Disease-associated loci share features with loci that regulate gene expression in response to environmental perturbations

Many of the genetic loci associated with disease are expected to have context-dependent regulatory effects that are underrepresented in the transcriptomes of healthy, steady-state adult tissues. To understand genetic gene regulation across diverse environmental conditions and cellular contexts, we perturbed a broad array of human cell types with three environmental exposures in vitro. With single-cell RNA-sequencing data from 1.4 million cells, we identified hundreds of dynamic eQTLs that regulate molecular responses to perturbation across multiple cellular contexts. These response eQTLs exhibit distinct signatures of regulatory complexity, evolutionary constraint, and functional enrichment that distinguish them from standard, steady- state eQTLs. Similar to GWAS loci, response eQTLs are enriched in distal enhancers and are linked to genes that experienced strong selective constraint, involve in complex regulatory landscapes, and diverse biological functions. We also observed that response eQTLs are more likely than standard eQTLs to colocalize with loci that affect complex traits. Our results highlight the complexity of genetic regulatory effects and suggest that our ability to interpret disease-associated loci may benefit from the pursuit of studies of gene-by-environment interactions in diverse biological contexts.