Single-cell genetics identifies cell type-specific causal mechanisms in complex traits and diseases

Genome-wide association studies (GWAS) have been instrumental in uncovering the genetic basis of complex traits. When integrated with expression quantitative trait loci (eQTL) mapping, they can elucidate how risk loci influence traits through gene regulatory mechanisms. Recent single-cell eQTL (sc-eQTL) studies suggest that genetic effects on gene expression are often cell type- and subtype-specific, but such datasets have so far been underpowered for causal inference. Here, we leverage results from sc-eQTL mapping in the TenK10K project, comprising 154,932 common variant sc-eQTL across 28 immune cell types derived from matched whole-genome sequencing (WGS) and single-cell RNA-sequencing (scRNA-seq) of over 5 million peripheral blood mononuclear cells (PBMCs) from 1,925 individuals. We present a catalogue of cell type-specific causal effects of gene expression on 53 diseases (spanning 58,058 causal associations across 8,672 genes and 28 cell types), and 31 biomarker traits (spanning 681,480 causal associations across 16,085 genes and 28 cell types). By quantifying polygenic enrichment at both the single-cell and cell-type levels, we identify distinct immune cell contributions to both immune-related and systemic conditions. We demonstrate differential polygenic enrichment of Crohn's disease and COVID-19 amongst dendritic cell subtypes, and high activity of B cell interferon II response in SLE. Integration with clinical drug development data reveals that therapeutic compounds targeting gene-trait associations identified in this study are three times more likely to have secured regulatory approval. Using Crohn's disease as a motivating example, we demonstrate how population-based sc-eQTL data can pinpoint risk loci, effector genes and cell types, complementing findings from disease-focused tissue samples. Our findings provide a foundational resource for understanding the cell type-specific genetic architecture of disease and for guiding therapeutic discovery.