Exposome-wide gene-environment interaction study of psychotic experiences in the UK Biobank

Background A previous study successfully identified 148 out of 23,098 exposures associated with any psychotic experiences (PE) in the UK Biobank using an exposome-wide association study (XWAS). Research has shown that the polygenic risk score for schizophrenia (PRS-SCZ) is associated with PE. However, the interaction of these exposures and PRS-SCZ remains unknown. Method To systematically investigate gene-environment interaction underlying PE through data-driven agnostic analyses, we conducted 1) a conditional XWAS adjusting for PRS-SCZ to estimate the main effects of the exposures and PRS-SCZ, respectively; 2) exposome-wide interaction studies (XWIS) to estimate multiplicative and additive interactions between PRS-SCZ and exposures; and 3) the correlations between PRS-SCZ and exposures. The study included 148,502 participants from UK biobank. Results In the conditional XWAS models, the significant effects of PRS-SCZ and 148 exposures on PE remained statistically significant. In the XWIS model, we found a significant multiplicative (Ms, 1.23, 95%CI, 1.10-1.37; P=4.0×10 -4 ) and additive (RERI, 0.55; 95%CI, 0.32-0.77; SI, 0.22; 95%CI, 0.14-0.30; AP, 1.59; 95%CI, 1.30-1.91; all P < 0.05/148) interaction between PRS-SCZ and variable “serious medical conditions or disability” on PE. There were six additive gene-environment interactions identified for mental distress, help/treatment-seeking behaviors, vitamin D and sleep problems. In the correlation test focused on seven exposures with significant interaction with PRS-SCZ, no significant or small (r2< 0.04) gene-environment correlations were estimated. Conclusion These findings reveal preliminary evidence for gene-environment interaction underlying PEs and suggest that genetic vulnerability and exposures might represent intertwined pathways leading to psychosis.