Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

COVID-STORM Clinicians, Amsterdam UMC Covid-19 Biobank, COVID Human Genetic Effort, COVIDeF Study Group, French COVID Cohort Study Group, CoV-Contact Cohort, COVID Clinicians, NIAID-USUHS COVID Study Group, Orchestra Working Group, Michela Botta, Sanne de Bruin, Esther Bulle, Mirjam Dijkstra, Dave A. Dongelmans, Romein W. G. Dujardin, Bram Goorhuis, Florianne Hafkamp, Laura Hagens, Jorg Hamann, Frederique PaulusDan A. I. Pina-Fuentes, Jorinde Raasveld, Maurits C. F. J. de Rotte, Marcus J. Schultz, Femke A. P. Schrauwen, Marleen A. Slim, Marry Smit, Cornelis S. Stijnis, Willemke Stilma, A. H. Zwinderman, Alexander P. J. Vlaar

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Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.
Original languageEnglish
Article number22
Pages (from-to)22
JournalGenome Medicine
Issue number1
Publication statusPublished - 1 Dec 2023


  • COVID-19
  • Immunity
  • Rare variants
  • Type I interferon

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