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Estimation of direct and indirect polygenic effects and gene–environment interactions using polygenic scores in case–parent trio studies - Nature Genetics

The researchers present PGS-TRI, a framework to analyze polygenic scores in case–parent trios for direct, indirect, and gene–environment effects.
The model uses a log-linear approach and within-family variance scaling to yield interpretable risk estimates like relative risk.
SPARK ASD data show a transmission-based direct PGS effect on autism risk across multiple ancestry groups.
Maternal PGS shows indirect effects on offspring ASD risk, suggesting maternal genetic factors influence child outcomes.
The framework accounts for ancestry distance, showing PGS effects diminish as training population distance increases.
OFC analysis identified robust direct effects across European and Asian ancestry groups for a specific PGS.
Gene-expression PGS analyses identified CADM2 as associated with ASD risk in transcriptome-wide analyses.
The study used SPARK, UK Biobank, and GENEVA data to validate PGS-TRI across diverse datasets.
PGS-TRI enables estimation of indirect parental effects without separate parental trait modeling.
The authors suggest PGS-TRI could extend to other family designs and multivariable analyses.

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