Severity-stratified, longitudinal cis-eQTL mapping enables high-sensitivity detection of candidate causal genes for critical COVID-19
Abstract
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.
Related
- Verification of the Short-term Effect of SGLT2 Inhibitors on Serum Magnesium Stratified by the Classification of Albuminuria Severity in Patients with Type 2 Diabetes Mellitus
- Clinical characteristics of cadonilimab-associated infusion reactions: a severity-stratified analysis of 52 cases and preliminary management framework
- Minimally invasive management of pediatric hereditary spherocytosis: severity-stratified biliary risk and indications for simultaneous cholecystectomy and biliary intervention at laparoscopic splenectomy – a single-center retrospective study
- Emergency Severity Index Stratified by Post-Triage Lactate: Association with In-Hospital Mortality in Admitted Patients.
- Calendar-defined missed-workday gaps in radiotherapy: a site- and phase-stratified audit with linkage sensitivity analyses.
BibTeX
@misc{chen2026severitystratified,
title = {{Severity-stratified, longitudinal cis-eQTL mapping enables high-sensitivity detection of candidate causal genes for critical COVID-19}},
author = {E. Chen and G. Gabernet and D. B. Corry and F. Kheradmand and L. R. Baden and R.-P. Sekaly and G. A. McComsey and E. K. Haddad and C. B. Cairns and N. Rouphael and A. Fernandez-Sesma and V. Simon and J. P. Metcalf and N. I. Agudelo Higuita and C. L. Hough and W. B. Messer and M. M. Davis and K. C. Nadeau and B. Pulendran and H. T. Maecker and M. Kraft and C. Bime and E. F. Reed and J. Schaenman and D. J. Erle and C. S. Calfee and M. A. Atkinson and S. C. Brakenridge and E. Melamed and L. I. R. Ehrlich and A. C. Shaw and D. A. Hafler and A. D. Augustine and P. M. Becker and B. Peters and A. Ozonoff and J. Diray-Arce and O. Levy and S. E. Bosinger and W. Eckalbar and IMPACC},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.14.26365529},
url = {https://www.medrxiv.org/content/10.64898/2026.10.14.26365529v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Severity-stratified, longitudinal cis-eQTL mapping enables high-sensitivity detection of candidate causal genes for critical COVID-19
AU - E. Chen
AU - G. Gabernet
AU - D. B. Corry
AU - F. Kheradmand
AU - L. R. Baden
AU - R.-P. Sekaly
AU - G. A. McComsey
AU - E. K. Haddad
AU - C. B. Cairns
AU - N. Rouphael
AU - A. Fernandez-Sesma
AU - V. Simon
AU - J. P. Metcalf
AU - N. I. Agudelo Higuita
AU - C. L. Hough
AU - W. B. Messer
AU - M. M. Davis
AU - K. C. Nadeau
AU - B. Pulendran
AU - H. T. Maecker
AU - M. Kraft
AU - C. Bime
AU - E. F. Reed
AU - J. Schaenman
AU - D. J. Erle
AU - C. S. Calfee
AU - M. A. Atkinson
AU - S. C. Brakenridge
AU - E. Melamed
AU - L. I. R. Ehrlich
AU - A. C. Shaw
AU - D. A. Hafler
AU - A. D. Augustine
AU - P. M. Becker
AU - B. Peters
AU - A. Ozonoff
AU - J. Diray-Arce
AU - O. Levy
AU - S. E. Bosinger
AU - W. Eckalbar
AU - IMPACC
PY - 2026
DA - 2026/10/14
PB - medRxiv
DO - 10.64898/2026.10.14.26365529
UR - https://www.medrxiv.org/content/10.64898/2026.10.14.26365529v1
AB - 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.
ER -