Disease-associated loci share properties with response eQTLs under common environmental exposures.

Many disease-associated genetic variants likely exert context-dependent regulatory effects that are underrepresented in healthy, steady-state adult tissues. To investigate gene regulation across diverse environmental and cellular contexts, we exposed heterogeneous differentiating cultures from 51 human induced pluripotent stem cell lines to nicotine, caffeine, or ethanol and profiled 1.4 million cells by single-cell RNA sequencing. We identified hundreds of response expression quantitative trait loci (eQTLs) across diverse cell types, as well as dynamic regulatory effects that vary along differentiation trajectories. In contrast to baseline steady-state eQTLs and similar to disease risk loci, response eQTLs are enriched in distal enhancers and regulate genes under strong selective constraint, contain complex regulatory landscapes, and display diverse biological functions. Response eQTLs also coincide with disease-associated loci not explained by baseline steady-state eQTLs. These findings indicate that interpreting disease-associated loci will benefit from studying gene-by-environment interactions across diverse biological contexts.