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

Abstract

AbstractBackgroundA 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.MethodTo 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.ResultsIn 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.ConclusionThese findings reveal preliminary evidence for gene-environment interaction underlying PEs and suggest that genetic vulnerability and exposures might represent intertwined pathways leading to psychosis.