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

The IMAGEN Consortium

doi:10.3389/fpsyt.2021.645746

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

The IMAGEN Consortium

Research output: Contribution to journal › Article › peer-review

6 Citations (Scopus)

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 (p_corrected =0.042, OR = 0.73) and rs507961 in MGLL (p_corrected = 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.

Original language	English
Article number	645746
Journal	Frontiers in Psychiatry
Volume	12
DOIs	https://doi.org/10.3389/fpsyt.2021.645746
Publication status	Published - 20 Apr 2021

Keywords

alcohol use disorder
cannabinoid receptor 1
CNR1
DAGL
endocannabinoid system
MGLL

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3389/fpsyt.2021.645746

Cite this

@article{c42febfeea564336b3f6d6a2bd94f949,

title = "Endocannabinoid Gene × Gene Interaction Association to Alcohol Use Disorder in Two Adolescent Cohorts",

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 = "alcohol use disorder, cannabinoid receptor 1, CNR1, DAGL, endocannabinoid system, MGLL",

author = "{The IMAGEN Consortium} and Laurent Elkrief and Sean Spinney and Vosberg, {Daniel E.} and Tobias Banaschewski and Bokde, {Arun L.W.} and Quinlan, {Erin Burke} and Sylvane Desrivi{\`e}res and Herta Flor and Hugh Garavan and Penny Gowland and Andreas Heinz and R{\"u}diger Br{\"u}hl and Martinot, {Jean Luc} and {Paill{\`e}re Martinot}, {Marie Laure} and Frauke Nees and {Papadopoulos Orfanos}, Dimitri and Luise Poustka and Sarah Hohmann and Sabina Millenet and Fr{\"o}hner, {Juliane H.} and Smolka, {Michael N.} and Henrik Walter and Robert Whelan and Gunter Schumann and Zdenka Pausova and Tom{\'a}{\v s} Paus and Guillaume Huguet and Patricia Conrod",

note = "Funding Information: GH is supported by the Sainte-Justine Foundation, the Merit scholarship program for foreign students, and the Network of Applied Genetic Medicine fellowships. PC is supported by a Tier 1 Canada Research Chair and this research was supported by a CIHR catalyst grant FRN155406 and the Canadian Cannabis and Psychosis Team Grant (FRN CA7170130). This work received support from the following sources: the European Union-funded FP6 Integrated Project IMAGEN (Reinforcement-related behavior in normal brain function and psychopathology) (LSHM-CT-2007-037286), the Horizon 2020 funded ERC Advanced Grant {\textquoteleft}STRATIFY{\textquoteright} (Brain network based stratification of reinforcement-related disorders) (695313), ERANID (Understanding the Interplay between Cultural, Biological and Subjective Factors in Drug Use Pathways) (PR-ST-0416-10004), BRIDGET (JPND: BRain Imaging, cognition Dementia and next generation GEnomics) (MR/N027558/1), Human Brain Project (HBP SGA 2, 785907), the FP7 project MATRICS (603016), the Medical Research Council Grant {\textquoteright}c-VEDA{\textquoteright} (Consortium on Vulnerability to Externalizing Disorders and Addictions) (MR/N000390/1), the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King{\textquoteright}s College London, the Bundesministeriumf{\"u}r Bildung und Forschung (BMBF grants 01GS08152; 01EV0711; Forschungsnetz AERIAL 01EE1406A, 01EE1406B), the Deutsche Forschungsgemeinschaft (DFG grants 186318919 [FOR 1617], 178833530 [SFB 940], and 402170461 [TRR 265]), the Medical Research Foundation and Medical Research Council (grants MR/R00465X/1 and MR/S020306/1), the