Single-cell eQTL mapping identifies disease-specific genetic control of COVID-19 infection

The impact of genotype on gene expression can depend on both cellular and organismal context. Here, we leverage an extensive blood atlas of genotyped patients with varying severity of infection produced by the COVID-19 Multi-omics Blood ATlas (COMBAT) Consortium to study the role of genetic regulation on gene expression in a context-specific manner. We analyzed single-cell transcriptomic and genome-wide genetic data from [~]500,000 cells and 76 donors of European ancestry. Across 15 cell types, we identified 2,607 independent cis-eQTLs in high linkage disequilibrium (R2>0.8) with 48 infectious and 386 inflammatory disease-associated risk variants, including rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Notably, we found infection-specific eQTLs absent from a general population dataset (OneK1K), such as REL, IRF5 and TRAF, all of which were differentially regulated by infection and whose variants are associated with RA and/or IBD. We also identified infection-modified eQTLs, including RPS26 and ADAM10, implying that the regulatory sequences context of these genes may play a role in specific immune cell subsets in infection. Our work demonstrates that the overriding effect of genetics on gene expression in blood immune cells is independent of infection status or severity. However, small numbers of eQTLs are modified by infection, and these differences can illustrate potentially important immune biology.