Single-cell resolution of splicing regulation in peripheral blood mononuclear cells uncovers heterogeneity-driven mechanisms underlying human complex traits

The influence of genetic variation on alternative splicing (AS) across immune cell types and demographic strata in European populations remains poorly understood. Here, we leveraged the OneK1K cohort, comprising 980 individuals of European ancestry with matched genotyping and single-cell RNA sequencing (scRNA-seq) data, to systematically investigate splicing variation at single-cell resolution. Across 13 immune cell types, we identified extensive cell-type-specific AS events and independent cis-splicing quantitative trait loci (cis-sQTLs), with subsets showing distinct sex- and age-biased patterns. Colocalization analysis identified numerous shared signals between cell-type-specific cis-sQTLs and GWAS loci for 30 polygenic traits, demonstrating that splicing regulation represents an important mechanism through which susceptibility loci influence complex traits. Through trans-sQTL analysis, we found that genetic variants exert distal effects on RPS24 splicing via proximal regulation of IVNS1ABP expression, a splicing regulator that interacts with the splicing factor HNRNPK. Collectively, our findings provide new insights into how genetic variation shapes splicing programs across cellular and demographic contexts in European populations, establishing a mechanistic framework for splicing-mediated regulation of complex traits. Genetic regulation of RNA splicing in immune cells remains incompletely understood in European populations. Here, the authors use single-cell data to map cell-type specific splicing QTLs, revealing how genetic variation influences complex trait risk through splicing regulation.