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. 2025 Feb 10;5(3):100460.
doi: 10.1016/j.bpsgos.2025.100460. eCollection 2025 May.

Exposome-Wide Gene-By-Environment Interaction Study of Psychotic Experiences in the UK Biobank

Bochao Danae Lin  1   2 , Lotta-Katrin Pries  1 , Angelo Arias-Magnasco  1 , Boris Klingenberg  1 , David E J Linden  1   3 , Gabriëlla A M Blokland  1 , Dennis van der Meer  1   4 , Jurjen J Luykx  1   5   6   7   8 , Bart P F Rutten  1 , Sinan Guloksuz  1   9
Affiliations

Exposome-Wide Gene-By-Environment Interaction Study of Psychotic Experiences in the UK Biobank

Bochao Danae Lin et al. Biol Psychiatry Glob Open Sci. .

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.

Keywords: Diathesis-stress model; Disability; Exposome; Gene-by-environment interaction; Psychotic experiences; XWIS.

Plain language summary

In this study, we explored how genetic risk for schizophrenia (PRS-SCZ) interacts with environmental factors to influence psychotic experiences (PEs). Using data from ˃ 148,000 UK Biobank participants, the researchers found that certain exposures, such as disability, mental distress, and sleep problems, interacted with PRS-SCZ to increase PE risk. These gene-by-environment interactions suggest that genetic predisposition and environmental factors jointly contribute to the development of psychosis. The findings highlight the importance of considering both genetic and environmental influences in understanding and potentially preventing psychosis.

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Figures

Figure 1
Figure 1
Odds ratios of psychotic experiences (PEs) in 55 exposures and polygenic risk score (PRS) subgroups. Fifty-five exposures are nominally significant in the additive interaction test. GP, general practitioner.
See this image and copyright information in PMC

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