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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19
Genome Medicine, Volume 15, No. 1, Article 22, Year 2023
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Description
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. © 2023, The Author(s).
Authors & Co-Authors
Matuozzo, Daniela
France, Paris
L'institut Des Maladies Génétiques Imagine
Talouarn, Estelle
France, Paris
L'institut Des Maladies Génétiques Imagine
Marchal, Astrid
France, Paris
L'institut Des Maladies Génétiques Imagine
Zhang, Peng
United States, New York
Rockefeller University
Manry, Jeremy
France, Paris
L'institut Des Maladies Génétiques Imagine
Seeleuthner, Yoann
France, Paris
L'institut Des Maladies Génétiques Imagine
Zhang, Yu
United States, Bethesda
National Institute of Allergy and Infectious Diseases Niaid
Bolze, Alexandre
United States, San Mateo
Helix
Chaldebas, Matthieu
United States, New York
Rockefeller University
Milisavljevic, Baptiste
United States, New York
Rockefeller University
Gervais, Adrian
France, Paris
L'institut Des Maladies Génétiques Imagine
Bastard, Paul
France, Paris
L'institut Des Maladies Génétiques Imagine
United States, New York
Rockefeller University
France, Paris
Ap-hp Assistance Publique - Hopitaux de Paris
Bizien, Lucy
France, Paris
L'institut Des Maladies Génétiques Imagine
Barzaghi, Federica
Italy, Milan
Irccs Ospedale San Raffaele
Abolhassani, Hassan
Sweden, Stockholm
Karolinska Institutet
Iran, Tehran
Children's Medical Center Tums
Abou Tayoun, Ahmad N.
United Arab Emirates, Dubai
Al Jalila Children's Specialty Hospital
United Arab Emirates, Dubai
Mohammed Bin Rashid University of Medicine and Health Sciences
Aïuti, Alessandro
Italy, Milan
Irccs Ospedale San Raffaele
Italy, Milan
Università Vita-salute San Raffaele
Alavi-Darazam, Ilad
Iran, Tehran
Shahid Beheshti University of Medical Sciences
Allende, Luís Miguel
Spain, Madrid
Universidad Complutense de Madrid
Alonso-Arias, R.
Spain, Oviedo
Instituto de Investigación Sanitaria Del Principado de Asturias
Arias, Andrés Augusto
United States, New York
Rockefeller University
Colombia, Medellin
Universidad de Antioquia
Aytekin, Gökhan
Turkey, Konya
Konya City Hospital
Bergman, P. W.
Sweden, Stockholm
Karolinska Universitetssjukhuset
Sweden, Stockholm
Division of Clinical Immunology
Bondesan, Simone
Italy, Milan
Irccs Ospedale San Raffaele
Bryceson, Yenan Troi
Sweden, Stockholm
Karolinska Institutet
Bustos, Ingrid Gisell
Colombia, Chía
Universidad de la Sabana
Cabrera-Marante, Oscar
Spain, Madrid
Hospital Universitario la Paz
Cárcel, Sheila
Spain, Cordoba
Instituto Maimónides de Investigación Biomédica de Córdoba Imibic
Carrera, Paola
Italy, Milan
Irccs Ospedale San Raffaele
Casari, Giorgio
Italy, Milan
Irccs Ospedale San Raffaele
Italy, Milan
Università Vita-salute San Raffaele
Chaibi, Khalil
France, Paris
Ap-hp Assistance Publique - Hopitaux de Paris
France, Paris
Maladies Rénales Fréquentes et Rares
Colobran Oriol, Roger
Spain, Barcelona
Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies
Spain, Barcelona
Hospital Universitari Vall D'hebron
Spain, Cerdanyola Del Valles
Universitat Autònoma de Barcelona
Condino‑Neto, Antonio A.
Brazil, Sao Paulo
Universidade de São Paulo
Covill, Laura E.
Sweden, Stockholm
Karolinska Institutet
Delmonte, Ottavia Maria
United States, Bethesda
National Institute of Allergy and Infectious Diseases Niaid
El Zein, Loubna
Lebanon, Beirut
Université Libanaise
Flores, Carlos M.
