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Impulsivity behaviors and white matter mediate the relationship between genetic risk for cannabis use disorder and early cannabis use in adolescents

Background and Aim Cannabis use disorder (CUD) is strongly influenced by genetic factors; however the mechanisms underpinning this association are not well understood. This study investigated whether a polygenic risk score (PRS) based on a genome-wide association study for CUD in adults predicts can...

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Main Authors: Cupertino, Renata Basso (Author) , Medland, Sarah Elizabeth (Author) , Ottino-Gonzalez, Jonatan (Author) , Cao, Zhipeng (Author) , Juliano, Anthony (Author) , Pancholi, Devarshi (Author) , Banaschewski, Tobias (Author) , Bokde, Arun L. W. (Author) , Desrivières, Sylvane (Author) , Flor, Herta (Author) , Grigis, Antoine (Author) , Gowland, Penny (Author) , Heinz, Andreas (Author) , Brühl, Rüdiger (Author) , Martinot, Jean-Luc (Author) , Martinot, Marie-Laure Paillère (Author) , Artiges, Eric (Author) , Nees, Frauke (Author) , Orfanos, Dimitri Papadopoulos (Author) , Lemaitre, Herve (Author) , Paus, Tomáš (Author) , Poustka, Luise (Author) , Hohmann, Sarah (Author) , Fröhner, Juliane H. (Author) , Smolka, Michael N. (Author) , Walter, Henrik (Author) , Whelan, Robert (Author) , Schumann, Gunter (Author) , Conrod, Patricia (Author) , Callas, Peter (Author) , Garavan, Hugh (Author) , Mackey, Scott (Author) , Consortium, Imagen (Author)
Format: Article (Journal)
Language:English
Published: May 2025
In: Addiction
Year: 2025, Volume: 120, Issue: 5, Pages: 984-996
ISSN:1360-0443
DOI:10.1111/add.16750
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1111/add.16750
Verlag, lizenzpflichtig, Volltext: http://onlinelibrary.wiley.com/doi/abs/10.1111/add.16750
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Author Notes:Renata Basso Cupertino, Sarah Elizabeth Medland, Jonatan Ottino-Gonzalez, Zhipeng Cao, Anthony Juliano, Devarshi Pancholi, Tobias Banaschewski, Arun L.W. Bokde, Sylvane Desrivières, Herta Flor, Antoine Grigis, Penny Gowland, Andreas Heinz, Rüdiger Brühl, Jean-Luc Martinot, Marie-Laure Paillère Martinot, Eric Artiges, Frauke Nees, Dimitri Papadopoulos Orfanos, Herve Lemaitre, Tomáš Paus, Luise Poustka, Sarah Hohmann, Juliane H. Fröhner, Michael N. Smolka, Henrik Walter, Robert Whelan, Gunter Schumann, Patricia Conrod, Peter Callas, Hugh Garavan, Scott Mackey, on behalf of Imagen Consortium
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Summary:Background and Aim Cannabis use disorder (CUD) is strongly influenced by genetic factors; however the mechanisms underpinning this association are not well understood. This study investigated whether a polygenic risk score (PRS) based on a genome-wide association study for CUD in adults predicts cannabis use in adolescents and whether the association can be explained by inter-individual variation in structural properties of brain white matter or risk-taking behaviors. Design and setting Longitudinal and cross-sectional analyses using data from the IMAGEN cohort, a European longitudinal study integrating genetic, neuroimaging and behavioral measures. We measured associations between PRS for CUD, novelty and sensation seeking traits and fractional anisotropy (FA) of white matter tracts. Mediation modeling explored whether novelty seeking and FA mediated the association between the PRS and cannabis use. Participants Participants were assessed at 14 (n = 1762), 19 (n = 1175) and 23 (n = 1139) years old. Measurements European School Survey Project on Alcohol and Other Drugs, substance use risk profile scale, Fagerstrom Test for Nicotine Dependence, temperament and character inventory, Kirby Monetary Questionnaire, diffusor tensor imaging and CUD-PRS. Findings CUD-PRS was associated with adolescent total cannabis exposure [P < 0.001, beta = 0.098 (95% confidence interval = 0.059, 0.137)] as well as with other substance use measures [alcohol P = 0.002, beta = 0.058 (0.020, 0.096); cigarettes smoked P < 0.001, beta = 0.086 (0.044, 0.128); fargestrom score P < 0.001, beta = 0.062 (0.028, 0.096); drug score P < 0.001, beta = 0.106 (0.065, 0.147)]. CUD-PRS was also associated with impulsivity, risk-taking behaviors [impulsivity P < 0.001, beta = 0.106 (0.060, 0.142); sensation seeking P < 0.001, beta = 0.094 (0.0523, 0.1357); novelty seeking P < 0.001, beta = 0.105 (0.064, 0.146); discounting task P < 0.001, beta = 0.051 (0.013, 0.089)] and average FA [P < 0.001, beta = −0.010 (−0.015, −0.005)]. Longitudinal mediation models showed that these behaviors and brain measures could mediate the association of PRS with cannabis use [overall indirect effect for novelty seeking P < 0.001, beta = 0.048 (0.028, 0.068); impulsivity P = 0.016, beta = 0.019 (0.004, 0.035); sensation seeking P < 0.001, beta = 0.034 (0.017, 0.05)]. Conclusions The genetic risk of adult cannabis use disorder appears to be associated with substance use behavior and white matter structure as early as age 14. The observed mediation effect is consistent with the notion that genetic risk increases novelty seeking in a way that leads to more cannabis use in adolescents.
Item Description:Erstmals veröffentlicht: 10. Januar 2025
Gesehen am 28.07.2025
Physical Description:Online Resource
ISSN:1360-0443
DOI:10.1111/add.16750

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