Sex Differences in the Independent and Combined Effects of Genomic and Exposomic Risks for Schizophrenia on Distressing Psychotic Experiences: Insights from the ABCD Study
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Purpose
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.
Method
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-SCZ 75 ) and ES-SCZ (ES-SCZ 75 ) 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.
Results
PRS-SCZ 75 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. However, a significant sex difference was only detected for lifetime distressing PEs. ES-SCZ 75 was significantly associated with past-month distressing PEs and all secondary outcomes without significant sex differences. No additive interaction between ES-SCZ 75 and PRS-SCZ 75 was detected for any PE outcomes.
Conclusion
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.
Article Highlights
▢ 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.
