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 (PRSSCZ), bipolar disorder (PRSBP), major depression (PRSDEP) and attention deficit hyperactivity disorder (PRSADHD) 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 PRSDEP and PRSADHD (but not PRSSCZ or PRSBP) 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.
Competing Interest Statement
The authors have declared no competing interest.
Funding Statement
JGG is supported by a Queen Mary Principal's Research Studentship in the School of Biological and Chemical Sciences. DMH is supported by a Sir Henry Wellcome Postdoctoral Fellowship (Reference 213674/Z/18/Z) and a 2018 NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation (Ref: 27404). PBM wishes to acknowledge support from the National Institutes of Health Research (NIHR) Cardiovascular Biomedical Centre at Barts and The London, Queen Mary University of London (QMUL). JR acknowledges support from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 786833. CHB acknowledges support from NIH grant No UO1 DA04440001A1. CHB is a member of the Royal Society Industry Fellows' College. RK is supported by Wellcome Trust Grant 208881/Z/17/Z.
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Yes
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Footnotes
Summary of changes included in revised manuscript: - Main and interaction analyses now include PRSs for bipolar disorder (Stahl et al. 2019). - The different diagnoses included as psychotic disorders (schizophrenia, mania, hypomania, bipolar or manic depression, or any other type of psychotic disorder including schizotypal and delusional disorders) are now specified on first usage in the text. - A shortened version of the paragraphs that summarize the analysis pipeline has been moved to the introduction. - A new paragraph including Psychotic Experience ∼ PRS analyses has been included in the main effects section, and the prediction of psychotic experiences in UK Biobank using PRSs for schizophrenia, depression, ADHD and bipolar disorder were moved from Supplementary Figure 1 to Figure 2 in the main text. - Treatment with antidepressants was taken into account in the original submitted manuscript, since the presence of antidepressant drugs in the 'treatment medication' field was part of the inclusion criteria for depression (Supplementary Table 4). Depression was included as covariate in the association analyses between psychotic experiences and smoking behaviour. However, presence of antipsychotics in the treatment medication field was not part of the inclusion criteria for psychotic disorders. This has been amended now and antipsychotic treatment is included in the criteria for psychotic disorders (Supplementary Table 4). The list of antipsychotic drugs included is specified in Supplementary Table 5. Using the new criteria to ascertain cases for psychotic disorders, the number of cases increased from 4,847 to 6,727, but the study results remained similar. - We have checked the sample overlap between the depression GWAS and UK Biobank and assessed its impact. Sample overlap was 0.079% for the discovery sample (351/446,238), and 0.242% for the target sample (351/144,818). This has been included in the manuscript.
Data Availability
All data referred to in this manuscript is available upon request