Schizophrenia polygenic risk is associated with child mental health problems through early childhood adversity: evidence for a gene-environment correlation

Koen Bolhuis, Lisa R. Steenkamp, Laura M. E. Blanken, Alexander Neumann, Philip R. Jansen, Manon H. J. Hillegers, Charlotte A. M. Cecil, Henning Tiemeier*, Steven A. Kushner

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Previous studies have shown that schizophrenia polygenic risk predicts a multitude of mental health problems in the general population. Yet it is unclear by which mechanisms these associations arise. Here, we explored a possible gene-environment correlation in the association of schizophrenia polygenic risk with mental health problems via childhood adversity. This study was embedded in the population-based Generation R Study, including N = 1901 participants with genotyping for schizophrenia polygenic risk, maternal reporting of childhood adversity, and Child Behaviour Checklist measurement of mental health problems. Independent replication was attempted in the Avon Longitudinal Study of Parents and Children (ALSPAC; N = 3641). Associations were analysed with Poisson regression and statistical mediation analysis. Higher burden of schizophrenia polygenic risk was associated with greater exposure to childhood adversity (P-value threshold < 0.5: Generation R Study, OR = 1.08, 95%CI 1.02-1.15, P = 0.01; ALSPAC, OR = 1.02, 95%CI 1.01-1.03, P < 0.01). Childhood adversities partly explained the relationship of schizophrenia polygenic risk with emotional, attention, and thought problems (proportion explained, range 5-23%). Direct effects of schizophrenia polygenic risk and adversity on mental health outcomes were also observed. In summary, genetic liability to schizophrenia increased the risk for mental health problems in the general paediatric population through childhood adversity. Although this finding could result from a mediated causal relationship between genotype and mental health, we argue that these observations most likely reflect a gene-environment correlation, i.e. adversities are a marker for the genetic risk that parents transmit to children. These and similar recent findings raise important conceptual questions about preventative interventions aimed at reducing childhood adversities.
Original languageEnglish
Pages (from-to)529-539
Number of pages11
JournalEuropean Child & Adolescent Psychiatry
Issue number3
Early online date26 Feb 2021
Publication statusPublished - Mar 2022

Bibliographical note

Funding Information:
The authors gratefully acknowledge the contribution of all children and parents, general practitioners, hospitals, midwives, and pharmacies involved in the Generation R Study and the Avon Longitudinal Study of Parents and Children. The generation and management of GWAS genotype data for the Generation R Study was done at the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, The Netherlands. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Manoushka Ganesh, Lizbeth Herrera and Marjolein Peters for their help in creating, managing and QC of the GWAS database.

Funding Information:
This work was supported by the European Union Seventh Framework Program (FP7/2007–2013): ACTION: Aggression in Children: Unravelling gene–environment interplay to inform Treatment and InterventiON strategies (grant number 602768), the Sophia Children’s Hospital Research Foundation (research fellowship grant 921) to KB, Netherlands Organization for Scientific Research (I-grant 016.VICI.170.200) to HT, Horizon 2020 European Commission Funding Network (ERA-PerMed2018-127) to SAK. CC is supported by the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie grant agreement No 707404 and grant agreement No 848158 (EarlyCause Project). Super computing resources were made possible through the I Physical Sciences Division ( AN was supported by a grant of the Dutch Ministry of Education, Culture, and Science and the Netherlands Organization for Scientific Research (NWO grant No. 024.001.003, Consortium on Individual Development) and by a Canadian Institutes of Health Research team grant.

Publisher Copyright:
© 2021, The Author(s).


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