Emerging evidence indicates that gene–environment interactions (GEIs) are important underlying mechanisms for the development of schizophrenia (SZ). We investigated the associations of polygenic risk score for SZ (PRS-SZ), environmental measures, and their interactions with case–control status and clinical phenotypes among patients with schizophrenia spectrum disorders (SSDs).

The PRS-SZ for 717 SSD patients and 356 healthy controls (HCs) were calculated using the LDpred model. The Korea-Polyenvironmental Risk Score-I (K-PERS-I) and Early Trauma Inventory-Self Report (ETI-SR) were utilized as environmental measures. Logistic and linear regression analyses were performed to identify the associations of PRS-SZ and two environmental measures with case–control status and clinical phenotypes.

The PRS-SZ explained 8.7% of SZ risk. We found greater associations of PRS-SZ and total scores of the K-PERS-I with case–control status compared to the ETI-SR total score. A significant additive interaction was found between PRS-SZ and K-PERS-I. With the subdomains of the K-PERS-I and ETI-SR, we identified significant multiplicative or additive interactions of PRS-SZ and parental socioeconomic status (pSES), childhood adversity, and recent life events in association with case–control status. For clinical phenotypes, significant interactions were observed between PRS-SZ and the ETI-SR total score for negative-self and between PRS-SZ and obstetric complications within the K-PERS-I for negative-others.

Our findings suggest that the use of aggregate scores for genetic and environmental measures, PRS-SZ and K-PERS-I, can more accurately predict case–control status, and specific environmental measures may be more suitable for the exploration of GEIs.