Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19
Authors: 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 Andrés Augusto , Aytekin Gokhan , Bergman Peter , Bondesan Simone , Bryceson Yenan T. , Bustos Ingrid G. , Cabrera-Marante Oscar , Carcel Sheila , Carrera Paola , Casari Giorgio , Chaïbi 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 , Hammarström Lennart , Hatipoğlu Nevin , Karbuz Adem , Keles Sevgi , Kyheng Christèle , 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-Hammarström Qiang , de Diego Rebeca Pérez , Planas-Serra Laura , Pleguezuelo Daniel E. , Prando Carolina , Pujol Aurora , Reyes Luis Felipe , Rivière Jacques G. , Rodriguez-Gallego Carlos , Rojas Julian , Rovere-Querini Patrizia , Schlüter 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-François , Nussbaum Robert , Kahn-Kirby Amanda , Mentre France , Tubiana Sarah , Gorochov Guy , Tubach Florence , Hausfater Pierre ,   COVID Human Genetic Effort, Abel Laurent , Al-Muhsen Saleh , Al-Mulla Fahd , Anderson Mark S. , Andreakos Evangelos , Arias Andrés A. , Feldman Hagit Baris , Belot Alexandre , Biggs Catherine M. , Bogunovic Dusan , Bondarenko Anastasiia , Bousfiha Ahmed A. , Brodin Petter , Bryceson Yenan , Bustamante Carlos D. , Chakravorty Samya , Christodoulou John , Desai Murkesh , Drolet Beth A. , Baghdadi Jamila El , Espinosa-Padilla Sara , Franco José Luis , Froidure Antoine , Hagin David , Henrickson Sarah E. , Hsieh Elena W. Y. , Husebye Eystein , Imai Kohsuke , Itan Yuval , Jarvis Erich D. , Karamitros Timokratis , Kisand Kai , Ku Cheng-Lung , Ling Yun , Lucas Carrie L. , Maródi László , Meyts Isabelle , Milner Joshua D. , Mironska Kristina , Morio Tomohiro , Ng Lisa F. P. , Notarangelo Luigi D. , O’Farrelly Cliona , Okada Satoshi , Planas Anna M. , Quintana-Murci Lluis , Renia Laurent , Resnick Igor , Rodríguez-Gallego Carlos , Sancho-Shimizu Vanessa , Sediva Anna , Seppänen Mikko R. J. , Shcherbina Anna , Slaby Ondrej , Snow Andrew L. , Soler-Palacín Pere , Spaan András N. , Tancevski Ivan , Tangye Stuart G. , Ramaswamy Sathishkumar , Turvey Stuart E. , Uddin Furkan , Uddin Mohammed J. , van de Beek Diederik , Vinh Donald C. , Zatz Mayana , Su Helen C. , Casanova Jean-Laurent ,   COVIDeF Study Group, Bureau Serge , Vacher Yannick , Gysembergh-Houal Anne , Demerville Lauren , Chachoua Abla , Abad Sebastien , Abassi Radhiya , Abdellaoui Abdelrafie , Abdelmalek Abdelkrim , Abdoul Hendy , Abergel Helene , Abeud Fariza , Abgrall Sophie , Abisror Noemie , Adechian Marylise , Aderdour Nordine , Admane Hakeem Farid , Adnet Frederic , Afritt Sara , Agostini Helene , Aguilar Claire , Agut Sophie , Aiello Tommaso Francesco , Kaci Marc Ait , Oufella Hafid Ait , Ajeenthiravasan Gokula , Alauzy Virginie , Alby-Laurent Fanny , Allard Lucie , Alyanakian Marie-Alexandra , Borrero Blanca Amador , Amam Sabrina , Amrouche Lucile , Andronikof Marc , Anglicheau Dany , Anguel Nadia , Annane Djillali , Aounzou Mohammed , Aparicio Caroline , Aratus Gladys , Arlet Jean-Benoit , Arzoine Jeremy , Aslangul Elisabeth , Assefi Mona , Aubry Adeline , Audiffred Laetitia , Audureau Etienne , Auger Christelle Nathalie , Auregan Jean-Charles , Awotar Celine , Milla Sonia Ayllon , Azan Delphine , Azemar Laurene , Azzouguen Billal , Elrufaai Marwa Bachir , Badsi Aïda , Bakouboula Prissile , Balcerowiak Coline , Balde Fanta , Baldivia Elodie , Bangamingo Eliane-Flore , Baptiste Amandine , Baran-Marszak Fanny , Barau Caroline , Barget Nathalie , Baronnet Flore , Barthelemy Romain , Baudel Jean-Luc , Baudry Camille , Baudry Elodie , Beaugerie Laurent , Belamri Adel , Belaube Nicolas , Belilita Rhida , Bellassen Pierre , Belmokhtar Rawan , Beltran Isabel , Benainous Ruben , Benallaoua Mourad , Benamouzig Robert , Benbara Amélie , Benhida Jaouad , Benkhelouf Anis , Benlagha Jihene , Benmostafa Chahinez , Benothmane Skander , Bentifraouine Miassa , Berard Laurence , Bernier Quentin , Berti Enora , Bertier Astrid , Berton Laure , Bessis Simon , Beurton Alexandra , Bianco Celine , Bianquis Clara , Bidar Frank , Blanche Philippe , Blayau Clarisse , Bleibtreu Alexandre , Blin Emmanuelle , Bloch-Queyrat Coralie , Boissier Marie-Christophe , Bollens Diane , Bolzoni Marion , Bompard Rudy pierre , Bonnet Nicolas , Bonnouvrier Justine , Botha Shirmonecrystal , Boucenna Wissam , Bouchama Fatiha , Bouchaud Olivier , Bouchghoul Hanane , Boudjebla Taoueslylia , Boudjema Noel , Bouffard Catherine , Bougle Adrien , Bouguerra Meriem , Bouras Leila , Bourcier Agnes , Durand Anne Bourgarit , Bourrier Anne , Bouscarat Fabrice , Bouvry Diane , Bouziri Nesrine , Bouzrara Ons , Bribier Sarah , Brugier Delphine , Brunel Melanie , Bui Eida , Buisson Anne , Bukreyeva Iryna , Bureau Côme , Cadranel Jacques , Cailhol Johann , Calin Ruxandra , Vega Clara Campos , Canavaggio Pauline , Cancella Marta , Cantin Delphine , Cao Albert , Carbillon Lionel , Carlier Nicolas , Cassard Clementine , Castor Guylaine , Cauchy Marion , Cha Olivier , Chaigne Benjamin , Challal Salima , Champion Karine , Chariot Patrick , Chas Julie , Chauveau Simon , Chauvin Anthony , Chauvin Clement , Chavarot Nathalie , Chebbout Kamélia , Cherai Mustapha , Cherubini Ilaria , Chevalier Amelie , Chiarabini Thibault , Chinet Thierry , Chocron Richard , Choinier Pascaline , Chommeloux Juliette , Choquet Christophe , Choupeaux Laure , Chousterman Benjamin , Ciocan Dragosmarius , Clarke Ada , Clavere Gaëlle , Clavier Florian , Clement Karine , Clerc Sebastien , Cohen Yves , Cohen Fleur , Cohen Adrien , Coilly Audrey , Colboc Hester , Colin Pauline , Collet Magalie , Comarmond Chloé , Combacon Emeline , Combes Alain , Comparon Celine , Constantin Jean-Michel , Cordel Hugues , Cordier Anne-Gael , Costantini Adrien , Chalumeau Nathalie Costedoat , Couffignal Camille , Coupeau Doriane , Creange Alain , Lamarre Yannie Cuvillier , Da Silveira Charlène , Kayani Sandrine Dautheville Guibal El , De Castro Nathalie , De Rycke Yann , Del Pozo Lucie , Delannoy Quentin , Delay Mathieu , Deleris Robin , Delforge Juliette , Delphine Laëtitia , Demare Noemie , Demeret Sophie , Demoule Alexandre , Deniau Aurore , Depret François , Derolez Sophie , Derradji Ouda , Derridj Nawal , Descamps Vincent , Deschamps Lydia , Desconclois Celine , Desnos Cyrielle , Desongins Karine , Dhote Robin , Diallo Benjamin , Didier Morgane , Diemer Myriam , Diez Stephane , Djadi-Prat Juliette , Monnory Fatima-Zohra Djamouri , Djebara Siham , Djebra Naoual , Djietcheu Minette , Djillali Hadjer , Djouadi Nouara , Donneger Severine , Dos Santos Catarina , Dournon Nathalie , Dres Martin , Droctove Laura , Drogrey Marie , Dropy Margot , Drouet Elodie , Dubosq Valérie , Dubreucq Evelyne , Dubus Estelle , Duchemann Boris , Duchenoy Thibault , Dudoignon Emmanuel , Dufau Romain , Dumas Florence , Duran Clara , Duron Emmanuelle , Durrbach Antoine , Duvivier Claudine , Ebstein Nathan , Khalifa Jihane El , Elabbadi Alexandre , Elie Caroline , Ernotte Gabriel , Esling Anne , Etienne Martin , Eyer Xavier , Fartoukh Muriel sarah , Fayali Takoua , Fermaut Marion , Fiorentino Arianna , Fliss Souha , Fournier Marie-Céline , Fournier Benjamin , Francois Hélène , Freynet Olivia , Frigout Yvann , Fromont Isaure , Fuentes Axelle , Furet Thomas , Galand Joris , Garnier Marc , Gaubert Agnes , Gaudry Stéphane , Gaugain Samuel , Gauthier Damien , Gautier Maxime , Georgin-Lavialle Sophie , Geromin Daniela , Ghalayini Mohamed , Ghaleh Bijan , Ghezal Myriam , Gibelin Aude , Gimeno Linda , Girard Benoit , Leprieur Bénédicte Giroux , Gomes Doryan , Gomes-Pires Elisabete , Gouge Anne , Gouja Amel , Goulet Helene , Goupil Sylvain , De Bouille Jeanne Goupil , Gras Julien , Greffe Segolene , Grimaldi Lamiae , Guedeney Paul , Guidet Bertrand , Guillo Matthias , Gulczynski Mariechristelle , Hadjam Tassadit , Haguenauer Didier , Hammal Soumeya , Hammoudi Nadjib , Hanon Olivier , Harrois Anarole , Hautem Coraline , Hekimian Guillaume , Heming Nicholas , Hermine Olivier , Ho Sylvie , Houllier Marie , Huot Benjamin , Huscenot Tessa , Saied Wafa Ibn , Ikherbane Ghilas , Imarazene Meriem , Ingiliz Patrick , Iratni Lina , Jaureguiberry Stephane , Jean-Marc Jean-Francois , Jeyarajasingham Deleena , Jouany Pauline , Jouis Veronique , Jourdaine Clement , Kafif Ouifiya , Kallala Rim , Katsahian Sandrine , Kelesyan Lilit , Keo Vixra , Ketz Flora , Khamis Warda , Khelili Enfel , Khellaf Mehdi , Youkou Christy Gaëlla Kotokpo , Kounis Ilias , Kpalma Gaelle , Krause Jessica , Labbe Vincent , Lacombe Karine , Lacorte Jean-Marc , Lafont Anne Gaelle , Lafont Emmanuel , Lagha Lynda , Lamhaut Lionel , Lancelot Aymeric , Landman Cecilia , Lanternier Fanny , Larcheveque Cecile , Combe Caroline Lascoux , Lassel Ludovic , Laverdant Benjamin , Lavergne Christophe , Lavillegrand Jean-Rémi , Lazureanu Pompilia , Le Guennec Loïc , Leberre Lamia , Leblanc Claire , Leboyer Marion , Lecomte Francois , Lecorre Marine , Leenhardt Romain , Lefebvre Marylou , Lefebvre Bénédicte , Legendre Paul , Leger Anne , Legros Laurence , Legrosse Justyna , Lehuunghia Sébastien , Lemarec Julien , Leporrier-Ext Jeremie , Lesein Manon , Lesur Hubert , Levy Vincent , Levy Albert , Lopes Edwige , Lopes Amanda , Lopez Vanessa , Lopinto Julien , Lortholary Olivier , Louadah Badr , Loze Bénédicte , Lucas Marie-Laure , Lucasamichi Axelle , Luong Liem Binh , Magazimama-Ext Arouna , Maingret David , Mameri Lakhdar , Manivet Philippe , Mansouri Cylia , Marcault Estelle , Marey Jonathan , Marin Nathalie , Marois Clémence , Martin Olivier , Martineau Lou , Martinez-Lopez Cannelle , Martyniuck Pierre , De Farcy Pauline Mary , Marzouk Nessrine , Masmoudi Rafik , Mebazaa Alexandre , Mechai