Federated single-cell QTL meta-analysis reveals novel disease mechanisms
Genetic effects on gene expression are often cell type-specific and obscured in bulk analyses. To resolve this context-dependent regulation, we performed a federated <i>cis</i>-eQTL meta-analysis across 12 PBMC datasets (2,032 individuals, 2.5 million cells). Across six immune cell types, we identified <i>cis</i>-eQTLs for 6,592 genes and fine-mapped 14,985 independent loci. Notably, the 42% of eQTLs that were undetected in a bulk eQTL study on 43,301 whole blood samples also showed stronger enrichment for disease GWAS loci. We further identified three genome-wide significant and 65 suggestive loci affecting the abundance of (rare) immune cell types and validated these using previously reported hematological GWAS and bulk-derived <i>trans</i>-eQTLs. Integrating single-cell <i>cis</i>-eQTLs with bulk <i>trans</i>-eQTLs enabled us to anchor 6,382 <i>trans</i>-eGenes (37.2% novel) to upstream regulators and reconstruct directed gene regulatory relationships. For example, a hemorrhoidal disease-associated variant showed a CD4+ T cell-specific <i>cis</i>-eQTL on <i>BACH1</i> that colocalized with 45 immune and metabolic <i>trans</i>-eGenes. These results demonstrate the power of single-cell QTL meta-analysis in interpreting complex trait genetics.
Authors
- Lieke Michielsen (ORCID: https://orcid.org/0000-0003-4615-1309)
- Matthias Heinig (ORCID: https://orcid.org/0000-0002-5612-1720)
- Wenchao Li (ORCID: https://orcid.org/0000-0001-5352-3196)
- Chung-Chau Hon (ORCID: https://orcid.org/0000-0002-3741-7577)
- Corinna Losert (ORCID: https://orcid.org/0000-0002-5997-4702)
- Daniel Considine (ORCID: https://orcid.org/0009-0008-7769-2195)
- Jonathan Moody
- Zhenhua Zhang (ORCID: https://orcid.org/0000-0002-1781-7127)
- Martijn Vochteloo (ORCID: https://orcid.org/0000-0002-6385-0550)
- Issiaka Soulama (ORCID: https://orcid.org/0000-0002-0993-0525)
- Irene V. van Blokland (ORCID: https://orcid.org/0000-0002-8545-8015)
- Tala Shahin (ORCID: https://orcid.org/0000-0001-8030-1257)
- Jeff R. Powell (ORCID: https://orcid.org/0000-0003-1091-2452)
- M Nawijn
- Jimmy Tsz Hang Lee (ORCID: https://orcid.org/0000-0003-1208-8356)
- Mame Massar Dieng (ORCID: https://orcid.org/0000-0002-3573-6697)
- Deepa Rajagopalan (ORCID: https://orcid.org/0000-0002-3652-7176)
- Pooja Kathail (ORCID: https://orcid.org/0000-0001-8860-0753)
- Younes Mokrab
- Jelmer Niewold (ORCID: https://orcid.org/0009-0008-5840-1399)
- A. Mahfouz
- J Ye
- Y. Okada
- Oliver Stegle (ORCID: https://orcid.org/0000-0002-8818-7193)
- Gosia Trynka (ORCID: https://orcid.org/0000-0002-6955-9529)
- Urmo Võsa
- Yang Li (ORCID: https://orcid.org/0000-0001-6743-4004)
- Roy Oelen
- Niek de Klein (ORCID: https://orcid.org/0000-0003-4640-9904)
- Marta Melé
- Vinu Manikanda
- Daniel Kaptijn
- Yakov A Tsepilov
- Haroon Naeem
- Marc Jan Bonder
- Hilde E. Groot
- Woong-Yang Park
- Maryna Korshevniuk
- M. Grace Gordon
- Stephen Sawcer
- Joseph E. Alquicira-Hernandez
- Seyhan Yazar
- Harm-Jan Westra
- Lude Franke
- Monique G.P. van der Wijst
- Mihai Netea
- Odmaa Bayaraa
- Marijn Berg
- Aida Ripoll-Cladellas
- Martin Hemberg
- Robert Warmerdam
- Pim van der Harst
- Maria Ban
Institutions
- Agency for Science, Technology and Research (SG)
- New York University Abu Dhabi (AE)
- Brigham and Women's Hospital (US)
- University Medical Center Groningen (NL)
- Garvan Institute of Medical Research (AU)
- Radboud University Nijmegen (NL)
- The University of Queensland (AU)
- University of Groningen (NL)
- German Cancer Research Center (DE)
- University of California, San Francisco (US)
- Heidelberg University (DE)
- University of Cambridge (GB)
- Barcelona Supercomputing Center (ES)
- Leiden University Medical Center (NL)
- Samsung Medical Center (KR)
- Wellcome Sanger Institute (GB)
- Helmholtz Zentrum München (DE)
- UNSW Sydney (AU)
- Medizinische Hochschule Hannover (DE)
- Open Targets (GB)
- Parker Institute for Cancer Immunotherapy (US)
- Oncode Institute (NL)
- Helmholtz Centre for Infection Research (DE)
- European Molecular Biology Laboratory (DE)
- Centre for Individualised Infection Medicine (DE)
- RIKEN Center for Integrative Medical Sciences (JP)
- Center for Experimental and Clinical Infection Research (DE)
- Weill Cornell Medical College in Qatar (QA)
- Institut de Recherche en Sciences de la Santé (BF)
- University of Tartu (EE)
- Qatar University (QA)
- Genome Institute of Singapore (SG)
- Universitat de Barcelona (ES)
- The University of Tokyo (JP)
- University of California, Berkeley (US)
- Universitat Politècnica de Catalunya (ES)
- The University of Osaka (JP)
- Delft University of Technology (NL)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-01-23
- DOI
- https://doi.org/10.64898/2026.01.20.700519
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Science Foundation
- U.S. Department of Health and Human Services
- Wellcome Trust
- New York University Abu Dhabi
- Scottish Government
- Sidra Medicine
- National Institute for Health and Care Research
- British Heart Foundation
- Department of Health and Social Care
- Multiple Sclerosis Society
- European Commission
- Public Health Agency
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Koninklijke Nederlandse Akademie van Wetenschappen
- ZonMw
- Fonds National de la Recherche Luxembourg
- Eesti Teadusagentuur
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Servier
- Tamkeen
- Oncode Institute
- National Institutes of Health
- Qatar National Research Fund
- Chief Scientist Office, Scottish Government Health and Social Care Directorate
- HORIZON EUROPE Framework Programme
- Medical Research Council
- Engineering and Physical Sciences Research Council
- Economic and Social Research Council
- European Regional Development Fund
- Health and Social Care Research and Development Division
- NIHR Cambridge Biomedical Research Centre