Federated single-cell QTL meta-analysis reveals novel disease mechanisms

Kaptijn, D.; Michielsen, L.; Neavin, D.; Ripoll-Cladellas, A.; Alquicira-Hernandez, J. E.; Korshevniuk, M.; Lee, J. T. H.; Oelen, R.; Vochteloo, M.; Warmerdam, R.; Ando, Y.; Ban, M.; Bayaraa, O.; Berg, M.; van Blokland, I.; Considine, D.; Dieng, M. M.; Edahiro, R.; Gordon, M. G.; Groot, H. E.; van der Harst, P.; Heinig, M.; Hon, C.-C.; Idaghdour, Y.; Kathail, P.; de Klein, N.; Li, W.; Li, Y.; Losert, C.; Manikanda, V.; Moody, J.; Naeem, H.; Mokrab, Y.; Nawijn, M. C.; Netea, M.; Niewold, J.; Okada, Y.; Sawcer, S.; Soulama, I.; Stegle, O.; Tsepilov, Y.; Park, W.-Y.; Rajagopalan, D.; Shahin, T.

doi:10.64898/2026.01.20.700519

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bioRxiv · 10.64898/2026.01.20.700519

Federated single-cell QTL meta-analysis reveals novel disease mechanisms

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Abstract

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 cis-eQTL meta-analysis across 12 PBMC datasets (2,032 individuals, 2.5 million cells). Across six immune cell types, we identified cis-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 trans-eQTLs. Integrating single-cell cis-eQTLs with bulk trans-eQTLs enabled us to anchor 6,382 trans-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 cis-eQTL on BACH1 that colocalized with 45 immune and metabolic trans-eGenes. These results demonstrate the power of single-cell QTL meta-analysis in interpreting complex trait genetics.

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Kaptijn, D., Michielsen, L., Neavin, D., Ripoll-Cladellas, A., Alquicira-Hernandez, J. E., Korshevniuk, M., Lee, J. T. H., Oelen, R., Vochteloo, M., Warmerdam, R., Ando, Y., Ban, M., Bayaraa, O., Berg, M., van Blokland, I., Considine, D., Dieng, M. M., Edahiro, R., Gordon, M. G., Groot, H. E., van der Harst, P., Heinig, M., Hon, C.-C., Idaghdour, Y., Kathail, P., de Klein, N., Li, W., Li, Y., Losert, C., Manikanda, V., Moody, J., Naeem, H., Mokrab, Y., Nawijn, M. C., Netea, M., Niewold, J., Okada, Y., Sawcer, S., Soulama, I., Stegle, O., Tsepilov, Y., Park, W.-Y., Rajagopalan, D., Shahin, T.. 2026-01-23. Federated single-cell QTL meta-analysis reveals novel disease mechanisms. https://doi.org/10.64898/2026.01.20.700519

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