Cell-type-specific eQTLs drive much of the genetic basis of complex traits

Using a variance-component model called CIGMA, the authors dissected expression quantitative trait loci (eQTLs) into components that are shared among peripheral blood cell types and those that are unique to individual types, based on single-cell RNA-sequencing from the OneK1K cohort. Cell-type-specific eQTLs were found to be more heritable, to concentrate in genes with higher selective constraint, more enhancers and greater co-expression network connectivity, and to be strongly enriched for the genetic architecture of several blood-related complex traits.

In contrast, eQTLs that act across all cell types contributed little to disease heritability. The results were replicated in the CLUES and ImmVar datasets, showing consistent specificity patterns across ancestries and health states. Trans-acting eQTLs were especially cell-type-specific, while cis-eQTLs tended to be shared. These findings suggest that much of the “missing” regulatory contribution to complex traits resides in weak, cell-type-specific genetic effects that are invisible in bulk-tissue analyses.