Federated single-cell QTL meta-analysis reveals novel disease mechanisms
Kaptijn D, Michielsen L, Neavin D, Ripoll-Cladellas A, Alquicira-Hernández J, Korshevniuk M, Lee J, Oelen R, Vochteloo M, Warmerdam R, Ando Y, Ban M, Bayaraa O, Berg M, van Blokland I, Considine D, Dieng M, Edahiro R, Gordon M, Groot H, van der Harst P, Heinig M, Hon C, Idaghdour Y, Kathail P, de Klein N, Li W, Li Y, Losert C, Manikanda V, Moody J, Naeem H, Mokrab Y, Nawijn M, Netea M, Niewold J, Okada Y, Sawcer S, Soulama I, Stegle O, Tsepilov Y, Park W, Rajagopalan D, Shahin T, Shin J, Trynka G, Võsa U, Westra H, Yazar S, Ye J, Zhang Z, eQTLGen consortium, Hemberg M, Mahfouz A, Melé M, Powell J, Bonder M, Franke L, van der Wijst M
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Biorxiv : The Preprint Server for Biology, Page 2026.01.20.700519
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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