka, L., Hohmann, S., Millenet, S. K., Fröhner, J. H., …Conrod, P. (2021). Endocannabinoid Gene x Gene Interaction Association to Alcohol Use Disorder in two Adolescent Cohorts. Frontiers in Psychiatry, 12, Article 645746. https://doi.org/10.3389/fpsyt.2021.645746

Journal Article Type Article
Acceptance Date Mar 2, 2021
Online Publication Date Apr 20, 2021
Publication Date Apr 1, 2021
Deposit Date Mar 3, 2021
Publicly Available Date Apr 1, 2021
Journal Frontiers Psychiatry
Electronic ISSN 1664-0640
Publisher Frontiers Media
Peer Reviewed Peer Reviewed
Volume 12
Article Number 645746
DOI https://doi.org/10.3389/fpsyt.2021.645746
Public URL https://nottingham-repository.worktribe.com/output/5364380
Publisher URL https://www.frontiersin.org/articles/10.3389/fpsyt.2021.645746/abstract

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