Cell-type-specific eQTLs underlie the genetic architecture of complex traits

Genetic effects on complex traits primarily act by regulating gene expression; however, this process is not well understood1. Studies of genetic effects on gene expression (expression quantitative trait loci (eQTLs)) can inform as to the gene regulatory layer between genetic variants and complex traits2. However, previous studies have not effectively captured cell-type-specific eQTLs, which are likely to be important for complex traits. Here we unbiasedly characterized cell-type-specific eQTLs by applying a variance component model to population-scale single-cell RNA-sequencing (RNA-seq) data. Using peripheral blood mononuclear cells from the OneK1K cohort, we demonstrated that cell-type-specific eQTLs enrich for complex trait heritability, which we did not observe for cell-type-shared eQTLs. We also found that eQTL specificity is associated with genes that have greater selective constraint, enhancer complexity and gene network connectivity, three features enriched in complex traits relative to known eQTLs3,4. Transcriptome-wide, trans eQTLs were mostly cell-type-specific (60% specific) whereas cis eQTLs were mostly shared (30% specific). We used a second single-cell RNA-seq dataset to replicate our findings and demonstrate that cell-type-shared and cell-type-specific eQTLs are consistent across ancestries. Our results establish eQTL cell-type specificity as a key feature of gene regulation and partly explain why known eQTLs are depleted in gene regulatory effects on complex traits. Single-cell RNA-sequencing shows that cell-type-specific expression quantitative trait loci drive much of complex trait heritability, highlighting cell-type-specific gene regulation as key to linking genetic variants with traits.