Spain, Granadilla de Abona
Instituto Tecnológico y de Energías Renovables, S.a.
Spain, Madrid
Instituto de Salud Carlos Iii
Spain, Santa Cruz de Tenerife
Hospital Universitario Nuestra Senora de Candelaria
Spain, Santa Maria de Guia de Gran Canaria
Universidad Fernando Pessoa Canarias
Gregersen, Peter K.
United States, New York
Northwell Health System
Gut, Marta
Spain, Barcelona
Barcelona Institute of Science and Technology Bist
Haerynck, Filomeen
Belgium, Ghent
Jeffrey Modell Diagnosis and Research Centre
Halwani, Rabih
United Arab Emirates, Sharjah
University of Sharjah
Hancerli, Selda
Turkey, Istanbul
Istanbul Üniversitesi
Hammarström, Lennart L.G.
Sweden, Stockholm
Karolinska Institutet
Hatipoǧlu, Nevin
Turkey, Istanbul
Bak?rkoy Dr. Sadi Konuk Egitim ve Arast?rma Hastanesi
Karbuz, Adem
Turkey, Istanbul
Prof. Dr. Cemil Tascioglu City Hospital
Keleş, Sevgi
Turkey, Meram
Necmettin Erbakan Üniversitesi
Kyheng, Christèle
France, Le Kremlin-bicetre
Hopital de Bicetre
León-López, Rafael
Spain, Cordoba
Instituto Maimónides de Investigación Biomédica de Córdoba Imibic
Franco, Josè Luis
Colombia, Medellin
Universidad de Antioquia
Mansouri, Davood
Iran, Tehran
National Research Institute of Tuberculosis and Lung Disease Tehran
Iran, Tehran
Shahid Beheshti University of Medical Sciences
Martínez-Picado, Javier
Spain, Badalona
Fundació Institut Dinvestigació en Ciències de la Salut Germans Trias I Pujol
Spain, Vic
Universitat de Vic - Universitat Central de Catalunya Uvic-ucc
Spain, Barcelona
Institució Catalana de Recerca I Estudis Avançats
Spain, Madrid
Instituto de Salud Carlos Iii
Metin-Akcan, Ozge
Turkey, Meram
Necmettin Erbakan Üniversitesi
Migeotte, Isabelle
Belgium, Brussels
Université Libre de Bruxelles
Morange, Pierre Emmanuel
France, Marseille
Hopital la Timone
France, Paris
Inrae
Morelle, Guillaume
France, Le Kremlin-bicetre
Hopital de Bicetre
Martín-Nalda, Andrea
Spain, Barcelona
Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies
Spain, Cerdanyola Del Valles
Universitat Autònoma de Barcelona
Spain, Barcelona
Hospital Universitari Vall D'hebron
Novelli, Giuseppe
Italy, Rome
Università Degli Studi Di Roma Tor Vergata
Italy, Pozzilli
Istituto Neurologico Mediterraneo Neuromed, Pozzilli
Palabiyik, Figen Bakirtas
Turkey, Istanbul
Bak?rkoy Dr. Sadi Konuk Egitim ve Arast?rma Hastanesi
Pan-Hammarström, Qiang
Sweden, Stockholm
Karolinska Institutet
Pérez de Diego, Rebeca
Spain, Madrid
Hospital Universitario la Paz
Planas-Serra, Laura
Spain, Hospitalet de Llobregat
Institut D'investigació Biomedica de Bellvitge
Spain, Madrid
Centro de Investigación Biomédica en Red de Enfermedades Raras
Pleguezuelo, Daniel Enrique
Spain, Madrid
Universidad Complutense de Madrid
Prando, Carolina Cardoso De Mello
Brazil, Curitiba
Faculdades Pequeno Príncipe
Pujol, Aurora
Spain, Barcelona
Institució Catalana de Recerca I Estudis Avançats
Spain, Hospitalet de Llobregat
Institut D'investigació Biomedica de Bellvitge
Spain, Madrid
Centro de Investigación Biomédica en Red de Enfermedades Raras
Reyes, Luis F.
