How Genetics and Environment (Including Cannabis) Combine to Influence Psychosis Risk

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.

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.

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.

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.

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.