Population-scale multiome immune cell atlas reveals complex disease drivers

Most genetic variants associated with complex diseases lie in non-coding regions, yet mechanistic insights have been limited by the lack of an empirical framework for characterizing the molecular consequences of regulatory variation. Single-cell profiling of molecular quantitative trait loci (QTL) can connect variants to gene regulation, but prior studies lacked the sample size to detect variants at disease-relevant genes and the simultaneous measurements across regulatory layers needed to trace complete mechanisms from chromatin state to gene expression. Here we show that population-scale simultaneous profiling of chromatin accessibility and gene expression across immune cell types reveals multi-layered regulatory pathways connecting genetic variants to disease. We generated paired single-nucleus ATAC-seq and RNA-seq profiles from 10 million peripheral blood mononuclear cells across 1,108 Finnish individuals, identifying 51,083 cis-eQTLs for 20,829 genes, 338,100 cis-caQTLs for 210,584 peaks, 119,094 fine-mapped variants, and 496,488 enhancer-gene links. Systematic classification of regulatory mechanisms revealed that variants with complete chromatin-to-expression cascades show twice the disease colocalization of chromatin-only effects, establishing a hierarchy where mechanistic cascade predicts disease relevance. Analysis of evolutionarily constrained genes revealed multi-layered regulatory buffering where chromatin accessibility changes occur with normal effect sizes, but transmission to gene expression is attenuated through systematically weaker enhancer-gene links, reconciling why disease variants preferentially target these genes despite apparent eQTL depletion. We incorporated base editing to experimentally validate causal variants and mechanisms at Finnish-enriched disease loci such as TNRC18. This resource provides testable mechanistic hypotheses for over half of immune disease associations.