Impulsivity behaviors and white matter mediate the relationship between genetic risk for cannabis use disorder and early cannabis use in adolescents
Authors: Cupertino Renata Basso , Medland Sarah Elizabeth , Ottino‐Gonzalez Jonatan , Cao Zhipeng , Juliano Anthony , Pancholi Devarshi , Banaschewski Tobias , Bokde Arun L. W. , Desrivières Sylvane , Flor Herta , Grigis Antoine , Gowland Penny , Heinz Andreas , Brühl Rüdiger , Martinot Jean‐Luc , Martinot Marie‐Laure Paillère , Artiges Eric , Nees Frauke , Orfanos Dimitri Papadopoulos , Lemaitre Herve , Paus Tomáš , Poustka Luise , Hohmann Sarah , Fröhner Juliane H. , Smolka Michael N. , Walter Henrik , Whelan Robert , Schumann Gunter , Conrod Patricia , Callas Peter , Garavan Hugh , Mackey Scott ,   IMAGEN Consortium
Published: January 2025

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.