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. 2025 Sep 8;51(5):1254-1265.
doi: 10.1093/schbul/sbae207.

Polygenic and Polyenvironment Interplay in Schizophrenia-Spectrum Disorder and Affective Psychosis; the EUGEI First Episode Study

Victoria Rodriguez  1   2 , Luis Alameda  1   3   4 , Monica Aas  5 , Charlotte Gayer-Anderson  6 , Giulia Trotta  1 , Edoardo Spinazzola  1 , Diego Quattrone  5 , Giada Tripoli  1   7 , Hannah E Jongsma  8   9 , Simona Stilo  10 , Caterina La Cascia  11 , Laura Ferraro  11 , Daniele La Barbera  11 , Antonio Lasalvia  12 , Sarah Tosato  12 , Ilaria Tarricone  13 , Elena Bonora  13 , Stéphane Jamain  14 , Jean-Paul Selten  15   16 , Eva Velthorst  17 , Lieuwe de Haan  18 , Pierre-Michel Llorca  19 , Manuel Arrojo  20 , Julio Bobes  21 , Miguel Bernardo  22 , Celso Arango  23 , James Kirkbride  24 , Peter B Jones  25   26 , Bart P Rutten  16 , Alexander Richards  27 , Pak C Sham  5   28 , Michael O'Donovan  27 , Jim Van Os  1   16   29 , Craig Morgan  30 , Marta Di Forti  5 , Robin M Murray  1 , Evangelos Vassos  5
Affiliations

Polygenic and Polyenvironment Interplay in Schizophrenia-Spectrum Disorder and Affective Psychosis; the EUGEI First Episode Study

Victoria Rodriguez et al. Schizophr Bull. .

Abstract

Background: Multiple genetic and environmental risk factors play a role in the development of both schizophrenia-spectrum disorders and affective psychoses. How they act in combination is yet to be clarified.

Methods: We analyzed 573 first episode psychosis cases and 1005 controls, of European ancestry. Firstly, we tested whether the association of polygenic risk scores for schizophrenia, bipolar disorder, and depression (PRS-SZ, PRS-BD, and PRS-D) with schizophrenia-spectrum disorder and affective psychosis differed when participants were stratified by exposure to specific environmental factors. Secondly, regression models including each PRS and polyenvironmental measures, including migration, paternal age, childhood adversity and frequent cannabis use, were run to test potential polygenic by polyenvironment interactions.

Results: In schizophrenia-spectrum disorder vs controls comparison, PRS-SZ was the strongest genetic predictor, having a nominally larger effect in nonexposed to strong environmental factors such as frequent cannabis use (unexposed vs exposed OR 2.43 and 1.35, respectively) and childhood adversity (3.04 vs 1.74). In affective psychosis vs controls, the relative contribution of PRS-D appeared to be stronger in those exposed to environmental risk. No evidence of interaction was found between any PRS with polyenvironmental score.

Conclusions: Our study supports an independent role of genetic liability and polyenvironmental risk for psychosis, consistent with the liability threshold model. Whereas schizophrenia-spectrum disorders seem to be mostly associated with polygenic risk for schizophrenia, having an additive effect with well-replicated environmental factors, affective psychosis seems to be a product of cumulative environmental insults alongside a higher genetic liability for affective disorders.

Keywords: GxE interaction; affective psychosis; cannabis; childhood adversity; environmental risk factor; polygenic risk score; psychosis; schizophrenia-spectrum disorder.

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Figures

Figure 1.
Figure 1.
Stratified Polygenic Associations of Schizophrenia-Spectrum Disorder vs Controls and Affective Psychosis vs Controls Based on Exposure to Relevant ERF. Results of OR on Top of Bars and Corresponding 95% CIs in the Bottom Table Based on Individual Simple Logistic Regressions in Subgroups Based on Exposure to the Different ERF; Adjusted by Sex, 10PCs and Site. Figure Shows by * and Bold CIs the Significant Results at P < .05. SSD, Schizophrenia-Spectrum Disorder; AP, Affective Psychosis; SLE, Stressful Life Event; PRS, Polygenic Risk Score; BD, Bipolar Disorder; SZ, Schizophrenia; D, Depression
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