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<p>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 (<i>n</i><sub>trio</sub> = 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) (<i>n</i><sub>trio</sub> = 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月2日

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  • Ziqiao Wang,
  • Luke Grosvenor,
  • Debashree Ray,
  • Tianyuan Cheng,
  • Ingo Ruczinski,
  • Terri H. Beaty,
  • Heather Volk,
  • Christine Ladd-Acosta,
  • Nilanjan Chatterjee

摘要

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.