{
  "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.\n\nSignificance 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.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 41,
  "authors": [
    {
      "name": "E. Chen"
    },
    {
      "name": "G. Gabernet"
    },
    {
      "name": "D. B. Corry"
    },
    {
      "name": "F. Kheradmand"
    },
    {
      "name": "L. R. Baden"
    },
    {
      "name": "R.-P. Sekaly"
    },
    {
      "name": "G. A. McComsey"
    },
    {
      "name": "E. K. Haddad"
    },
    {
      "name": "C. B. Cairns"
    },
    {
      "name": "N. Rouphael"
    },
    {
      "name": "A. Fernandez-Sesma"
    },
    {
      "name": "V. Simon"
    },
    {
      "name": "J. P. Metcalf"
    },
    {
      "name": "N. I. Agudelo Higuita"
    },
    {
      "name": "C. L. Hough"
    },
    {
      "name": "W. B. Messer"
    },
    {
      "name": "M. M. Davis"
    },
    {
      "name": "K. C. Nadeau"
    },
    {
      "name": "B. Pulendran"
    },
    {
      "name": "H. T. Maecker"
    },
    {
      "name": "M. Kraft"
    },
    {
      "name": "C. Bime"
    },
    {
      "name": "E. F. Reed"
    },
    {
      "name": "J. Schaenman"
    },
    {
      "name": "D. J. Erle"
    },
    {
      "name": "C. S. Calfee"
    },
    {
      "name": "M. A. Atkinson"
    },
    {
      "name": "S. C. Brakenridge"
    },
    {
      "name": "E. Melamed"
    },
    {
      "name": "L. I. R. Ehrlich"
    },
    {
      "name": "A. C. Shaw"
    },
    {
      "name": "D. A. Hafler"
    },
    {
      "name": "A. D. Augustine"
    },
    {
      "name": "P. M. Becker"
    },
    {
      "name": "B. Peters"
    },
    {
      "name": "A. Ozonoff"
    },
    {
      "name": "J. Diray-Arce"
    },
    {
      "name": "O. Levy"
    },
    {
      "name": "S. E. Bosinger"
    },
    {
      "name": "W. Eckalbar"
    },
    {
      "name": "IMPACC"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4fg1ksvc8fph9.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.14.26365529",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.10.14.26365529v1.full",
  "id": "4fg1ksvc8fph9",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.10.14.26365529v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "genetic and genomic medicine"
    ],
    [
      "openalex",
      "1311|Genetic Associations and Epidemiology"
    ]
  ],
  "openalex": "W7223092014",
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.10.14.26365529v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-14",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/4fg1ksvc8fph9.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:21:27Z",
      "native_id": "10.64898/2026.10.14.26365529",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.10.14.26365529v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:genetic and genomic medicine",
      "subfield": "human-genetics"
    }
  ],
  "title": "Severity-stratified, longitudinal cis-eQTL mapping enables high-sensitivity detection of candidate causal genes for critical COVID-19",
  "title_text": "Severity-stratified, longitudinal cis-eQTL mapping enables high-sensitivity detection of candidate causal genes for critical COVID-19",
  "type": "preprint",
  "updated_at": "2026-10-30T12:21:27Z",
  "url": "https://research.draconitic.com/paper/4fg1ksvc8fph9",
  "venue": "medRxiv",
  "versions": []
}