Frédéric , Mecozzi Fabio , Mediouni Chamseddine , Megarbane Bruno , Meghadecha Mohamed , Mejean Élodie , Mekinian Arsene , Abdelhadi Nour Mekki , Mekni Rania , Meliti Thinhinan Sabrina , Lima Breno Melo , Meng Paris , Merbah Soraya , Messani Fadhila , Messaoudi Yasmine , Mewasing Baboo-Irwinsingh , Meziane Lydia , Michelot-Burger Carole , Mignot Françoise , Minka Fadi Hillary , Miyara Makoto , Moine Pierre , Molina Jean-Michel , Montegnies-Boulet Anaïs , Monti Alexandra , Montlahuc Claire , Montout Anne-Lise , Moores Alexandre , Morbieu Caroline , Mortelette Helene , Mouly Stéphane , Muzaffar Rosita , Nacerddine Cherifa Iness , Nadal Marine , Nadif Hajer , Nassarmadji Kladoum , Natella Pierre , Ndingamondze Sandrine , Neraal Stefan , Nguyen Caroline , N’Guyen Bao , Larmurier Isabelle Nion , Nlomenyengue Luc , Noel Nicolas , Nunes Hilario , Omar Edris , Ouazene Zineb , Ouedraogo Elise , Ouelaa Wassila , Oukhedouma Anissa , Amara Yasmina Ould , Oya Herve , Oziel Johanna , Padilla Thomas , Paillaud Elena , Paiva Solenne , Parfait Beatrice , Parize Perrine , Parizot Christophe , Parrot Antoine , Pavot Arthur , Peaudecerf Laetitia , Pene Frédéric , Pepin Marion , Pernet Julie , Pernin Claire , Petit Mylène , Peyrony Olivier , Pietri Marie-Pierre , Pietri Olivia , De Chambrun Marc Pineton , Pinson Michelle , Pintado Claire , Piquard Valentine , Pires Christine , Planquette Benjamin , Poirier Sandrine , Pomel Anne-Laure , Pons Stéphanie , Ponscarme Diane , Pourcelot Annegaelle , Pourcher Valérie , Pouvaret Anne , Prever Florian , Previlon Miresta , Prevost Margot , Provoost Marie-Julie , Quemeneur Cyril , Rafat Cédric , Rami Agathe , Ranque Brigitte , Raphael Maurice , Raphalen Jean Herle , Rastoin Anna , Raux Mathieu , Rebai Amani , Reby Michael , Regent Alexis , Regrag Asma , Resche-Rigon Matthieu , Ressaire Quentin , Richard Christian , Richard Mariecaroline , Robert Maxence , Rohaut Benjamin , Rolland-Debord Camille , Ropers Jacques , Roque-Afonso Anne-Marie , Rosso Charlotte , Rousseaux Mélanie , Rousseaux Nabila , Roux Swasti , Roux Lorène , Rouzaud Claire , Rozes Antoine , Rubenstein Emma , Sabate Jean-Marc , Sabet Sheila , Sacleux Sophie-Caroline , Kermanach Nathalie Saidenberg , Saliba Faouzi , Salmon Dominique , Savale Laurent , Savary Guillaume , Sberro Rebecca , Scemla Anne , Schlemmer Frederic , Schwartz Mathieu , Sedfi Saïd , Sefir-Kribel Samia , Seksik Philippe , Sellier Pierre , Selves Agathe , Sembach Nicole , Semerano Luca , Senat Marie-Victoire , Sene Damien , Serris Alexandra , Sese Lucile , Sghiouar Naima , Sigaux Johanna , Siguier Martin , Silvain Johanne , Simon Noémie , Simon Tabassome , Skandri Lina Innes , Slimani Miassa , Snauwaert Aurélie , Sokol Harry , Soliman Heithem , Soltani Nisrine , Soyer Benjamin , Steg Gabriel , Suarez Lydia , Szwebel Tali-Anne , Taffame Kossi , Tantet Claire , Tateo Mariagrazia , Theodose Igor , Thiebaud Pierre clement , Thomas Caroline , Tiercelet Kelly , Tisserand Julie , Tomczak Carole , Torelino Krystel , Touam-Ext Fatima , Toumi Lilia , Toury Gustave , Toy-Miou Mireille , Lien Olivia Tran Dinh Thanh , Trandinh Alexy , Treluyer Jean-Marc , Trinque Baptiste , Truchot Jennifer , Tunesi Simone , Turpin