Estimation of Direct and Indirect Polygenic Effects and Gene-Environment Interactions using Polygenic Scores in Case-Parent Trio Studies

medRxiv [Preprint]. 2024 Oct 9:2024.10.08.24315066. doi: 10.1101/2024.10.08.24315066.

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 for estimation of 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 compared to alternative methods. We apply PGS-TRI to multi-ancestry trio studies of autism spectrum disorders (Ntrio = 1,517) and orofacial clefts (Ntrio = 1,904) to establish the first transmission-based estimates of risk associated with pre-defined PGS for these conditions and other related traits. For both conditions, we further explored offspring risk associated with polygenic gene-environment interactions, and direct and indirect effects of genetically predicted levels of gene expression and metabolite traits.

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  • Preprint