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

  • Nat Commun. 2025 Aug 4;16(1):7134. doi: 10.1038/s41467-025-61192-4.
Zhenhua Zhang  1  2 ,  Wenchao Li  1  2 ,  Qiuyao Zhan  1  2 ,  Michelle Aillaud  3 ,  Javier Botey-Bataller  1  2  4 ,  Martijn Zoodsma  1  2 ,  Rob Ter Horst  5 ,  Leo A B Joosten  4  6 ,  Christoph Bock  5  7 ,  Leon N Schulte  3  8 ,  Cheng-Jian Xu  1  2  4  9 ,  Mihai G Netea  4  10 ,  Marc Jan Bonder  11  12  13  14 ,  Yang Li  15  16  17  18  19
Affiliations
  • 1. Department of Computational Biology for Individualised Infection Medicine, Centre for Individualised Infection Medicine (CiiM), a joint venture between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany.
  • 2. TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany.
  • 3. Institute for Lung Research, Philipps University, Marburg, Germany.
  • 4. Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 5. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • 6. Department of Medical Genetics, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
  • 7. Institute of Artificial Intelligence, Center for Medical Data Science, Medical University of Vienna, Vienna, Austria.
  • 8. German Center for Lung Research (DZL), Giessen, Germany.
  • 9. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
  • 10. Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany.
  • 11. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
  • 12. Division of Computational Genomics and Systems Genetics, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
  • 13. European Molecular Biology Laboratory, Genome Biology Unit, 69117, Heidelberg, Germany.
  • 14. Oncode Institute, Utrecht, The Netherlands.
  • 15. Department of Computational Biology for Individualised Infection Medicine, Centre for Individualised Infection Medicine (CiiM), a joint venture between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany. [email protected].
  • 16. TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany. [email protected].
  • 17. Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands. [email protected].
  • 18. Cluster of Excellence Resolving Infection Susceptibility (RESIST; EXC 2155), Hannover Medical School, Hannover, Germany. [email protected].
  • 19. Lower Saxony center for artificial intelligence and causal methods in medicine (CAIMed), Hannover, Germany. [email protected].
PMID: 40759647 DOI: 10.1038/s41467-025-61192-4
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.

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