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Unveiling genetic signatures of immune response in immune-related diseases through single-cell eQTL analysis across diverse conditions

Author

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  • Zhenhua Zhang

    (a joint venture between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH)
    a joint venture between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH))

  • Wenchao Li

    (a joint venture between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH)
    a joint venture between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH))

  • Qiuyao Zhan

    (a joint venture between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH)
    a joint venture between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH))

  • Michelle Aillaud

    (Philipps University)

  • Javier Botey-Bataller

    (a joint venture between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH)
    a joint venture between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH)
    Radboud University Medical Center)

  • Martijn Zoodsma

    (a joint venture between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH)
    a joint venture between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH))

  • Rob Horst

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Leo A. B. Joosten

    (Radboud University Medical Center
    Iuliu Haţieganu University of Medicine and Pharmacy)

  • Christoph Bock

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
    Medical University of Vienna)

  • Leon N. Schulte

    (Philipps University
    German Center for Lung Research (DZL))

  • Cheng-Jian Xu

    (a joint venture between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH)
    a joint venture between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH)
    Radboud University Medical Center
    Hannover Medical School)

  • Mihai G. Netea

    (Radboud University Medical Center
    University of Bonn)

  • Marc Jan Bonder

    (University Medical Center Groningen
    German Cancer Research Center (DKFZ)
    Genome Biology Unit
    Oncode Institute)

  • Yang Li

    (a joint venture between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH)
    a joint venture between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH)
    Radboud University Medical Center
    Hannover Medical School)

Abstract

Deciphering the intricate regulatory mechanisms underlying biological processes holds promise for elucidating how genetic variants contribute to immune-related disorders. We map genetic effects on gene expression (expression quantitative trait locus, eQTL) using single-cell transcriptomes of 152 samples from 38 healthy individuals, covering baseline state and lipopolysaccharide challenge either before or after Bacillus Calmette-Guerin vaccination. Interestingly, we uncover a monocyte eQTL linked to the LCP1, shedding light on inter-individual variations in trained immunity. Furthermore, we elucidate genetic and epigenetic regulatory networks of CD55 and SLFN5. Of note, our results support the pivotal roles of SLFN5 in COVID-19 pathogenesis by incorporating disease-associated loci, chromatin accessibility, and transcription factor binding affinities, aligning with the established functions of SLFN5 in restricting virus replication during viral infection. Our study provides a paradigm to decipher genetic underpinnings of complex traits by integrating single-cell eQTLs with multi-omics data from patients and public databases.

Suggested Citation

  • Zhenhua Zhang & Wenchao Li & Qiuyao Zhan & Michelle Aillaud & Javier Botey-Bataller & Martijn Zoodsma & Rob Horst & Leo A. B. Joosten & Christoph Bock & Leon N. Schulte & Cheng-Jian Xu & Mihai G. Nete, 2025. "Unveiling genetic signatures of immune response in immune-related diseases through single-cell eQTL analysis across diverse conditions," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61192-4
    DOI: 10.1038/s41467-025-61192-4
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    as
    1. Kyle J. Travaglini & Ahmad N. Nabhan & Lolita Penland & Rahul Sinha & Astrid Gillich & Rene V. Sit & Stephen Chang & Stephanie D. Conley & Yasuo Mori & Jun Seita & Gerald J. Berry & Joseph B. Shrager , 2020. "A molecular cell atlas of the human lung from single-cell RNA sequencing," Nature, Nature, vol. 587(7835), pages 619-625, November.
    2. Roy Oelen & Dylan H. Vries & Harm Brugge & M. Grace Gordon & Martijn Vochteloo & Chun J. Ye & Harm-Jan Westra & Lude Franke & Monique G. P. Wijst, 2022. "Single-cell RNA-sequencing of peripheral blood mononuclear cells reveals widespread, context-specific gene expression regulation upon pathogenic exposure," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Gao Wang & Abhishek Sarkar & Peter Carbonetto & Matthew Stephens, 2020. "A simple new approach to variable selection in regression, with application to genetic fine mapping," Journal of the Royal Statistical Society Series B, Royal Statistical Society, vol. 82(5), pages 1273-1300, December.
    4. Sergey Abramov & Alexandr Boytsov & Daria Bykova & Dmitry D. Penzar & Ivan Yevshin & Semyon K. Kolmykov & Marina V. Fridman & Alexander V. Favorov & Ilya E. Vorontsov & Eugene Baulin & Fedor Kolpakov , 2021. "Landscape of allele-specific transcription factor binding in the human genome," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    5. Julia Minderjahn & Andreas Schmidt & Andreas Fuchs & Rudolf Schill & Johanna Raithel & Magda Babina & Christian Schmidl & Claudia Gebhard & Sandra Schmidhofer & Karina Mendes & Anna Ratermann & Dagmar, 2020. "Mechanisms governing the pioneering and redistribution capabilities of the non-classical pioneer PU.1," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    6. Ken Suzuki & Konstantinos Hatzikotoulas & Lorraine Southam & Henry J. Taylor & Xianyong Yin & Kim M. Lorenz & Ravi Mandla & Alicia Huerta-Chagoya & Giorgio E. M. Melloni & Stavroula Kanoni & Nigel W. , 2024. "Genetic drivers of heterogeneity in type 2 diabetes pathophysiology," Nature, Nature, vol. 627(8003), pages 347-357, March.
    7. Aparna Nathan & Samira Asgari & Kazuyoshi Ishigaki & Cristian Valencia & Tiffany Amariuta & Yang Luo & Jessica I. Beynor & Yuriy Baglaenko & Sara Suliman & Alkes L. Price & Leonid Lecca & Megan B. Mur, 2022. "Single-cell eQTL models reveal dynamic T cell state dependence of disease loci," Nature, Nature, vol. 606(7912), pages 120-128, June.
    8. Oliver Stegle & Leopold Parts & Richard Durbin & John Winn, 2010. "A Bayesian Framework to Account for Complex Non-Genetic Factors in Gene Expression Levels Greatly Increases Power in eQTL Studies," PLOS Computational Biology, Public Library of Science, vol. 6(5), pages 1-11, May.
    9. Gibran Hemani & Kate Tilling & George Davey Smith, 2017. "Orienting the causal relationship between imprecisely measured traits using GWAS summary data," PLOS Genetics, Public Library of Science, vol. 13(11), pages 1-22, November.
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