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

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; IMAGEN Consortium

doi:10.1111/add.16750

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

Addiction. 2025 Jan 10. doi: 10.1111/add.16750. Online ahead of print.

Authors

Renata Basso Cupertino¹, Sarah Elizabeth Medland², Jonatan Ottino-Gonzalez³, Zhipeng Cao⁴, Anthony Juliano⁵, Devarshi Pancholi⁵, Tobias Banaschewski⁶, Arun L W Bokde⁷, Sylvane Desrivières⁸, Herta Flor^{9

10}, Antoine Grigis¹¹, Penny Gowland¹², Andreas Heinz¹³, Rüdiger Brühl¹⁴, Jean-Luc Martinot¹⁵, Marie-Laure Paillère Martinot^{15

16}, Eric Artiges^{15

17}, Frauke Nees^{6

18}, Dimitri Papadopoulos Orfanos¹⁰, Herve Lemaitre^{11

19}, Tomáš Paus^{20

21}, Luise Poustka²², Sarah Hohmann⁶, Juliane H Fröhner²³, Michael N Smolka²⁴, Henrik Walter¹³, Robert Whelan²⁵, Gunter Schumann^{24

26}, Patricia Conrod²⁰, Peter Callas²⁷, Hugh Garavan⁵, Scott Mackey⁵; IMAGEN Consortium

Affiliations

¹ Department of Psychiatry, University of California San Diego, San Diego, California, USA.
² QIMR Berghofer Medical Research Center, Department of Psychiatric Genetics, Brisbane, Queensland, Australia.
³ Division of Endocrinology, Children's Hospital Los Angeles, The Saban Research Institute, Los Angeles, CA, USA.
⁴ Shanghai Xuhui Mental Health Center, Shanghai, China.
⁵ Department of Psychiatry, University of Vermont, Burlington, Vermont, USA.
⁶ Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
⁷ Discipline of Psychiatry, School of Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
⁸ Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
⁹ Institute of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
¹⁰ Department of Psychology, School of Social Sciences, University of Mannheim, Mannheim, Germany.
¹¹ NeuroSpin, CEA, Université Paris-Saclay, Gif-sur-Yvette, France.
¹² Sir Peter Mansfield Imaging Centre School of Physics and Astronomy, University of Nottingham, Nottingham, UK.
¹³ Department of Psychiatry and Psychotherapy CCM, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
¹⁴ Physikalisch-Technische Bundesanstalt (PTB), Braunschweig and Berlin, Germany.
¹⁵ Institut National de la Santé et de la Recherche Médicale, INSERM U A10 "Trajectoires développementales en psychiatrie", Université Paris-Saclay, Ecole Normale supérieure Paris-Saclay, CNRS, Centre Borelli, Gif-sur-Yvette, France.
¹⁶ Department of Child and Adolescent Psychiatry, Pitié-Salpêtrière Hospital, AP-HP. Sorbonne Université, Paris, France.
¹⁷ Psychiatry Department, EPS Barthélémy Durand, Etampes, France.
¹⁸ Institute of Medical Psychology and Medical Sociology, University Medical Center Schleswig Holstein, Kiel University, Kiel, Germany.
¹⁹ Institut des Maladies Neurodégénératives, UMR 5293, CNRS, CEA, Université de Bordeaux, Bordeaux, France.
²⁰ Department of Psychiatry, Faculty of Medicine and Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Montreal, Quebec, Canada.
²¹ Departments of Psychiatry and Psychology, University of Toronto, Toronto, Ontario, Canada.
²² Department of Child and Adolescent Psychiatry and Psychotherapy, University Medical Centre Göttingen, Göttingen, Germany.
²³ Department of Psychiatry and Neuroimaging Center, Technische Universität Dresden, Dresden, Germany.
²⁴ Department of Psychiatry and Psychotherapy, Technische Universität Dresden, Dresden, Germany.
²⁵ School of Psychology and Global Brain Health Institute, Trinity College Dublin, Dublin, Ireland.
²⁶ Centre for Population Neuroscience and Precision Medicine (PONS), Institute for Science and Technology of Brain-inspired Intelligence (ISTBI), Fudan University, Shanghai, China.
²⁷ Department of Biostatistics, University of Vermont, Burlington, Vermont, USA.

PMID: 39789945
DOI: 10.1111/add.16750

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.

Keywords: DTI; adolescents; cannabis; mediation; novelty seeking; polygenic risk score; risk‐taking; substance use disorder.

Abstract

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