Colombia, Chía
Universidad de la Sabana
Rivière, Jacques G.
Spain, Barcelona
Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies
Spain, Cerdanyola Del Valles
Universitat Autònoma de Barcelona
Spain, Barcelona
Hospital Universitari Vall D'hebron
Rodríguez-Gallego, Carlos
Spain, Las Palmas de Gran Canaria
Hospital de Gran Canaria Dr. Negrin
Spain, Santa Maria de Guia de Gran Canaria
Universidad Fernando Pessoa Canarias
Rojas, Julian
Colombia, Medellin
Universidad de Antioquia
Rovere-Querini, Patrizia
Italy, Milan
Università Vita-salute San Raffaele
Italy, Milan
Irccs Ospedale San Raffaele
Schlüter, Agatha
Spain, Hospitalet de Llobregat
Institut D'investigació Biomedica de Bellvitge
Spain, Madrid
Centro de Investigación Biomédica en Red de Enfermedades Raras
Shahrooei, Mohammad
Iran, Ahvaz
Sina Medical Complex
Belgium, Leuven
Ku Leuven
Sobh, Ali
Egypt, Mansoura
Mansoura University Children's Hospital
Soler-Palacín, P.
Spain, Barcelona
Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies
Spain, Cerdanyola Del Valles
Universitat Autònoma de Barcelona
Spain, Barcelona
Hospital Universitari Vall D'hebron
Tandjaoui-Lambiotte, Yacine
France, Paris
Ap-hp Assistance Publique - Hopitaux de Paris
Tipu, Imran
Pakistan, Lahore
University of Management and Technology Lahore
Tresoldi, Cristina
Italy, Milan
Irccs Ospedale San Raffaele
Troya, Jesus
Spain, Madrid
Hospital Universitario Infanta Leonor
van de Beek, Diederik V.D.
Netherlands, Amsterdam
Amsterdam Neuroscience
Zatz, Mayana
Brazil, Sao Paulo
Universidade de São Paulo
Zawadzki, Pawel
United States, Cambridge
Gordion Bioscience Inc
Poland, Poznan
Uniwersytet Im. Adama Mickiewicza w Poznaniu
Al-Muhsen, Saleh Zaid
Saudi Arabia, Riyadh
King Saud University
Alosaimi, Mohammed F.
Saudi Arabia, Riyadh
King Saud University
Alsohime, Fahad M.
Saudi Arabia, Riyadh
King Saud University
Baris-Feldman, Hagit
Israel, Tel Aviv-yafo
Tel Aviv Sourasky Medical Center
Israel, Tel Aviv-yafo
Tel Aviv University
Butte, Manish J.
United States, Los Angeles
University of California, Los Angeles
Constantinescu, Stefan N.
Belgium, Brussels
Ludwig Institute for Cancer Research Brussels
Belgium, Louvain-la-neuve
Université Catholique de Louvain
Belgium, Brussels
Walloon Excellence in Life Sciences and Biotechnology Welbio
United Kingdom, Oxford
Ludwig Institute for Cancer Research, Oxford
Cooper, Megan A.
United States, St. Louis
Washington University in St. Louis
Dalgard, Clifton L.
United States, Bethesda
Uniformed Services University of the Health Sciences
Fellay, Jacques
Switzerland, Lausanne
École Polytechnique Fédérale de Lausanne
Switzerland, Lausanne
Sib Swiss Institute of Bioinformatics
Switzerland, Lausanne
Université de Lausanne Unil
Heath, James R.
United States, Seattle
Institute for Systems Biology
Lau, Yu Lung
Hong Kong, Hong Kong
The University of Hong Kong
Lifton, Richard P.
