Matuozzo, DanielaTalouarn, EstelleMarchal, AstridZhang, PengManry, JeremySeeleuthner, YoannZhang, YuBolze, AlexandreChaldebas, MatthieuMilisavljevic, BaptisteGervais, AdrianBastard, PaulAsano, TakakiBizien, LucyBarzaghi, FedericaAbolhassani, HassanAbou Tayoun, AhmadAiuti, AlessandroAlavi Darazam, IladAllende, Luis M.Alonso-Arias, RebecaArias, Andres AugustoAytekin, GokhanBergman, PeterBondesan, SimoneBryceson, Yenan T.Bustos, Ingrid G.Cabrera-Marante, OscarCarcel, SheilaCarrera, PaolaCasari, GiorgioChaibi, KhalilColobran, RogerCondino-Neto, AntonioCovill, Laura E.Delmonte, Ottavia M.El Zein, LoubnaFlores, CarlosGregersen, Peter K.Gut, MartaHaerynck, FilomeenHalwani, RabihHancerli, SeldaHammarstroem, LennartHatipoglu, NevinKarbuz, AdemKeles, SevgiKyheng, ChristeleLeon-Lopez, RafaelFranco, Jose LuisMansouri, DavoodMartinez-Picado, JavierMetin Akcan, OzgeMigeotte, IsabelleMorange, Pierre-EmmanuelMorelle, GuillaumeMartin-Nalda, AndreaNovelli, GiuseppeNovelli, AntonioOzcelik, TayfunPalabiyik, FigenPan-Hammarstroem, Qiangde Diego, Rebeca PerezPlanas-Serra, LauraPleguezuelo, Daniel E.Prando, CarolinaPujol, AuroraReyes, Luis FelipeRiviere, Jacques G.Rodriguez-Gallego, CarlosRojas, JulianRovere-Querini, PatriziaSchlueter, AgathaShahrooei, MohammadSobh, AliSoler-Palacin, PereTandjaoui-Lambiotte, YacineTipu, ImranTresoldi, CristinaTroya, Jesusvan de Beek, DiederikZatz, MayanaZawadzki, PawelAl-Muhsen, Saleh ZaidAlosaimi, Mohammed FarajAlsohime, Fahad M.Baris-Feldman, HagitButte, Manish J.Constantinescu, Stefan N.Cooper, Megan A.Dalgard, Clifton L.Fellay, JacquesHeath, James R.Lau, Yu-LungLifton, Richard P.Maniatis, TomMogensen, Trine H.von Bernuth, HorstLermine, AlbanVidaud, MichelBoland, AnneDeleuze, Jean-FrancoisNussbaum, RobertKahn-Kirby, AmandaMentre, FranceTubiana, SarahGorochov, GuyTubach, FlorenceHausfater, PierreEffort, C. O. V. I. D. Human GeneticMeyts, IsabelleZhang, Shen-YingPuel, AnneNotarangelo, Luigi D.Boisson-Dupuis, StephanieSu, Helen C.Boisson, BertrandJouanguy, EmmanuelleCasanova, Jean-LaurentZhang, QianAbel, LaurentCobat, Aurelie2023-09-112023-09-112023-09-112023-04-0510.1186/s13073-023-01173-8https://infoscience.epfl.ch/handle/20.500.14299/200638WOS:001022167700001BackgroundWe 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 similar to 80% of cases.MethodsWe 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.ResultsNo 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=1.1x10(-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=2.1x10(-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=3.4x10(-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=7.7x10(-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=1.68x10(-5)).ConclusionsRare 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.Genetics & HeredityGenetics & Heredityrare variantscovid-19immunitytype i interferonwide associationdiseasenpc2text::journal::journal article::research article