Gene × environment effects and mediation involving adverse childhood events, mood and anxiety disorders, and substance dependence

Henry R. Kranzler (), Christal N. Davis, Richard Feinn, Zeal Jinwala, Yousef Khan, Ariadni Oikonomou, Damaris Silva-Lopez, Isabel Burton, Morgan Dixon, Jackson Milone, Sarah Ramirez, Naomi Shifman, Daniel Levey, Joel Gelernter, Emily E. Hartwell and Rachel L. Kember
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Henry R. Kranzler: University of Pennsylvania Perelman School of Medicine
Christal N. Davis: University of Pennsylvania Perelman School of Medicine
Richard Feinn: Frank H. Netter School of Medicine at Quinnipiac University
Zeal Jinwala: University of Pennsylvania Perelman School of Medicine
Yousef Khan: University of Pennsylvania Perelman School of Medicine
Ariadni Oikonomou: University of Pennsylvania Perelman School of Medicine
Damaris Silva-Lopez: University of Pennsylvania Perelman School of Medicine
Isabel Burton: University of Pennsylvania Perelman School of Medicine
Morgan Dixon: University of Pennsylvania Perelman School of Medicine
Jackson Milone: University of Pennsylvania Perelman School of Medicine
Sarah Ramirez: University of Pennsylvania Perelman School of Medicine
Naomi Shifman: University of Pennsylvania Perelman School of Medicine
Daniel Levey: Yale University School of Medicine
Joel Gelernter: Yale University School of Medicine
Emily E. Hartwell: University of Pennsylvania Perelman School of Medicine
Rachel L. Kember: University of Pennsylvania Perelman School of Medicine

Nature Human Behaviour, 2024, vol. 8, issue 8, 1616-1627

Abstract: Abstract Adverse childhood events (ACEs) contribute to the development of mood and anxiety disorders and substance dependence. However, the extent to which these effects are direct or indirect and whether genetic risk moderates them is unclear. We examined associations among ACEs, mood/anxiety disorders and substance dependence in 12,668 individuals (44.9% female, 42.5% African American/Black, 42.1% European American/white). Using latent variables for each phenotype, we modelled direct and indirect associations of ACEs with substance dependence, mediated by mood/anxiety disorders (the forward or ‘self-medication’ model) and of ACEs with mood/anxiety disorders, mediated by substance dependence (the reverse or ‘substance-induced’ model). In a subsample, we tested polygenic scores for the substance dependence and mood/anxiety disorder factors as moderators in the mediation models. Although there were significant indirect paths in both directions, mediation by mood/anxiety disorders (the forward model) was greater than that by substance dependence (the reverse model). Greater genetic risk for substance use disorders was associated with a weaker direct association between ACEs and substance dependence in both ancestry groups (reflecting gene × environment interactions) and a weaker indirect association in European-ancestry individuals (reflecting moderated mediation). We found greater evidence that substance dependence reflects self-medication of mood/anxiety disorders than that mood/anxiety disorders are substance induced. Among individuals at higher genetic risk for substance dependence, ACEs were less associated with that outcome. Following exposure to ACEs, multiple pathways appear to underlie the associations between mood/anxiety disorders and substance dependence. Specification of these pathways could inform individually targeted prevention and treatment approaches.

Date: 2024
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DOI: 10.1038/s41562-024-01885-w

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