United States, New York
Rockefeller University
United States, New Haven
Yale School of Medicine
Maniatis, Tom
United States, New York
Columbia University
United States, New York
New York Genome Center
Mogensen, Trine Hyrup
Denmark, Aarhus
Aarhus Universitet
Denmark, Aarhus
Aarhus Universitetshospital
von Bernuth, Horst
Germany, Berlin
Charité – Universitätsmedizin Berlin
Lermine, Alban
France, Paris
Laboratoire de Biologie Médicale Multisites Seqoia
Vidaud, Michel
France, Paris
Laboratoire de Biologie Médicale Multisites Seqoia
Boland, Anne
France, Gif-sur-yvette
Commissariat a L'energie Atomique et Aux Energies Alternatives
Deleuze, Jean François
France, Gif-sur-yvette
Commissariat a L'energie Atomique et Aux Energies Alternatives
Nussbaum, Robert Luke
United States, San Francisco
Invitae Corporation
Mentré, France
France, Paris
Ap-hp Assistance Publique - Hopitaux de Paris
Tubiana, Sarah
France, Paris
Ap-hp Assistance Publique - Hopitaux de Paris
Gorochov, Guy
France, Paris
Sorbonne Université
Tubach, Florence
France, Paris
Sorbonne Université
Hausfater, Pierre
France, Paris
Sorbonne Université
Al-Mulla, F.
Unknown Affiliation
Andreakos, Evangelos Th
Unknown Affiliation
Belot, Alexandre
Unknown Affiliation
Biggs, Catherine M.
Unknown Affiliation
Bogunovic, Dusan
Unknown Affiliation
Bondarenko, Anastasiia V.
Unknown Affiliation
Bousfiha, Ahmed Aziz
Unknown Affiliation
Brodin, Petter
Unknown Affiliation
Christodoulou, John
Unknown Affiliation
Baghdadi, Jamila El I.
Unknown Affiliation
Espinosa-Padilla, Sara Elva
Unknown Affiliation
Hagin, David
Unknown Affiliation
Henrickson, Sarah E.
Unknown Affiliation
Hsieh, Elena Wen Yuan
Unknown Affiliation
Husebye, Eystein Sverre
Unknown Affiliation
Imai, Kohsuke
Unknown Affiliation
Itan, Yuval
Unknown Affiliation
Jarvis, Erich D.
Unknown Affiliation
Karamitros, Timokratis
Unknown Affiliation
Kisand, Kai E.
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Ku, Cheng-Lung
Unknown Affiliation
Ling, Yun
Unknown Affiliation
Lucas, Carrie L.
Unknown Affiliation
Máródi, László D.R.
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Milner, Joshua D.
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Mironska, Kristina
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Morio, Tomohiro
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Ng, Lisa F.P.
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Okada, Satoshi
Unknown Affiliation
Planas, Anna M.
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Quintana-Murci, Lluís
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RENIA, LAURENT
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Unknown Affiliation
Ramaswamy, Sathishkumar
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Unknown Affiliation
Vinh, Donald C.
Unknown Affiliation
Casanova, Jean Laurent
France, Paris
L'institut Des Maladies Génétiques Imagine
United States, New York
Rockefeller University
United States, Chevy Chase
Howard Hughes Medical Institute
Casanova, Jean Laurent
Unknown Affiliation
Abgrall, Sophie
Unknown Affiliation
Adnet, Frédéric
Unknown Affiliation
Agostini, Hélène
Unknown Affiliation
Alyanakian, Marie Alexandra
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Anglicheau, Dany
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Anguel, Nadia
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Annane, Djillali
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Arlet, Jean Benoît
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Audureau, Étienne
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Azemar, Laurene
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Barau, Caroline
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Blanché, Philippe
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Bleibtreu, Alexandre
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Boissier, M. C.
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Bollens, Diane
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Bonnet, Nicolas
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Bouscarat, Fabrice
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Cadranel, Jacques L.
