GEOTranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE281237GEOGSEfalseWidespread gene-environment interactions shape the immune response to SARS-CoV-2 infectionGenome-wide association studies performed in COVID-19 patients have uncovered various loci significantly associated with susceptibility to SARS-CoV-2 infection and disease severity. However, the underlying cis-regulatory genetic factors contributing to heterogeneity in the response to SARS-CoV-2 infection and their impact on clinical phenotypes remain enigmatic. Here, we use single-cell RNA-sequencing to quantify genetic contributions to cis-regulatory variation in 361,119 peripheral blood mononuclear cells of 63 acute COVID-19 patients, 39 convalescent samples, and 106 healthy controls. Expression quantitative trait loci mapping across cell types within each disease state group reveals thousands of cis-associated variants, of which hundreds are detected exclusively in immune cells derived from acute patients. Patient-specific genetic effects dissipate as infection resolves, suggesting that distinct gene regulatory networks are at play in the active infection state. Further, 20.3% of tested loci demonstrate significant cell state interactions with genotype, with pathways related to interferon responses and oxidative phosphorylation showing pronounced cell state-dependent variation, predominantly in CD14+ monocytes. Overall, we estimate that 16.8% of tested genes exhibit gene-environment interaction effects, highlighting the importance of environmental modifiers in the transcriptional regulation of the immune response to SARS-CoV-2. Our findings argue for the existence of extensive gene-environment effects among patients responding to an infection.2026/04/01GSE281237GSM8615469GSM8615467GSM8615489GSM8615468GSM8615487GSM8615465GSM8615466GSM8615488GSM8615485GSM8615464GSM8615486GSM8615483GSM8615484GSM8615481GSM8615482GSM8615480GSM8615478GSM8615479GSM8615476GSM8615477GSM8615474GSM8615475GSM8615472GSM8615473GSM8615470GSM8615492GSM8615471GSM8615490GSM861549124676281237Homo sapiens