Severity-stratified, longitudinal cis-eQTL mapping enables high-sensitivity detection of candidate causal genes for critical COVID-19
Year: 2026
Type: preprint
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.
Source: medRxiv
Authors: Ernie Chen, Gisela Gabernet, David B. Corry, Farrah Kheradmand, Lindsey R. Baden, Rafick-Pierre Sekaly, Grace A. McComsey, Elias K. Haddad, Charles B. Cairns, Nadine Rouphael, Ana Fernandez-Sesma, Viviana Simon, Jordan P. Metcalf, Nelson I. Agudelo Higuita, Catherine L. Hough, William B. Messer, Mark M. Davis, Kari C. Nadeau, Bali Pulendran, Holden T. Maecker, Monica Kraft, Chris Bime, Elaine F. Reed, Joanna Schaenman, David J. Erle, Carolyn S. Calfee, Mark A. Atkinson, Scott C. Brakenridge, Esther Melamed, Lauren I. R. Ehrlich, Albert C. Shaw, David A. Hafler, Alison D. Augustine, Patrice M. Becker, Bjoern Peters, Al Ozonoff, Joann Diray-Arce, Ofer Levy, Steven E. Bosinger, Walter Eckalbar, IMPACC Network, Ruth R. Montgomery, Ira M. Hall, Steven H. Kleinstein, Dylan Duchen
Institutions: Yale University, Baylor College of Medicine, Brigham and Women's Hospital, Harvard University, University Hospitals of Cleveland, Case Western Reserve University, Drexel University, Emory University, Icahn School of Medicine at Mount Sinai, OU Health, University of Oklahoma Health Sciences Center, Oregon Health & Science University, Stanford University, University of Arizona, University of California, Los Angeles, University of California, San Francisco, University of Florida, The University of Texas at Austin, National Institutes of Health, National Institute of Allergy and Infectious Diseases, La Jolla Institute for Immunology, Boston Children's Hospital
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: National Science Foundation, U.S. Department of Defense, Bristol-Myers Squibb, Pfizer, AstraZeneca, Sanofi, Yale University, Gilead Sciences, Teva Pharmaceutical Industries, Regeneron Pharmaceuticals, Shenzhen Center for Health Information, Compass Therapeutics, Moderna, Seqirus, National Institutes of Health, Centers for Disease Control and Prevention, Genentech, EMD Serono, Biomedical Advanced Research and Development Authority, Sanofi Genzyme, National Institute on Drug Abuse, National Institute of Allergy and Infectious Diseases, National Center for Advancing Translational Sciences, David Geffen School of Medicine, University of California, Los Angeles
Awards: FUNGAL PATHOGENESIS OF MODERATE TO SEVERE ASTHMA, G1636177350, Long Term Immunity Following Yellow Fever Vaccination, Dengue Human Immunology Project Consortium (DHIPC), G5316515788, System Biological Analyses of Innate and Adaptive Responses to Vaccination, Genomics of NFκB-mediated gene regulation in multiple sclerosis, Molecular and Immunologic Analysis of the Pathobiology of Human Anthrax, Mapping Immune Responses to CMV in Renal Transplant Recipients, A 3D Tissue Map of the Human Lymphatic System, Clinical and Translational Science Collaborative of Northern Ohio, Catalyzing Linkages for Everyone's Health (CLE Health), Discriminating the contributions of CCR4 and CCR7 to thymic central tolerance, Innate Immunity and Viral Infection in Asthma, Immune signatures of vaccine responses in vulnerable populations, Pre-Doctoral Training in Interdisciplinary Neuroscience
OpenAlex ID: W7223092014