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. 2025 Apr 11:55:e111.
doi: 10.1017/S0033291725000753.

Associations of polygenic risk score, environmental factors, and their interactions with the risk of schizophrenia spectrum disorders

Fatima Zahra Rami  1   2 , Hyungwoo Seo  3 , Chaeyeong Kang  1 , Seunghwan Park  3 , Ling Li  1   2 , Thi-Hung Le  1   2 , Sung-Wan Kim  4 , Seung-Hee Won  5 , Wonil Chung  3   6 , Young-Chul Chung  1   2
Affiliations

Associations of polygenic risk score, environmental factors, and their interactions with the risk of schizophrenia spectrum disorders

Fatima Zahra Rami et al. Psychol Med. .

Abstract

Background: 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).

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Korea-Polyenvironmental Risk Score; Schizophrenia spectrum disorders; gene–environment interactions; polygenic risk score.

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Conflict of interest statement

The authors declare no competing interests exist.

Figures

Figure 1.
Figure 1.
(a) Additive effects of PRS-SZ and K-PERS-I, (b) additive effects of PRS-SZ and pSES, (c) additive effects of PRS-SZ and CA, and (d) additive effects of PRS-SZ and Recent life events. Note: CA, childhood adversity; K-PERS-I, Korea Polyenvironmental Risk Score-I; PRS-SZ, Polygenic Risk Score-Schizophrenia; pSES, parental socioeconomic status; RERI, relative excess risk due to interaction.
Figure 2.
Figure 2.
Regression results of subgroups of the K-PERS-I /ETI-SR and PRS-SZ were divided with a 75% cutoff of the control group. Note: ETI-SR, Early Trauma Inventory Self Report; K-PERS-I, Korea Polyenvironmental Risk Score-I; N, number; OR, odd ratio; PRS-SZ, Polygenic Risk Score-Schizophrenia.
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