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

AI Summary

PGS-TRI framework estimates direct and indirect polygenic effects and gene-environment interactions in case-parent trio studies, including asymmetric maternal and paternal indirect effects.
Simulations demonstrate robustness to complex population structure and assortative mating, ensuring unbiased estimation under realistic confounding scenarios.
Applied to 18,383 autism and 1,904 orofacial cleft trios, PGS-TRI revealed transmission based direct effects, asymmetric parental indirect effects and maternal PGS interactions.

AI Summary

We have proposed PGS-TRI, a framework for analyzing polygenic scores (PGSs) in case-parent trio studies that estimate the risk of an index condition associated with direct PGS effects, gene-environment interactions and asymmetrical maternal and paternal indirect effects. Applied to multi-ancestry autism spectrum disorders (ASD) trios (ntrio = 18,383), PGS-TRI yielded transmission-based direct effects of PGSs for ASD and other neurocognitive traits along a genetic ancestry continuum, and identified asymmetrical indirect effects of parental PGSs for body mass index and neurocognitive traits on children's ASD risk. In a trio study of European and Asian orofacial clefts (OFCs) (ntrio = 1,904), PGS-TRI estimated direct and indirect effects of an established PGS and its interaction with maternal risk factors.

Basic summary

Nat Genet. 2026 Jun 2. doi: 10.1038/s41588-026-02601-2. Online ahead of print.

ABSTRACT

We have proposed PGS-TRI, a framework for analyzing polygenic scores (PGSs) in case-parent trio studies that estimate the risk of an index condition associated with direct PGS effects, gene-environment interactions and asymmetrical maternal and paternal indirect effects. Simulations confirm its robustness in the presence of complex population structure and assortative mating. Applied to multi-ancestry autism spectrum disorders (ASD) trios (n_trio = 18,383), PGS-TRI yielded transmission-based direct effects of PGSs for ASD and other neurocognitive traits along a genetic ancestry continuum, and identified asymmetrical indirect effects of parental PGSs for body mass index and neurocognitive traits on children’s ASD risk. In a trio study of European and Asian orofacial clefts (OFCs) (n_trio = 1,904), PGS-TRI estimated direct and indirect effects of an established PGS and its interaction with maternal risk factors. Finally, we applied PGS-TRI to large-scale, transcriptome-wide and metabolome-wide traits to examine their direct and indirect effects on ASD and OFC risk.

PMID:42230772 | DOI:10.1038/s41588-026-02601-2

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