Exposome-wide gene-by-environment interaction study of psychotic experiences in the UK Biobank

Lin, Bochao Danae, Pries, Lotta-Katrin, Arias-Magnasco, Angelo, Klingenberg, Boris, Linden, David E.J. ORCID: https://orcid.org/0000-0002-5638-9292, Blokland, Gabriëlla A.M., van der Meer, Dennis, Luykx, Jurjen J., Rutten, Bart P.F. and Guloksuz, Sinan 2025. Exposome-wide gene-by-environment interaction study of psychotic experiences in the UK Biobank. Biological Society Global Open Science 5 (3) , 100460. 10.1016/j.bpsgos.2025.100460

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Abstract

Background: A previous study successfully identified 148 of 23,098 exposures associated with any psychotic experiences (PEs) in the UK Biobank using an exposome-wide association study (XWAS). Furthermore, research has shown that the polygenic risk score for schizophrenia (PRS-SCZ) is associated with PEs. However, the interaction of these exposures with PRS-SCZ remains unknown. Method: To systematically investigate possible gene-by-environment interactions underlying PEs through data-driven agnostic analyses, we conducted 1) conditional XWAS adjusting for PRS-SCZ to estimate the main effects of the exposures and of PRS-SCZ, 2) exposome-wide interaction study (XWIS) to estimate multiplicative and additive interactions between PRS-SCZ and exposures, and 3) correlation analyses between PRS-SCZ and exposures. The study included 148,502 participants from the UK Biobank. Results: In the conditional XWAS models, significant effects of PRS-SCZ and 148 exposures on PEs remained statistically significant. In the XWIS model, we found significant multiplicative (multiplicative scale, 1.23; 95% CI, 1.10–1.37; p = 4.0 × 10−4) and additive (relative excess risk due to interaction, 0.55; 95% CI, 0.32–0.77; synergy index, 0.22; 95% CI, 0.14–0.30; and attributable proportion, 1.59; 95% CI, 1.30–1.91; all ps < .05/148) interactions of PRS-SCZ and the variable serious medical conditions/disability with PEs. We additionally identified 6 additive gene-by-environment interactions for mental distress, help-/treatment-seeking behaviors (3 variables), sadness, and sleep problems. In the correlation test focused on 7 exposures that exhibited significant interactions with PRS-SCZ, nonsignificant or small (r < 0.04) gene-by-environment correlations were observed. Conclusions: These findings reveal evidence for gene-by-environment interactions underlying PEs and suggest that intertwined pathways of genetic vulnerability and exposures may contribute to psychosis risk.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Publisher:	Elsevier
ISSN:	2667-1743
Date of First Compliant Deposit:	10 March 2025
Date of Acceptance:	29 January 2025
Last Modified:	16 Apr 2025 10:00
URI:	https://orca.cardiff.ac.uk/id/eprint/176686

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