Psychotic experiences, encompassing hallucinations and delusions, affect 5–10% of the general population and are core symptoms of severe mental disorders like schizophrenia. Understanding their etiology is crucial for identifying individual susceptibility and developing targeted prevention strategies. Genetic factors contribute significantly to the variance in psychotic experiences, with twin studies indicating heritability of 30–50% and molecular genetic studies revealing that common genetic variations explain 3–17% of the variance. These genetic influences are shared with psychiatric disorders like schizophrenia, bipolar disorder, depression, and ADHD. Environmental factors also play a crucial role, accounting for 50–70% of the variance. Smoking has emerged as a prominent environmental risk factor, consistently linked to psychotic experiences in various studies, with evidence suggesting a causal relationship. While less established, maternal smoking and other smoking phenotypes also show potential associations with psychotic experiences. Despite evidence linking genetic risk for psychiatric disorders and smoking to psychotic experiences, the interplay between these factors remains unclear. This study aimed to examine the independent and combined effects of smoking and genetic predisposition (measured by PRSs for schizophrenia, bipolar disorder, depression, and ADHD) on psychotic experiences using the large UK Biobank dataset.

Existing literature highlights the significant contribution of both genetic and environmental factors to psychotic experiences. Twin studies have established a substantial heritable component, while genome-wide association studies (GWAS) have identified specific genetic variants associated with these experiences. The genetic correlation between psychotic experiences and various psychiatric disorders, including schizophrenia, bipolar disorder, depression, and ADHD, has also been demonstrated. Smoking stands out as a prominent environmental risk factor, with considerable evidence supporting a causal link between smoking and psychotic experiences. This association appears independent of pre-existing mental health conditions. While maternal smoking during pregnancy has also been linked to increased risk in offspring, the evidence remains debated. Prior research has highlighted the association between PRSs for psychiatric disorders and smoking behavior, hinting at potential shared genetic influences. However, the interplay between smoking and genetic predisposition to psychiatric disorders in the development of psychotic experiences required further investigation, which this study addresses.

This study utilized data from the UK Biobank, a large population-based cohort study. The researchers analyzed data from 157,366 participants who completed an online mental health questionnaire. Three psychotic experience phenotypes were defined: delusions, hallucinations, and any psychotic experience. Smoking variables included smoking status (never, former, current), pack-years smoked, and maternal smoking around birth. Lifetime diagnoses of psychiatric disorders (depression, ADHD, and psychotic disorders) were also recorded. Polygenic risk scores (PRSs) for schizophrenia, bipolar disorder, major depression, and ADHD were calculated using summary statistics from published GWAS. The study employed regression models to assess the associations between smoking variables and psychotic experiences, first independently and then adjusting for psychiatric diagnoses and PRSs. Gene-environment interaction (GxE) analyses explored whether the effects of PRSs on psychotic experiences were modified by smoking variables using both additive and multiplicative models. Sensitivity analyses were conducted to address potential biases from including participants with psychotic disorders. The statistical analyses were performed in R.

The study revealed significant associations between various smoking phenotypes (smoking status, maternal smoking, and pack-years smoked) and all three psychotic experience phenotypes (delusions, hallucinations, and any psychotic experience). These associations were attenuated but remained significant after adjusting for psychiatric diagnoses and PRSs, indicating independent effects of smoking. Importantly, gene-environment interaction analyses demonstrated significant additive interactions between PRSs for depression and ADHD and current smoking status on delusions. Specifically, the combined effect of these PRSs and current smoking on delusions was greater than the sum of their individual effects. This interaction effect was not observed for hallucinations or any psychotic experience, and there were no significant gene-environment interactions for maternal smoking or pack-years smoked. Sensitivity analyses excluding participants with psychotic disorders confirmed the robustness of these key findings.

This study provides compelling evidence for the independent and synergistic effects of both genetic predisposition to psychiatric disorders and smoking behavior on psychotic experiences. The findings highlight the importance of considering both genetic and environmental factors in understanding the risk for psychotic experiences. The significant interaction between PRSs for depression and ADHD and current smoking on delusions suggests that smoking may exacerbate the effect of genetic vulnerability for specific psychotic symptoms. This interaction effect is of particular importance and emphasizes the potential value of interventions targeting smoking cessation in individuals with increased genetic risk for depression and ADHD. Future studies could explore the underlying biological mechanisms contributing to this gene-environment interaction. The findings contribute to a more nuanced understanding of psychotic experiences, which may inform preventative measures and tailored intervention strategies.

This study demonstrates that both genetic risk for certain psychiatric disorders and smoking status independently contribute to psychotic experiences, with a notable synergistic effect between genetic risk for depression and ADHD and current smoking on the development of delusions. These findings highlight the importance of considering both genetic and environmental risk factors in a comprehensive approach to understanding and managing psychotic experiences. Future research should focus on investigating the biological mechanisms underlying these interactions and exploring the effectiveness of interventions targeting both genetic and environmental risk factors.

The study's reliance on self-reported data from the UK Biobank questionnaire might introduce recall bias and subjective interpretation of psychotic experiences. The cross-sectional design limits causal inferences, and further longitudinal studies are needed to confirm the causal relationships. The study focused primarily on individuals of European ancestry, limiting the generalizability of findings to other populations. The analysis of gene-environment interaction did not include all potential interactions. The choice of PRS threshold might have influenced the findings.