Unknown Affiliation
Cailhol, Johann
Unknown Affiliation
Cǎlin, Ruxandra Oana
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Carbillon, Lionel
Unknown Affiliation
Chas, Julie
Unknown Affiliation
Cheraï, Mustapha
Unknown Affiliation
Choupeaux, Laure
Unknown Affiliation
Chousterman, Benjamin Glenn
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Cohen, Yves
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Cohen, Fleur Aubart
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Coilly, Audrey
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Comarmond, Cloé
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Constantin, Jean Michel
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Couffignal, Camille
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Créange, Alain
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de Castro, Nathalie
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Demoule, Alexandre
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Depret, François
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Descamps, Vincent
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Deschamps, Lydia
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Dhôte, Robin
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Elie, Caroline
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Fournier, Benjamin
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Heming, Nicholas
Unknown Affiliation
Hermine, Olivier
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Ingiliz, Patrick
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Jauréguiberry, Stèphane
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Katsahian, Sandrine
Unknown Affiliation
Khellaf, Mehdi
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Lacombe, Karine
Unknown Affiliation
Lacorte, Jean Marc
Unknown Affiliation
Lanternier, Fanny L.
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Lavergne, Christophe L.J.
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Lecomte, François
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Silvain, Johanne
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Tantet, Claire
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Tréluyer, Jean Marc
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Uzunhan, Yurdagül
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Verstuyft, Céline
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Unknown Affiliation
Ecobichon, Jean Luc
Unknown Affiliation
Houhou-Fidouh, Nadhira
Unknown Affiliation
Lina, Bruno
Unknown Affiliation
Manchon, Pauline
Unknown Affiliation
Waucquier, Nawal
Unknown Affiliation
Djossou, Félix
Unknown Affiliation
Demar, Magalie Pierre
Unknown Affiliation
Bruneau, Leá
Unknown Affiliation
Gérardin, Patrick
Unknown Affiliation
Lainé, Fabrice
Unknown Affiliation
Pistone, Thierry
Unknown Affiliation
Chirouze, Catherine
Unknown Affiliation
Bouiller, Kevin
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Desmarets, Maxime
Unknown Affiliation
Lefèvre, Benjamin
Unknown Affiliation
Jeulin, Hélène
Unknown Affiliation
Legrand, Karine
Unknown Affiliation
Lomazzi, Sandra
Unknown Affiliation
Tardy, Bernhard
Unknown Affiliation
Gagneux-Brunon, Amandine
Unknown Affiliation
Bertholon, Frédérique
Unknown Affiliation
Botelho-Nevers, Elisabeth
Unknown Affiliation
Couffin-Cadièrgues, Sandrine
Unknown Affiliation
Foti, Giuseppe
Unknown Affiliation
Bellani, Giacomo
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Citerio, Giuseppe
Unknown Affiliation
Pesci, Alberto
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Valsecchi, Maria Grazia
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Aguilera-Albesa, Sergio
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Khan, Taj Ali
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Nadji, Seyed Alireza
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AlKhater, Suzan A.
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Alshahrani, Mohammed Saeed Saad
Unknown Affiliation
Alsina, Laia
Unknown Affiliation
Amoura, Zahir
Unknown Affiliation
Aubart, Mélodie
Unknown Affiliation
Bahram, Seiamak
Unknown Affiliation
Baldanti, F.
Unknown Affiliation
Bezrodnik, Liliana
Unknown Affiliation
Blanco, Ignacio
Unknown Affiliation
Blázquez-Gamero, Daniel
Unknown Affiliation
Bloomfield, Markéta
Unknown Affiliation
Borghesi, Alessandro
Unknown Affiliation
Borie, Raphaël
Unknown Affiliation
Bousquet, Aurore A.
Unknown Affiliation
Boutolleau, David
Unknown Affiliation
Boyarchuk, Oksana R.
Unknown Affiliation
Bukhari, Huda
Unknown Affiliation
Bustamante, Jacinta C.
Unknown Affiliation
Carapito, Raphaël
Unknown Affiliation
Casasnovas, C.
Unknown Affiliation
Cassaniti, Irene
Unknown Affiliation
Castelle, Martin
Unknown Affiliation
Castelli, Francesco
Unknown Affiliation
Catherinot, Émilie
Unknown Affiliation
Chalumeau, Martin
Unknown Affiliation
Charbit, Bruno
Unknown Affiliation
Statistics
Citations: 27
Authors: 390
Affiliations: 87
Identifiers
Doi:
10.1186/s13073-023-01173-8
ISSN:
1756994X
Research Areas
Covid
Genetics And Genomics