Interaction of schizophrenia polygenic risk and cortisol level on pre-adolescent brain structure

Koen Bolhuis, Henning Tiemeier, Philip R. Jansen, Ryan L. Muetzel, Alexander Neumann, Manon H.J. Hillegers, Erica T.L. van den Akker, Elisabeth F.C. van Rossum, Vincent W.V. Jaddoe, Meike W. Vernooij, Tonya White, Steven A. Kushner*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review


The etiology of schizophrenia is multi-factorial with early neurodevelopmental antecedents, likely to result from a complex interaction of genetic and environmental risk. However, few studies have examined how schizophrenia polygenic risk scores (PRS) are moderated by environmental factors in shaping neurodevelopmental brain structure, prior to the onset of psychotic symptoms. Here, we examined whether hair cortisol, a quantitative metric of chronic stress, moderated the association between genetic risk for schizophrenia and pre-adolescent brain structure. This study was embedded within the Generation R Study, involving pre-adolescents of European ancestry assessed regarding schizophrenia PRS, hair cortisol, and brain imaging (n = 498 structural; n = 526 diffusion tensor imaging). Linear regression was performed to determine the association between schizophrenia PRS, hair cortisol level, and brain imaging outcomes. Although no single measure exceeded the multiple testing threshold, nominally significant interactions were observed for total ventricle volume (P interaction = 0.02) and global white matter microstructure (P interaction = 0.01) – two of the most well replicated brain structural findings in schizophrenia. These findings provide suggestive evidence for the joint effects of schizophrenia liability and cortisol levels on brain correlates in the pediatric general population. Given the widely replicated finding of ventricular enlargement and lower white matter integrity among schizophrenia patients, our findings generate novel hypotheses for future research on gene-environment interactions affecting the neurodevelopmental pathophysiology of schizophrenia.

Original languageEnglish
Pages (from-to)295-303
Number of pages9
Early online date24 Dec 2018
Publication statusPublished - Mar 2019


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 Netherlands Organization for Scientific Research (NWO-grant 016.VICI.170.200 ) to HT. Super computing resources were made possible through the NWO Physical Sciences Division (

FundersFunder number
Seventh Framework Programme602768
Nederlandse Organisatie voor Wetenschappelijk Onderzoek016.VICI.170.200
Seventh Framework Programme


    • Diffusion tensor imaging
    • Gene-environment
    • Genetic
    • Neuroimaging
    • Psychosis
    • Stress


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