冲动行为和白质介导了青少年大麻使用障碍的遗传风险与早期大麻使用之间的关系。

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

作者信息

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

机构信息

Department of Psychiatry, University of California San Diego, San Diego, California, USA.

QIMR Berghofer Medical Research Center, Department of Psychiatric Genetics, Brisbane, Queensland, Australia.

出版信息

Addiction. 2025 May;120(5):984-996. doi: 10.1111/add.16750. Epub 2025 Jan 10.

DOI:10.1111/add.16750

PMID:39789945

Abstract

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.

摘要

背景与目的

大麻使用障碍（CUD）受遗传因素的影响很大；然而，这种关联背后的机制尚未完全明确。本研究调查了基于成年人CUD全基因组关联研究的多基因风险评分（PRS）是否能预测青少年的大麻使用情况，以及这种关联是否可以通过脑白质结构特性或冒险行为的个体差异来解释。

设计与背景

使用IMAGEN队列的数据进行纵向和横断面分析，IMAGEN队列是一项整合了遗传、神经影像和行为测量的欧洲纵向研究。我们测量了CUD的PRS、新奇性和寻求刺激特质与白质束各向异性分数（FA）之间的关联。中介模型探讨了寻求新奇和FA是否介导了PRS与大麻使用之间的关联。

参与者

在14岁（n = 1762）、19岁（n = 1175）和23岁（n = 1139）时对参与者进行评估。

测量方法

欧洲酒精及其他药物学校调查项目、物质使用风险概况量表、尼古丁依赖的Fagerstrom测试、气质与性格问卷、柯比货币问卷、扩散张量成像和CUD-PRS。

研究结果

CUD-PRS与青少年大麻总暴露量相关[P < 0.001，β = 0.098（95%置信区间 = 0.059，0.137）]，也与其他物质使用指标相关[酒精P = 0.002，β = 0.058（0.020，0.096）；吸烟量P < 0.001，β = 0.086（0.044，0.128）；Fagerstrom评分P < 0.001，β = 0.062（0.028，0.096）；药物评分P < 0.001，β = 0.106（0.065，0.147）]。CUD-PRS还与冲动性、冒险行为相关[冲动性P < 0.001，β = 0.106（0.060，0.142）；寻求刺激P < 0.001，β = 0.094（0.0523，0.1357）；寻求新奇P < 0.001，β = 0.105（0.064，0.146）；折扣任务P < 0.001，β = 0.051（0.013，0.089）]以及平均FA[P < 0.001，β = -0.010（-0.015，-0.005）]。纵向中介模型表明，这些行为和脑测量指标可以介导PRS与大麻使用之间的关联[寻求新奇的总体间接效应P < 0.001，β = 0.048（0.028，0.068）；冲动性P = 0.016，β = 0.019（0.004，0.035）；寻求刺激P < 0.001，β = 0.034（0.017，0.05）]。