TY - JOUR
T1 - Exposome-Wide Gene-By-Environment Interaction Study of Psychotic Experiences in the UK Biobank
AU - Lin, Bochao Danae
AU - Pries, Lotta-Katrin
AU - Arias-Magnasco, Angelo
AU - Klingenberg, Boris
AU - Linden, David E. J.
AU - Blokland, Gabriella A. M.
AU - van der Meer, Dennis
AU - Luykx, Jurjen J.
AU - Rutten, Bart P. F.
AU - Guloksuz, Sinan
PY - 2025/5/1
Y1 - 2025/5/1
N2 - BACKGROUND: A previous study successfully identified 148 of 23,098 exposures associated with any psychotic experiences (PEs) in the UK Biobank using an exposome-wide association study (XWAS). Furthermore, research has shown that the polygenic risk score for schizophrenia (PRS-SCZ) is associated with PEs. However, the interaction of these exposures with PRS-SCZ remains unknown. METHOD: To systematically investigate possible gene-by-environment interactions underlying PEs through data- driven agnostic analyses, we conducted 1) conditional XWAS adjusting for PRS-SCZ to estimate the main effects of the exposures and of PRS-SCZ, 2) exposome-wide interaction study (XWIS) to estimate multiplicative and additive interactions between PRS-SCZ and exposures, and 3) correlation analyses between PRS-SCZ and exposures. The study included 148,502 participants from the UK Biobank. RESULTS: In the conditional XWAS models, significant effects of PRS-SCZ and 148 exposures on PEs remained statistically significant. In the XWIS model, we found significant multiplicative (multiplicative scale, 1.23; 95% CI, 1.10-1.37; p = 4.0 3 1024) and additive (relative excess risk due to interaction, 0.55; 95% CI, 0.32-0.77; synergy index, 0.22; 95% CI, 0.14-0.30; and attributable proportion, 1.59; 95% CI, 1.30-1.91; all ps < .05/148) interactions of PRS-SCZ and the variable serious medical conditions/disability with PEs. We additionally identified 6 additive gene-by-environment interactions for mental distress, help-/treatment-seeking behaviors (3 variables), sadness, and sleep problems. In the correlation test focused on 7 exposures that exhibited significant interactions with PRS-SCZ, nonsignificant or small (r < 0.04) gene-by-environment correlations were observed. CONCLUSIONS: These findings reveal evidence for gene-by-environment interactions underlying PEs and suggest that intertwined pathways of genetic vulnerability and exposures may contribute to psychosis risk.
AB - BACKGROUND: A previous study successfully identified 148 of 23,098 exposures associated with any psychotic experiences (PEs) in the UK Biobank using an exposome-wide association study (XWAS). Furthermore, research has shown that the polygenic risk score for schizophrenia (PRS-SCZ) is associated with PEs. However, the interaction of these exposures with PRS-SCZ remains unknown. METHOD: To systematically investigate possible gene-by-environment interactions underlying PEs through data- driven agnostic analyses, we conducted 1) conditional XWAS adjusting for PRS-SCZ to estimate the main effects of the exposures and of PRS-SCZ, 2) exposome-wide interaction study (XWIS) to estimate multiplicative and additive interactions between PRS-SCZ and exposures, and 3) correlation analyses between PRS-SCZ and exposures. The study included 148,502 participants from the UK Biobank. RESULTS: In the conditional XWAS models, significant effects of PRS-SCZ and 148 exposures on PEs remained statistically significant. In the XWIS model, we found significant multiplicative (multiplicative scale, 1.23; 95% CI, 1.10-1.37; p = 4.0 3 1024) and additive (relative excess risk due to interaction, 0.55; 95% CI, 0.32-0.77; synergy index, 0.22; 95% CI, 0.14-0.30; and attributable proportion, 1.59; 95% CI, 1.30-1.91; all ps < .05/148) interactions of PRS-SCZ and the variable serious medical conditions/disability with PEs. We additionally identified 6 additive gene-by-environment interactions for mental distress, help-/treatment-seeking behaviors (3 variables), sadness, and sleep problems. In the correlation test focused on 7 exposures that exhibited significant interactions with PRS-SCZ, nonsignificant or small (r < 0.04) gene-by-environment correlations were observed. CONCLUSIONS: These findings reveal evidence for gene-by-environment interactions underlying PEs and suggest that intertwined pathways of genetic vulnerability and exposures may contribute to psychosis risk.
KW - CHILDHOOD TRAUMA
KW - CANNABIS USE
KW - RISK
KW - SCHIZOPHRENIA
KW - ASSOCIATION
KW - ADOLESCENCE
U2 - 10.1016/j.bpsgos.2025.100460
DO - 10.1016/j.bpsgos.2025.100460
M3 - Article
SN - 2667-1743
VL - 5
JO - Biological Psychiatry: Global Open Science
JF - Biological Psychiatry: Global Open Science
IS - 3
M1 - 100460
ER -