Severity-stratified, longitudinal cis-eQTL mapping enables high-sensitivity detection of candidate causal genes for critical COVID-19

Host genetic variation influences heterogeneity in infectious disease severity. Genome-wide association studies (GWAS) have identified 69 lead single nucleotide polymorphisms (SNPs) associated with critical COVID-19, but most lack known regulatory mechanisms. To date, the genetic cis-regulatory effects of critical COVID-19 GWAS lead SNPs have not been systematically characterized across acute illness and convalescent phases in a COVID-19 specific cohort. Here, performing severity-stratified, longitudinal cis-expression quantitative trait loci (cis-eQTL) mapping and colocalization with critical COVID-19 GWAS signals, we find that host cis-regulatory effects vary across clinical severity and disease phase. We analyzed peripheral blood mononuclear cells from 1,031 patients in the Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC), a prospective multicenter study of adults hospitalized with COVID-19, profiled across 10 timepoints spanning acute illness and convalescence. We identified 23 GWAS lead SNPs that colocalized with cis-eQTLs at 26 candidate causal genes, with 16 detectable only when severity stratification and longitudinal sampling were incorporated. A colocalized, protective allele (chr19:4,717,660) at the TMIGD2 locus upregulated TMIGD2 expression exclusively during the acute phase in the prolonged-critical/fatal cohort, with no detectable effect in the rapid-recovery cohort. Our results show that host genetic effects on critical COVID-19 can be context-dependent, with cis-regulatory effects varying across clinical severity and disease phase. Severity-stratified, longitudinal cis-eQTL designs have greater sensitivity to identify candidate causal genes for critical COVID-19 GWAS associations than single-timepoint cross-sectional studies. Significance StatementGenome-wide association studies have identified 69 loci associated with life-threatening COVID-19, but most lead SNPs, the strongest association signal at each locus, lie outside protein-coding regions and act via unknown effects on gene regulation. We analyzed paired genetic and gene expression data from 1,031 hospitalized COVID-19 patients in IMPACC, sampled across ten timepoints and stratified by clinical severity. This analysis linked 23 of these risk variants to candidate genes, more than doubling the single-timepoint yield. Many effects appeared only in specific severity cohorts or timepoints. In critically ill patients early in hospitalization, the GWAS-associated allele increased expression of TMIGD2, a costimulatory receptor that amplifies T cell activation and may support antiviral responses. These variant-gene pairs warrant functional validation.