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

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 (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. 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.