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<p>Genome-wide association studies performed in COVID-19 patients have uncovered various loci significantly associated with susceptibility to SARS-CoV-2 infection and disease severity. However, the underlying <i>cis</i>-regulatory genetic factors contributing to heterogeneity in the response to SARS-CoV-2 infection and their impact on clinical phenotypes remain enigmatic. Here, we use single-cell RNA-sequencing to quantify genetic contributions to <i>cis</i>-regulatory variation in 361,119 peripheral blood mononuclear cells of 63 acute COVID-19 patients, 39 convalescent samples, and 106 healthy controls. Expression quantitative trait loci mapping across cell types within each disease state group reveals thousands of <i>cis</i>-associated variants, of which hundreds are detected exclusively in immune cells derived from acute patients. Patient-specific genetic effects dissipate as infection resolves, suggesting that distinct gene regulatory networks are at play in the active infection state. Further, 20.3% of tested loci demonstrate significant cell state interactions with genotype, with pathways related to interferon responses and oxidative phosphorylation showing pronounced cell state-dependent variation, predominantly in CD14<sup>+</sup> monocytes. Overall, we estimate that 16.8% of tested genes exhibit gene-environment interaction effects, highlighting the importance of environmental modifiers in the transcriptional regulation of the immune response to SARS-CoV-2. Our findings argue for the existence of extensive gene-environment effects among patients responding to an infection.</p>

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Widespread gene-environment interactions shape the immune response to SARS-CoV-2 infection in hospitalized COVID-19 patients

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月28日

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  • Haley E. Randolph,
  • Raúl Aguirre-Gamboa,
  • Elsa Brunet-Ratnasingham,
  • Tomoko Nakanishi,
  • Zepeng Mu,
  • Veronica Locher,
  • Ellen Ketter,
  • Cary Brandolino,
  • Catherine Larochelle,
  • Alexandre Prat,
  • Nathalie Arbour,
  • Anne Dumaine,
  • Andrés Finzi,
  • Madeleine Durand,
  • J. Brent Richards,
  • Daniel E. Kaufmann,
  • Luis B. Barreiro

摘要

Genome-wide association studies performed in COVID-19 patients have uncovered various loci significantly associated with susceptibility to SARS-CoV-2 infection and disease severity. However, the underlying cis-regulatory genetic factors contributing to heterogeneity in the response to SARS-CoV-2 infection and their impact on clinical phenotypes remain enigmatic. Here, we use single-cell RNA-sequencing to quantify genetic contributions to cis-regulatory variation in 361,119 peripheral blood mononuclear cells of 63 acute COVID-19 patients, 39 convalescent samples, and 106 healthy controls. Expression quantitative trait loci mapping across cell types within each disease state group reveals thousands of cis-associated variants, of which hundreds are detected exclusively in immune cells derived from acute patients. Patient-specific genetic effects dissipate as infection resolves, suggesting that distinct gene regulatory networks are at play in the active infection state. Further, 20.3% of tested loci demonstrate significant cell state interactions with genotype, with pathways related to interferon responses and oxidative phosphorylation showing pronounced cell state-dependent variation, predominantly in CD14+ monocytes. Overall, we estimate that 16.8% of tested genes exhibit gene-environment interaction effects, highlighting the importance of environmental modifiers in the transcriptional regulation of the immune response to SARS-CoV-2. Our findings argue for the existence of extensive gene-environment effects among patients responding to an infection.