# Sex differences in the independent and combined effects of genomic and exposomic risks for schizophrenia on distressing psychotic experiences: insights from the ABCD study

## TL;DR

The study finds that genetic risks for schizophrenia are linked to distressing psychotic experiences only in female adolescents, while environmental risks affect both sexes.

## Contribution

This study reveals sex-specific effects of genetic and environmental risks on distressing psychotic experiences in early adolescence.

## Key findings

- Genomic risk for schizophrenia was associated with distressing psychotic experiences only in female adolescents.
- Environmental risk factors for schizophrenia were linked to distressing experiences in both sexes.
- Environmental risks showed dose-response effects on the persistence of distressing experiences.

## Abstract

To investigate sex-dependent effects of polygenic risk (PRS-SCZ) and exposome score (ES-SCZ) for schizophrenia, both independently and jointly, on distressing psychotic experiences (PEs) in early adolescents.

Baseline to 3-year follow-up data of the Adolescent Brain and Cognitive Development Study (ABCD) were used. PRS-SCZ and ES-SCZ were calculated to assess cumulative genetic and environmental (childhood adversity, cannabis use, hearing impairment, and winter births) risk for schizophrenia, respectively. The primary outcome was past-month distressing PEs at the 3-year follow-up. Secondary outcomes included distressing PEs across four yearly assessments: lifetime (≥ 1 wave), repeated (≥ 2 or ≥ 3 waves), and persisting (≥ 4 waves). Sex-stratified multilevel logistic regression models were used to test the independent and joint associations of binary modes (> 75th percentile) of PRS-SCZ (PRS-SCZ75) and ES-SCZ (ES-SCZ75) on the outcomes. As sensitivity analysis, the sex-stratified analyses were repeated on a randomly selected unrelated sample, and the coefficients of males and females were compared.

PRS-SCZ75 was not associated with past-month distressing PEs in either sex but significantly associated with lifetime and repeated (≥ 2 waves) distressing PEs only in females. In both sexes, ES-SCZ75 was significantly associated with all PE outcomes but did not additively interact with PRS-SCZ75 in predicting them. Sensitivity analysis confirmed the findings and revealed a significant sex difference in the association between PRS-SCZ75 and lifetime distressing PEs.

The influence of genomic risk for schizophrenia on distressing PEs might be sex-dependent, whereas that of the exposomic risk was universal in early adolescence. Further studies in larger samples are needed.

The online version contains supplementary material available at 10.1007/s00737-025-01644-4.

Genomic risks for schizophrenia were associated with distressing PEs only in female adolescents.Environmental risks for schizophrenia were associated with distressing PEs regardless of sex in early adolescence.Dose-response effects of the environmental risks on PE persistence support them as potential preventive targets.A sex-informed approach is needed to better understand genetic and environmental contributions to psychosis expression.

Genomic risks for schizophrenia were associated with distressing PEs only in female adolescents.

Environmental risks for schizophrenia were associated with distressing PEs regardless of sex in early adolescence.

Dose-response effects of the environmental risks on PE persistence support them as potential preventive targets.

A sex-informed approach is needed to better understand genetic and environmental contributions to psychosis expression.

The online version contains supplementary material available at 10.1007/s00737-025-01644-4.