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Genome Medicine

Publication date: 2023-04-05
Volume: 15
Publisher: Springer Nature

Author:

Matuozzo, Daniela
Talouarn, Estelle ; Marchal, Astrid ; Zhang, Peng ; Manry, Jeremy ; Seeleuthner, Yoann ; Zhang, Yu ; Bolze, Alexandre ; Chaldebas, Matthieu ; Milisavljevic, Baptiste ; Gervais, Adrian ; Bastard, Paul ; Asano, Takaki ; Bizien, Lucy ; Barzaghi, Federica ; Abolhassani, Hassan ; Abou Tayoun, Ahmad ; Aiuti, Alessandro ; Alavi Darazam, Ilad ; Allende, Luis M ; Alonso-Arias, Rebeca ; Arias, Andres Augusto ; Aytekin, Gokhan ; Bergman, Peter ; Bondesan, Simone ; Bryceson, Yenan T ; Bustos, Ingrid G ; Cabrera-Marante, Oscar ; Carcel, Sheila ; Carrera, Paola ; Casari, Giorgio ; Chaibi, Khalil ; Colobran, Roger ; Condino-Neto, Antonio ; Covill, Laura E ; Delmonte, Ottavia M ; El Zein, Loubna ; Flores, Carlos ; Gregersen, Peter K ; Gut, Marta ; Haerynck, Filomeen ; Halwani, Rabih ; Hancerli, Selda ; Hammarstroem, Lennart ; Hatipoglu, Nevin ; Karbuz, Adem ; Keles, Sevgi ; Kyheng, Christele ; Leon-Lopez, Rafael ; Franco, Jose Luis ; Mansouri, Davood ; Martinez-Picado, Javier ; Metin Akcan, Ozge ; Migeotte, Isabelle ; Morange, Pierre-Emmanuel ; Morelle, Guillaume ; Martin-Nalda, Andrea ; Novelli, Giuseppe ; Novelli, Antonio ; Ozcelik, Tayfun ; Palabiyik, Figen ; Pan-Hammarstroem, Qiang ; de Diego, Rebeca Perez ; Planas-Serra, Laura ; Pleguezuelo, Daniel E ; Prando, Carolina ; Pujol, Aurora ; Reyes, Luis Felipe ; Riviere, Jacques G ; Rodriguez-Gallego, Carlos ; Rojas, Julian ; Rovere-Querini, Patrizia ; Schlueter, Agatha ; Shahrooei, Mohammad ; Sobh, Ali ; Soler-Palacin, Pere ; Tandjaoui-Lambiotte, Yacine ; Tipu, Imran ; Tresoldi, Cristina ; Troya, Jesus ; van de Beek, Diederik ; Zatz, Mayana ; Zawadzki, Pawel ; Al-Muhsen, Saleh Zaid ; Alosaimi, Mohammed Faraj ; Alsohime, Fahad M ; Baris-Feldman, Hagit ; Butte, Manish J ; Constantinescu, Stefan N ; Cooper, Megan A ; Dalgard, Clifton L ; Fellay, Jacques ; Heath, James R ; Lau, Yu-Lung ; Lifton, Richard P ; Maniatis, Tom ; Mogensen, Trine H ; von Bernuth, Horst ; Lermine, Alban ; Vidaud, Michel ; Boland, Anne ; Deleuze, Jean-Francois ; Nussbaum, Robert ; Kahn-Kirby, Amanda ; Mentre, France ; Tubiana, Sarah ; Gorochov, Guy ; Tubach, Florence ; Hausfater, Pierre ; Effort, COVID Human Genetic ; Meyts, Isabelle ; Zhang, Shen-Ying ; Puel, Anne ; Notarangelo, Luigi D ; Boisson-Dupuis, Stephanie ; Su, Helen C ; Boisson, Bertrand ; Jouanguy, Emmanuelle ; Casanova, Jean-Laurent ; Zhang, Qian ; Abel, Laurent ; Cobat, Aurelie

Keywords:

Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, Rare variants, COVID-19, Immunity, Type I interferon, WIDE ASSOCIATION, DISEASE, NPC2, Humans, Young Adult, Adult, Middle Aged, SARS-CoV-2, Toll-Like Receptor 3, Toll-Like Receptor 7, Interferon Type I, Autoantibodies, COVID Human Genetic Effort, COVIDeF Study Group, French COVID Cohort Study Group, CoV-Contact Cohort, COVID-STORM Clinicians, COVID Clinicians, Orchestra Working Group, Amsterdam UMC Covid-19 Biobank, NIAID-USUHS COVID Study Group, C16/18/007#54690355, 0604 Genetics, 1103 Clinical Sciences, 3105 Genetics

Abstract:

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.