National Institutes of Health (NIH) funded ENIGMA (grants 5U54EB020403-05 and 1R56AG058854-01). Further support was provided by grants from: ANR (project AF12-NEUR0008-01 - WM2NA, and ANR-12-SAMA-0004), the Eranet Neuron (ANR-18-NEUR00002-01), the Fondation de France (00081242), the Fondation pour la Recherche M{\'e}dicale (DPA20140629802), the Mission Interminist{\'e}rielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA), Funding Information: Funding. GH is supported by the Sainte-Justine Foundation, the Merit scholarship program for foreign students, and the Network of Applied Genetic Medicine fellowships. PC is supported by a Tier 1 Canada Research Chair and this research was supported by a CIHR catalyst grant FRN155406 and the Canadian Cannabis and Psychosis Team Grant (FRN CA7170130). This work received support from the following sources: the European Union-funded FP6 Integrated Project IMAGEN (Reinforcement-related behavior in normal brain function and psychopathology) (LSHM-CT- 2007-037286), the Horizon 2020 funded ERC Advanced Grant ?STRATIFY' (Brain network based stratification of reinforcement-related disorders) (695313), ERANID (Understanding the Interplay between Cultural, Biological and Subjective Factors in Drug Use Pathways) (PR-ST-0416-10004), BRIDGET (JPND: BRain Imaging, cognition Dementia and next generation GEnomics) (MR/N027558/1), Human Brain Project (HBP SGA 2, 785907), the FP7 project MATRICS (603016), the Medical Research Council Grant 'c-VEDA' (Consortium on Vulnerability to Externalizing Disorders and Addictions) (MR/N000390/1), the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, the Bundesministeriumf?r Bildung und Forschung (BMBF grants 01GS08152; 01EV0711; Forschungsnetz AERIAL 01EE1406A, 01EE1406B), the Deutsche Forschungsgemeinschaft (DFG grants 186318919 [FOR 1617], 178833530 [SFB 940], and 402170461 [TRR 265]), the Medical Research Foundation and Medical Research Council (grants MR/R00465X/1 and MR/S020306/1), the National Institutes of Health (NIH) funded ENIGMA (grants 5U54EB020403-05 and 1R56AG058854-01). Further support was provided by grants from: ANR (project AF12-NEUR0008-01 - WM2NA, and ANR-12-SAMA-0004), the Eranet Neuron (ANR-18-NEUR00002-01), the Fondation de France (00081242), the Fondation pour la Recherche M?dicale (DPA20140629802), the Mission Interminist?rielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA), the Assistance-Publique-H?pitaux-de-Paris and INSERM (interface grant), Paris Sud University IDEX 2012, the fondation de l'Avenir (grant AP-RM-17-013); the National Institutes of Health, Science Foundation Ireland (16/ERCD/3797), U.S.A. (Axon, Testosterone and Mental Health during Adolescence; RO1 MH085772-01A1), and by NIH Consortium grant U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centres of Excellence. The Saguenay Youth Study project was funded by the Canadian Institutes of Health Research, Heart and Stroke Foundation of Quebec, and the Canadian Foundation for Innovation. Publisher Copyright: {\textcopyright} Copyright {\textcopyright} 2021 Elkrief, Spinney, Vosberg, Banaschewski, Bokde, Quinlan, Desrivi{\`e}res, Flor, Garavan, Gowland, Heinz, Br{\"u}hl, Martinot, Paill{\`e}re Martinot, Nees, Papadopoulos Orfanos, Poustka, Hohmann, Millenet, Fr{\"o}hner, Smolka, Walter, Whelan, Schumann, Pausova, Paus, Huguet, Conrod and the IMAGEN consortium. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = apr,

