Atlas of cell type-specific post-transcriptional genetic impacts in immune-related diseases
Abstract
Genetic variants contribute to immune disease risk through complex, cell type-specific regulatory mechanisms, yet post-transcriptional processes including alternative polyadenylation (APA) and RNA editing remain poorly characterized. Using single-cell RNA-sequencing of >7.27 million peripheral blood mononuclear cells from 2,022 individuals, we mapped 32,763 single-cell quantitative trait loci (sc-xQTLs) across 31 immune cell types and diverse stimulation conditions. Unexpectedly, APA and RNA editing QTLs are more strongly enriched for immune disease heritability than expression QTLs. Immune stimulation, rather than sex or ancestry, drove 73.65% context-dependent sc-xQTLs. We identified 382 putative causal genes, 85.08% acting through expression-independent mechanisms. Integration with protein QTLs further identified 32 disease risk genes, including 19 druggable targets. Functional assays confirmed the allelic effect of sc-xQTL in shortening DLD 3′UTR, leading to reduced protein levels and increased ulcerative colitis risk. This study reveals a previously underappreciated role for post-transcriptional regulation in immune disease susceptibility.
