The effects of polygenic risk for psychiatric disorders and smoking behaviour on psychotic experiences in UK Biobank

ABSTRACT While psychotic experiences are core symptoms of mental health disorders like schizophrenia, they are also reported by 5-10% of the population. Both smoking behaviour and genetic risk for psychiatric disorders have been associated with psychotic experiences, but the interplay between these factors remains poorly understood. We tested whether smoking status, maternal smoking around birth, and number of packs smoked/year were associated with lifetime occurrence of three psychotic experiences phenotypes: delusions (n=2 067), hallucinations (n=6 689), and any psychotic experience (delusions or hallucinations; n=7 803) in 157 366 UK Biobank participants. We next calculated polygenic risk scores for schizophrenia (PRS SCZ ), bipolar disorder (PRS BP ), major depression (PRS DEP ) and attention deficit hyperactivity disorder (PRS ADHD ) in 144 818 UK Biobank participants of European ancestry to assess whether association between smoking and psychotic experiences was attenuated after adjustment of diagnosis of psychiatric disorders and the PRSs. Finally, we investigated whether smoking exacerbates the effects of genetic predisposition on the psychotic phenotypes in gene-environment interaction models. Smoking status, maternal smoking, and number of packs smoked/year were associated with psychotic experiences ( p <1.77×10 -5 ). Except for packs smoked/year, effects were attenuated but remained significant after adjustment for diagnosis of psychiatric disorders and PRSs ( p <1.99×10 -3 ). Gene-environment interaction models showed the effects of PRS DEP and PRS ADHD (but not PRS SCZ or PRS BP ) on delusions (but not hallucinations) were significantly greater in current smokers compared to never smokers ( p <0.002). There were no significant gene-environment interactions for maternal smoking nor for number of packs smoked/year. Our results suggest that both genetic risk of psychiatric disorders and smoking status may have independent and synergistic effects on specific types of psychotic experiences.