Genetic risk and environmental exposures like cannabis use appear to contribute independently to psychosis, with schizophrenia-spectrum disorders driven more by genetics and affective psychosis shaped more by environmental factors.
People interested in understanding the genetics of psychosis and how cannabis fits into the risk picture.
Genetic risk effect: OR 2.43 without cannabis vs 1.35 with cannabis
What the researchers found
In 573 first-episode psychosis cases and 1,005 controls, polygenic risk for schizophrenia was the strongest genetic predictor of schizophrenia-spectrum disorders, with a notably larger effect in people not exposed to strong environmental risks like frequent cannabis use (OR 2.43 unexposed vs 1.35 exposed). For affective psychosis, genetic risk for depression appeared stronger among those exposed to environmental risk factors. No statistical interaction was found between genetic and environmental risk scores.
Why it matters
Understanding how genes and environment combine in psychosis risk is critical for prevention. The finding that genetic and environmental risks appear to act independently (rather than multiplying each other) has implications for how risk is assessed and communicated.
The numbers in context
573 first-episode psychosis cases, 1,005 controls. Schizophrenia-spectrum PRS-SZ effect: OR 2.43 (cannabis-unexposed) vs 1.35 (cannabis-exposed). Environmental factors examined: migration, paternal age, childhood adversity, frequent cannabis use.
How the study worked
Case-control study analyzing 573 first-episode psychosis patients and 1,005 controls of European ancestry from the EUGEI study. Polygenic risk scores were calculated for schizophrenia, bipolar disorder, and depression. Environmental measures included migration, paternal age, childhood adversity, and frequent cannabis use. Regression models tested gene-environment interactions.
What this study cannot tell us
European ancestry only; findings may not generalize. Cross-sectional design limits causal inference. Environmental exposures measured retrospectively. Cannabis use assessed as binary (frequent vs not), missing dose-response nuance. PRS explains only a fraction of genetic risk.
How to read the evidence
Moderate: large, well-designed case-control study with polygenic risk scoring, but cross-sectional and limited to European ancestry.
When this study was published
Published in 2025.
The bigger picture
This study supports a liability threshold model where genetic and environmental risks accumulate independently. For schizophrenia-spectrum disorders, high genetic risk alone may be sufficient, while cannabis use and other environmental factors add risk additively. For affective psychosis, the environmental contribution appears relatively larger.
Questions still open
- Why does genetic risk appear to have a larger effect in people not exposed to cannabis?
- Would these patterns replicate in non-European populations?
- Could individual genetic profiles predict who is most vulnerable to cannabis-related psychosis risk?
Common questions
Does cannabis use interact with genetic risk for psychosis?
Is schizophrenia more genetic or environmental?
Read the original research
Polygenic and Polyenvironment Interplay in Schizophrenia-Spectrum Disorder and Affective Psychosis; the EUGEI First Episode Study.
Schizophrenia bulletin, 51(5), 1254-1265
Citation
Rodriguez, Victoria; Alameda, Luis; Aas, Monica; Gayer-Anderson, Charlotte; Trotta, Giulia; Spinazzola, Edoardo; Quattrone, Diego; Tripoli, Giada; Jongsma, Hannah E; Stilo, Simona; La Cascia, Caterina; Ferraro, Laura; La Barbera, Daniele; Lasalvia, Antonio; Tosato, Sarah; Tarricone, Ilaria; Bonora, Elena; Jamain, Stéphane; Selten, Jean-Paul; Velthorst, Eva; de Haan, Lieuwe; Llorca, Pierre-Michel; Arrojo, Manuel; Bobes, Julio; Bernardo, Miguel; Arango, Celso; Kirkbride, James; Jones, Peter B; Rutten, Bart P; Richards, Alexander; Sham, Pak C; O'Donovan, Michael; Van Os, Jim; Morgan, Craig; Di Forti, Marta; Murray, Robin M; Vassos, Evangelos. (2025). Polygenic and Polyenvironment Interplay in Schizophrenia-Spectrum Disorder and Affective Psychosis; the EUGEI First Episode Study.. Schizophrenia bulletin, 51(5), 1254-1265. https://doi.org/10.1093/schbul/sbae207
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