Modeling heterogeneity in single-cell perturbation states enhances detection of response eQTLs

Identifying response expression quantitative trait loci (reQTLs) can help to elucidate mechanisms of disease associations. Typically, such studies model the effect of perturbation as discrete conditions. However, perturbation experiments usually affect perturbed cells heterogeneously. We demonstrated that modeling of per-cell perturbation state enhances power to detect reQTLs. We use public single-cell peripheral blood mononuclear cell (PBMC) data, to study the effect of perturbations with Influenza A virus (IAV), Candida albicans (CA), Pseudomonas aeruginosa (PA), and Mycobacterium tuberculosis (MTB) on gene regulation. We found on average 36.9% more reQTLs by accounting for single cell heterogeneity compared to the standard discrete reQTL model. For example, we detected a decrease in the eQTL effect of rs11721168 for PXK in IAV. Furthermore, we found that on average of 25% reQTLs have cell-type-specific effects. For example, in IAV the increase of the eQTL effect of rs10774671 for OAS1 was stronger in CD4+T and B cells. Similarly, in all four perturbation experiments, the reQTL effect for RPS26 was stronger in B cells. Our work provides a general model for more accurate reQTL identification and underscores the value of modeling cell-level variation.