Childhood maltreatment mediates the effect of the genetic background on psychosis risk in young adults

Mattia Marchi, Laurent Elkrief, Anne Alkema, Willemijn van Gastel, Chris D. Schubart, Kristel R. van Eijk, Jurjen J. Luykx, Susan Branje, Stefanos Mastrotheodoros, Gian M. Galeazzi, Jim van Os, Charlotte A. Cecil, Patricia J. Conrod, Marco P. Boks*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Childhood maltreatment (CM) and genetic vulnerability are both risk factors for psychosis, but the relations between them are not fully understood. Guided by the recent identification of genetic risk to CM, this study investigates the hypothesis that genetic risk to schizophrenia also increases the risk of CM and thus impacts psychosis risk. The relationship between schizophrenia polygenetic risk, CM, and psychotic-like experiences (PLE) was investigated in participants from the Utrecht Cannabis Cohort (N = 1262) and replicated in the independent IMAGEN cohort (N = 1740). Schizophrenia polygenic risk score (SZ-PRS) were calculated from the most recent GWAS. The relationship between CM, PRS, and PLE was first investigated using multivariate linear regression. Next, mediation of CM in the pathway linking SZ-PRS and PLE was examined by structural equation modeling, while adjusting for a set of potential mediators including cannabis use, smoking, and neuroticism. In agreement with previous studies, PLE were strongly associated with SZ-PRS (B = 0.190, p = 0.009) and CM (B = 0.575, p < 0.001). Novel was that CM was also significantly associated with SZ-PRS (B = 0.171, p = 0.001), and substantially mediated the effects of SZ-PRS on PLE (proportion mediated = 29.9%, p = 0.001). In the replication cohort, the analyses yielded similar results, confirming equally strong mediation by CM (proportion mediated = 34.7%, p = 0.009). Our results suggest that CM acts as a mediator in the causal pathway linking SZ-PRS and psychosis risk. These findings open new perspectives on the relations between genetic and environmental risks and warrant further studies into potential interventions to reduce psychosis risk in vulnerable people.

Original languageEnglish
Article number219
JournalTranslational Psychiatry
Issue number1
Publication statusPublished - 1 Jun 2022

Bibliographical note

Funding Information:
The authors would like to thank all of the participants of both Utrecht Cannabis Cohort and IMAGEN studies. We thank the investigators of the IMAGEN consortium: Tobias Banaschewski; Gareth J. Barker; Arun L.W. Bokde; Erin Burke Quinlan; Sylvane Desrivières; Herta Flor; Antoine Grigis; Hugh Garavan; 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; Sabina Millenet; Juliane H. Fröhner; Michael N. Smolka; Henrik Walter; Robert Whelan; Gunter Schumann, for making data available. This work was supported by the Dutch council for scientific research (ZonMW TOP grant no. 91207039). The funders of the study had no role in study design, data analysis, data interpretation, or writing of the report. All the authors had full access to all the data in the study and accept the responsibility to submit it for publication.

Publisher Copyright:
© 2022, The Author(s).


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