day = "20",

doi = "10.3389/fpsyt.2021.645746",

language = "English",

volume = "12",

journal = "Frontiers in Psychiatry",

issn = "1664-0640",

publisher = "Frontiers Media",

}

TY - JOUR

T1 - Endocannabinoid Gene × Gene Interaction Association to Alcohol Use Disorder in Two Adolescent Cohorts

AU - The IMAGEN Consortium

AU - Elkrief, Laurent

AU - Spinney, Sean

AU - Vosberg, Daniel E.

AU - Banaschewski, Tobias

AU - Bokde, Arun L.W.

AU - Quinlan, Erin Burke

AU - Desrivières, Sylvane

AU - Flor, Herta

AU - Garavan, Hugh

AU - Gowland, Penny

AU - Heinz, Andreas

AU - Brühl, Rüdiger

AU - Martinot, Jean Luc

AU - Paillère Martinot, Marie Laure

AU - Nees, Frauke

AU - Papadopoulos Orfanos, Dimitri

AU - Poustka, Luise

AU - Hohmann, Sarah

AU - Millenet, Sabina

AU - Fröhner, Juliane H.

AU - Smolka, Michael N.

AU - Walter, Henrik

AU - Whelan, Robert

AU - Schumann, Gunter

AU - Pausova, Zdenka

AU - Paus, Tomáš

AU - Huguet, Guillaume

AU - Conrod, Patricia

N1 - Funding Information: GH is supported by the Sainte-Justine Foundation, the Merit scholarship program for foreign students, and the Network of Applied Genetic Medicine fellowships. PC is supported by a Tier 1 Canada Research Chair and this research was supported by a CIHR catalyst grant FRN155406 and the Canadian Cannabis and Psychosis Team Grant (FRN CA7170130). This work received support from the following sources: the European Union-funded FP6 Integrated Project IMAGEN (Reinforcement-related behavior in normal brain function and psychopathology) (LSHM-CT-2007-037286), the Horizon 2020 funded ERC Advanced Grant ‘STRATIFY’ (Brain network based stratification of reinforcement-related disorders) (695313), ERANID (Understanding the Interplay between Cultural, Biological and Subjective Factors in Drug Use Pathways) (PR-ST-0416-10004), BRIDGET (JPND: BRain Imaging, cognition Dementia and next generation GEnomics) (MR/N027558/1), Human Brain Project (HBP SGA 2, 785907), the FP7 project MATRICS (603016), the Medical Research Council Grant ’c-VEDA’ (Consortium on Vulnerability to Externalizing Disorders and Addictions) (MR/N000390/1), the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, the Bundesministeriumfür Bildung und Forschung (BMBF grants 01GS08152; 01EV0711; Forschungsnetz AERIAL 01EE1406A, 01EE1406B), the Deutsche Forschungsgemeinschaft (DFG grants 186318919 [FOR 1617], 178833530 [SFB 940], and 402170461 [TRR 265]), the Medical Research Foundation and Medical Research Council (grants MR/R00465X/1 and MR/S020306/1), the National Institutes of Health (NIH) funded ENIGMA (grants 5U54EB020403-05 and 1R56AG058854-01). Further support was provided by grants from: ANR (project AF12-NEUR0008-01 - WM2NA, and ANR-12-SAMA-0004), the Eranet Neuron (ANR-18-NEUR00002-01), the Fondation de France (00081242), the Fondation pour la Recherche Médicale (DPA20140629802), the Mission Interministérielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA), Funding Information: Funding. GH is supported by the Sainte-Justine Foundation, the Merit scholarship program for foreign students, and the Network of Applied Genetic Medicine fellowships. PC is supported by a Tier 1 Canada Research Chair and this research was supported by a CIHR catalyst grant FRN155406 and the Canadian Cannabis and Psychosis Team Grant (FRN CA7170130). This work received support from the following sources: the European Union-funded FP6 Integrated Project IMAGEN (Reinforcement-related behavior in normal brain function and psychopathology) (LSHM-CT- 2007-037286), the Horizon 2020 funded ERC Advanced Grant ?STRATIFY' (Brain network based stratification of reinforcement-related disorders) (695313), ERANID (Understanding the Interplay between Cultural, Biological and Subjective Factors in Drug Use Pathways) (PR-ST-0416-10004), BRIDGET (JPND: BRain Imaging, cognition Dementia and next generation GEnomics) (MR/N027558/1), Human Brain Project (HBP SGA 2, 785907), the FP7 project MATRICS (603016), the Medical Research Council Grant 'c-VEDA' (Consortium on Vulnerability to Externalizing Disorders and Addictions) (MR/N000390/1), the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, the Bundesministeriumf?r Bildung und Forschung (BMBF grants 01GS08152; 01EV0711; Forschungsnetz AERIAL 01EE1406A, 01EE1406B), the Deutsche Forschungsgemeinschaft (DFG grants 186318919 [FOR 1617], 178833530 [SFB 940], and 402170461 [TRR 265]), the Medical Research Foundation and Medical Research Council (grants MR/R00465X/1 and MR/S020306/1), the National Institutes of Health (NIH) funded ENIGMA (grants 5U54EB020403-05 and 1R56AG058854-01). Further support was provided by grants from: ANR (project AF12-NEUR0008-01 - WM2NA, and ANR-12-SAMA-0004), the Eranet Neuron (ANR-18-NEUR00002-01), the Fondation de France (00081242), the Fondation pour la Recherche M?dicale (DPA20140629802), the Mission Interminist?rielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA), the Assistance-Publique-H?pitaux-de-Paris and INSERM (interface grant), Paris Sud University IDEX 2012, the fondation de l'Avenir (grant AP-RM-17-013); the National Institutes of Health, Science Foundation Ireland (16/ERCD/3797), U.S.A. (Axon, Testosterone and Mental Health during Adolescence; RO1 MH085772-01A1), and by NIH Consortium grant U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centres of Excellence. The Saguenay Youth Study project was funded by the Canadian Institutes of Health Research, Heart and Stroke Foundation of Quebec, and the Canadian Foundation for Innovation. Publisher Copyright: © Copyright © 2021 Elkrief, Spinney, Vosberg, Banaschewski, Bokde, Quinlan, Desrivières, Flor, Garavan, Gowland, Heinz, Brühl, Martinot, Paillère Martinot, Nees, Papadopoulos Orfanos, Poustka, Hohmann, Millenet, Fröhner, Smolka, Walter, Whelan, Schumann, Pausova, Paus, Huguet, Conrod and the IMAGEN consortium. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/4/20

Y1 - 2021/4/20

N2 - 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.

AB - 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.

KW - alcohol use disorder

KW - cannabinoid receptor 1

KW - CNR1

KW - DAGL

KW - endocannabinoid system

KW - MGLL

UR - http://www.scopus.com/inward/record.url?scp=85105132404&partnerID=8YFLogxK

U2 - 10.3389/fpsyt.2021.645746

DO - 10.3389/fpsyt.2021.645746

M3 - Article

AN - SCOPUS:85105132404

SN - 1664-0640

VL - 12

JO - Frontiers in Psychiatry

JF - Frontiers in Psychiatry

M1 - 645746

ER -

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

Abstract

Keywords

UN SDGs

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