Bayaraa, O. | bioRxiv Science

bioRxiv2026

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 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.

genetics↗

bioRxiv2025

Multi-region spatial transcriptomics reveals region specific differences in response to amyloid beta (Aβ) plaque induced changes in Alzheimer's Disease (AD)

Alzheimers disease (AD) is the leading cause of dementia affecting 55 million people worldwide. The pathological hallmarks of AD, beta-amyloid (A{beta}) plaques and neurofibrillary tangles (NFT), follow distinct stereotypical patterns of progression across brain regions and trigger a multicellular response that ultimately leads to neuronal loss and cognitive decline. Despite the uniform spread of A{beta} plaque across the cortex during AD progression, different regions demonstrate varying levels of vulnerability and resilience to temporal A{beta} plaque induced changes, such as NFT accumulation. There is a critical gap in our understanding of the cell types and molecular mechanisms that underlie these region-specific differences in resilience to A{beta} plaque induced changes. In this study, we hypothesized that brain region and cell type specific transcriptional responses within the A{beta} microenvironment, and more broadly within the grey matter, may contribute to this variation. We carried out matched multi-region spatial transcriptomics and A{beta} immunofluorescence staining from the entorhinal, occipito-temporal, dorsolateral prefrontal and striate cortices from two individuals with Braak III and Thal 4 AD. Spatiotemporal comparisons of cell type proportions, gene expression, and cell-cell communication revealed differences in the vulnerability of somatostatin and somatostatin chondrolectin inhibitory neurons and the expression of endosomal and lysosomal trafficking and metallothionein genes within the A{beta} plaque microenvironment. We also observed variations in blood-brain-barrier dysfunction, fibroblast growth factor signaling, and vascular impairment and repair related cell-cell communication networks within the grey matter. Our results demonstrate the value of simultaneously profiling AD-omic and spatial modalities in multiple regions to elucidate how cortical region-specific differences contribute to selective vulnerability and resilience during neurodegeneration.

genomics↗