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

Abstract Family-based studies provide a unique opportunity to characterize genetic risks of diseases in the presence of population structure, assortative mating, and indirect genetic effects. We propose a novel framework, PGS-TRI, for the analysis of polygenic scores (PGS) in case-parent trio studies to estimate the risk of an index condition associated with direct effects of inherited PGS, indirect effects of parental PGS, and gene-environment interactions. Extensive simulation studies demonstrate the robustness of PGS-TRI in the presence of complex population structure and assortative mating. We applied PGS-TRI to multi-ancestry trio studies of autism spectrum disorders (ASD) (N trio = 18,383), deriving transmission-based estimates of risk for the direct effects of established PGS for ASD and other neurocognitive traits PGS across different ancestry groups and along a genetic ancestry continuum. Our analysis also identified significant indirect effects from parental PGS for BMI and several neurocognitive traits on children’s ASD risk. We also employed PGS-TRI in a trio study of European and Asian orofacial clefts (OFCs) (N trio = 1,904), investigating both direct and indirect effect of an established PGS and its interaction with maternal risk factors. Finally, we applied PGS-TRI to investigate the direct and indirect effects of large-scale transcriptome-wide and metabolome-wide traits on ASD and OFCs risks.