Matthieu , Turpin Agathe , Urbina Tomas , Narvaez Rafael Usubillaga , Uzunhan Yurdagul , Vaittinadaayar Prabakar , Valent Arnaud , Valentian Maelle , Valin Nadia , Vallet Hélène , Vaz Marina , Vazquezibarra Miguel-Alejandro , Vedie Benoit , Velly Laetitia , Verstuyft Celine , Viallette Cedric , Vicaut Eric , Vignes Dorothee , Vimpere Damien , Virlouvet Myriam , Voiriot Guillaume , Voisot Lena , Weiss Emmanuel , Weiss Nicolas , Winchenne Anaïs , Yordanov Youri , Zafrani Lara , Zaidan Mohamad , Zaidi Wissem , Zak Cathia , Zarhrate-Ghoul Aida , Zatout Ouassila , Zeino Suzanne , Zeitouni Michel , Zemirli Naïma , Zerah Lorene , Zia Ounsa , Ziol Marianne , Zolario Oceane , Zuber Julien ,   French COVID Cohort Study Group, Abel Laurent , Andrejak Claire , Angoulvant François , Bachelet Delphine , Bartoli Marie , Basmaci Romain , Behilill Sylvie , Beluze Marine , Benkerrou Dehbia , Bhavsar Krishna , Bouadma Lila , Bouchez Sabelline , Bouscambert Maude , Cervantes-Gonzalez Minerva , Chair Anissa , Chirouze Catherine , Coelho Alexandra , Couffignal Camille , Couffin-Cadiergues Sandrine , d’Ortenzio Eric , Debray Marie-Pierre , Deconinck Lauren , Deplanque Dominique , Descamps Diane , Desvallée Mathilde , Diallo Alpha , Diouf Alphonsine , Dorival Céline , Dubos François , Duval Xavier , Elharrar Brigitte , Eloy Philippine , Enouf Vincent , Esperou Hélène , Esposito-Farese Marina , Etienne Manuel , Devouge Eglantine Ferrand , Gault Nathalie , Gaymard Alexandre , Ghosn Jade , Gigante Tristan , Gilg Morgane , Guedj Jérémie , Hoctin Alexandre , Hoffmann Isabelle , Houas Ikram , Hulot Jean-Sébastien , Jaafoura Salma , Kafif Ouifiya , Kaguelidou Florentia , Kali Sabrina , Khalil Antoine , Khan Coralie , Laouénan Cédric , Laribi Samira , Le Minh , Le Hingrat Quentin , Le Mestre Soizic , Le Nagard Hervé , Lescure François-Xavier , Letrou Sophie , Levy Yves , Lina Bruno , Lingas Guillaume , Lucet Jean Christophe , Malvy Denis , Mambert Marina , Mentré France , Meziane Amina , Mouquet Hugo , Mullaert Jimmy , Neant Nadège , Nguyen Duc , Noret Marion , Nseir Saad , Papadopoulos Aurélie , Paul Christelle , Peiffer-Smadja Nathan , Perpoint Thomas , Petrov-Sanchez Ventzislava , Peytavin Gilles , Pham Huong , Picone Olivier , Piquard Valentine , Puéchal Oriane , Rabaud Christian , Rosa-Calatrava Manuel , Rossignol Bénédicte , Rossignol Patrick , Roy Carine , Schneider Marion , Su Richa , Tardivon Coralie , Tellier Marie-Capucine , Téoulé François , Terrier Olivier , Timsit Jean-François , Tual Christelle , Van Der Werf Sylvie , Vanel Noémie , Veislinger Aurélie , Visseaux Benoit , Wiedemann Aurélie , Yazdanpanah Yazdan ,   CoV-Contact Cohort, Alavoine Loubna , Behillil Sylvie , Burdet Charles , Charpentier Charlotte , Dechanet Aline , Descamps Diane , Duval Xavier , Ecobichon Jean-Luc , Enouf Vincent , Frezouls Wahiba , Houhou Nadhira , Kafif Ouifiya , Lehacaut Jonathan , Letrou Sophie , Lina Bruno , Lucet Jean-Christophe , Manchon Pauline , Nouroudine Mariama , Piquard Valentine , Quintin Caroline , Thy Michael , van der Werf Sylvie , Vignali Valérie , Visseaux Benoit , Yazdanpanah Yazdan , Chahine Abir , Waucquier Nawal , Migaud Maria-Claire , Deplanque Dominique , Djossou Félix , Mergeay-Fabre Mayka , Lucarelli Aude , Demar Magalie , Bruneau Léa , Gérardin Patrick , Maillot Adrien , Payet Christine , Laviolle Bruno , Laine Fabrice , Paris Christophe , Desille-Dugast Mireille , Fouchard Julie , Malvy Denis , Nguyen Duc , Pistone Thierry , Perreau Pauline , Gissot Valérie , Goas Carole L. E. , Montagne Samatha , Richard Lucie , Chirouze Catherine , Bouiller Kévin , Desmarets Maxime , Meunier Alexandre , Bourgeon Marilou , Lefévre Benjamin , Jeulin Hélène , Legrand Karine , Lomazzi Sandra , Tardy Bernard , Gagneux-Brunon Amandine , Bertholon Frédérique , Botelho-Nevers Elisabeth , Christelle Kouakam , Nicolas Leturque , Roufai Layidé , Amat Karine , Couffin-Cadiergues Sandrine , Espérou Hélène , Hendou Samia ,   COVID-STORM Clinicians, Foti Giuseppe , Bellani Giacomo , Citerio Giuseppe , Contro Ernesto , Pesci Alberto , Valsecchi Maria Grazia , Cazzaniga Marina ,   COVID Clinicians, Abad Jorge , Accordino Giulia , Achille Cristian , Aguilera-Albesa Sergio , Aguiló-Cucurull Aina , Özkan Esra Akyüz , Albisures Jonathan Antonio Roblero , Aldave Juan C. , Ramos Miquel Alfonso , Khan Taj Ali , Aliberti Anna , Nadji Seyed Alireza , Alkan Gulsum , AlKhater Suzan A. , Allardet-Servent Jerome , Alshahrani Mohammed S. , Alsina Laia , Alyanakian Marie-Alexandra , Borrero Blanca Amador , Amoura Zahir , Antolí Arnau , Arrestier Romain , Aubart Mélodie , Auguet Teresa , Avramenko Iryna , Aytekin Gökhan , Azot Axelle , Bahram Seiamak , Bajolle Fanny , Baldanti Fausto , Baldolli Aurélie , Ballester Maite , Feldman Hagit Baris , Barrou Benoit , Basso Sabrina , Bayhan Gulsum Iclal , Belot Alexandre , Bezrodnik Liliana , Bilbao Agurtzane , Blanchard-Rohner Geraldine , Blanco Ignacio , Blandinières Adeline , Blázquez-Gamero Daniel , Bleibtreu Alexandre , Bloomfield Marketa , Bolivar-Prados Mireia , Bondarenko Anastasiia , Borghesi Alessandro , Borie Raphael , Botdhlo-Nevers Elisabeth , Bousfiha Ahmed A. , Bousquet Aurore , Boutolleau David , Bouvattier Claire , Boyarchuk Oksana , Bravais Juliette , Briones M. Luisa , Brunner Marie-Eve , Bruno Raffaele , Bueno Maria Rita P. , Bukhari Huda , Bustamante Jacinta , Agra Juan José Cáceres , Capra Ruggero , Carapito Raphael , Carrabba Maria , Casasnovas Carlos , Caseris Marion , Cassaniti Irene , Castelle Martin , Castelli Francesco , de Vera Martín Castillo , Castro Mateus V. , Catherinot Emilie , Celik Jale Bengi , Ceschi Alessandro , Chalumeau Martin , Charbit Bruno , Cheng Matthew P. , Clavé Père , Clotet Bonaventura , Codina Anna , Cohen Yves , Comarmond Cloé , Combes Alain , Comoli Patrizia , Corsico Angelo G. , Sozeri Betul , Coşkuner Taner , Cvetkovski Aleksandar , Cyrus Cyril , Dalmau David , Danion François , Darley David Ross , Das Vincent , Dauby Nicolas , Dauger Stéphane , De Munter Paul , de Pontual Loic , Dehban Amin , Delplancq Geoffroy , Demoule Alexandre , Desguerre Isabelle , Di Sabatino Antonio , Diehl Jean-Luc , Dobbelaere Stephanie , Domínguez-Garrido Elena , Dubost Clément , Ekwall Olov , Bozdemir Şefika Elmas , Elnagdy Marwa H. , Emiroglu Melike , Endo Akifumi , Erdeniz Emine Hafize , Aytekin Selma Erol , Lasa Maria Pilar Etxart , Euvrard Romain , Fabio Giovanna , Faivre Laurence , Falck Antonin , Fartoukh Muriel , Faure Morgane , Arquero Miguel Fernandez , Ferrer Ricard , Ferreres Jose , Francois Bruno , Fumadó Victoria , Fung Kitty S. C. , Fusco Francesca , Gagro Alenka , Solis Blanca Garcia , Garçon Pierre , Gaussem Pascale , Gayretli Zeynep , Gil-Herrera Juana , Gilardin Laurent , Gatineau Audrey Giraud , Girona-Alarcón Mònica , Godínez Karen Alejandra Cifuentes , Goffard Jean-Christophe , Gonzales Nacho , Gonzalez-Granado Luis I. , González-Montelongo Rafaela , Guerder Antoine , Gülhan Belgin , Gumucio Victor Daniel , Hanitsch Leif Gunnar , Gunst Jan , Hadjadj Jérôme , Hariyan Tetyana , Hatipoglu Nevin , Heppekcan Deniz , Hernandez-Brito Elisa , Ho Po-ki , Holanda-Peña María Soledad , Horcajada Juan P. , Hraiech Sami , Humbert Linda , Hung Ivan F. N. , Iglesias Alejandro D. , Íñigo-Campos Antonio , Jamme Matthieu , Arranz María Jesús , Jimeno Marie-Thérèse , Jordan Iolanda , Kanik-Yüksek Saliha , Kara Yalcin Burak , Karahan Aydın , Yasar Kadriye Kart , Kasapcopur Ozgur , Kashimada Kenichi , Demirkol Yasemin Kendir , Kido Yasutoshi , Kizil Can , Kılıç Ahmet Osman , Klocperk Adam , Koutsoukou Antonia , Król Zbigniew J. , Ksouri Hatem , Kuentz Paul , Kwan Arthur M. C. , Kwan Yat Wah M. , Kwok Janette S. Y. , Lagier Jean-Christophe , Lam David S. Y. , Lampropoulou Vicky , Lanternier Fanny , Le Bourgeois Fleur , Leo Yee-Sin , Lopez Rafael Leon , Leung Daniel , Levin Michael , Levy Michael , Lévy Romain , Li Zhi , Lilleri Daniele , Lima Edson Jose Adrian Bolanos , Linglart Agnes , López-Collazo Eduardo , Lorenzo-Salazar José M. , Louapre Céline , Lubetzki Catherine , Lung Kwok-Cheung , Luyt Charles-Edouard , Lye David C. , Magnone Cinthia , Marchioni Enrico , Marioli Carola , Marjani Majid , Marques Laura , Pereira Jesus Marquez , Martín-Nalda Andrea , Pueyo David Martínez , Marzana Iciar , Mata-Martínez Carmen , Mathian Alexis , Matos Larissa R. B. , Matthews Gail V. , Mayaux Julien , McLaughlin-Garcia Raquel , Meersseman Philippe , Mège Jean-Louis , Mekontso-Dessap Armand , Melki Isabelle , Meloni Federica , Meritet Jean-François , Merlani Paolo , Akcan Özge Metin , Meyts Isabelle , Mezidi Mehdi , Millereux Maude , Million Matthieu , Mirault Tristan , Mircher Clotilde , Mirsaeidi Mehdi , Mizoguchi Yoko , Modi Bhavi P. , Mojoli Francesco , Moncomble Elsa , Melián Abián Montesdeoca , Martinez Antonio Morales , Morandeira Francisco , Mordacq Cléemence , Mouly Stéphane J. , Muñoz-Barrera Adrián , Nafati Cyril , Nagashima Shintaro , Nakagama Yu , Neven Bénédicte , Neves João Farela , Ng Lisa F. P. , Ng Yuk-Yung , Nielly hubert , Medina Yeray Novoa , Cuadros Esmeralda Nuñez , Ocejo-Vinyals J. Gonzalo , Okamoto Keisuke , Oualha Mehdi , Ouedrani Amani , Özçelik Tayfun , Ozkaya-Parlakay Aslinur , Pagani Michele , Papadaki Maria , Parizot Christophe , Parola Philippe , Pascreau Tiffany , Paul Stéphane , Paz-Artal Estela , Pedraza Sigifredo , Pellecer Nancy Carolina González , Pellegrini Silvia , Pérez-Fernández Xosé Luis , Philippe Aurélien , Philippot Quentin , Picod Adrien , de Chambrun Marc Pineton , Piralla Antonio , Ploin Dominique , Poissy Julien , Poncelet Géraldine , Poulakou Garyphallia , Pouletty Marie S. , Pourshahnazari Persia , Qiu-Chen Jia Li , Quentric Paul , Rambaud Thomas , Raoult Didier , Raoult Violette , Rebillat Anne-Sophie , Redin Claire , Resmini Léa , Ricart Pilar , Richard Jean-Christophe , Rigo-Bonnin Raúl , rivet Nadia , Rocamora-Blanch Gemma , Rodero Mathieu P. , Rodrigo Carlos , Rodriguez Luis Antonio , Rodriguez-Palmero Agustí , Romero Carolina Soledad , Rothenbuhler Anya , Roux Damien , Rovina Nikoletta , Rozenberg Flore , Ruch Yvon , Ruiz Montse , del Prado Maria Yolanda Ruiz , Ruiz-Rodriguez Juan Carlos , Sabater-Riera Joan , Saks Kai , Salagianni Maria , Sanchez Oliver , Sánchez-Montalvá Adrián , Sánchez-Ramón Silvia , Schidlowski Laire , Schluter Agatha , Schmidt Julien , Schmidt Matthieu , Schuetz Catharina , Schweitzer Cyril E. , Scolari Francesco , Sediva Anna , Seijo Luis , Seminario Analia Gisela , Sene Damien , Seng Piseth , Senoglu Sevtap , Seppänen Mikko , Llovich Alex Serra , Shcherbina Anna , Siguret Virginie , Siouti Eleni , Smadja David M. , Smith Nikaia , Solanich Xavier , Solé-Violán Jordi , Soler Catherine , Soler-Palacín Pere , Sözeri Betül , Stella Giulia Maria , Stepanovskiy Yuriy , Stoclin Annabelle , Taccone Fabio , Taupin Jean-Luc , Tavernier Simon J. , Tello Loreto Vidaur , Terrier Benjamin , Thiery Guillaume , Thorball Christian , Thorn Karolina , Thumerelle Caroline , Tolstrup Martin , Tomasoni Gabriele , Toubiana Julie , Alvarez Josep Trenado , Triantafyllia Vasiliki , Trouillet-Assant Sophie , Troya Jesús , Tsang Owen T. Y. , Tserel Liina , Tso Eugene Y. K. , Tucci Alessandra , Öz Şadiye Kübra Tüter , Ursini Matilde Valeria , Utsumi Takanori , Uzunhan Yurdagul , Vabres Pierre , Valencia-Ramos Juan , Van Den Rym Ana Maria , Vandernoot Isabelle , Velez-Santamaria Valentina , Veliz Silvia Patricia Zuniga , Vidigal Mateus C. , Viel Sébastien , Villain Cédric , Vilaire-Meunier Marie E. , Villar-García Judit , Vincent Audrey , Voiriot Guillaume , Volokha Alla , Vuotto Fanny , Wauters Els , Wauters Joost , Wu Alan K. L. , Wu Tak-Chiu , Yahşi Aysun , Yesilbas Osman , Yildiz Mehmet , Young Barnaby E. , Yükselmiş Ufuk , Zatz Mayana , Zecca Marco , Zuccaro Valentina , Van Praet Jens , Lambrecht Bart N. , Van Braeckel Eva , Bosteels Cédric , Hoste Levi , Hoste Eric , Bauters Fré , De Clercq Jozefien , Heijmans Catherine , Slabbynck Hans , Naesens Leslie , Florkin Benoit , Boulanger Cécile , Vanderlinden Dimitri ,   Orchestra Working Group, Abel Laurent , Berkell Matilda , Carelli Valerio , Fiorentino Alessia , Malhotra Surbi , Mattiaccio Alessandro , Pippucci Tommaso , Seri Marco , Tacconelli Evelina ,   Amsterdam UMC Covid-19 Biobank, van Agtmael Michiel , Algera Anne Geke , Appelman Brent , van Baarle Frank , Bax Diane , Beudel Martijn , Bogaard Harm Jan , Bomers Marije , Bonta Peter , Bos Lieuwe , Botta Michela , de Brabander Justin , de Bree Godelieve , de Bruin Sanne , Buis David T. P. , Bugiani Marianna , Bulle Esther , Cloherty Osoul Chouchane Alex , Dijkstra Mirjam , Dongelmans Dave A. , Dujardin Romein W. G. , Elbers Paul , Fleuren Lucas , Geijtenbeek Suzanne Geerlings Theo , Girbes Armand , Goorhuis Bram , Grobusch Martin P. , Hafkamp Florianne , Hagens Laura , Hamann Jorg , Harris Vanessa , Hemke Robert , Heunks Sabine M. Hermans Leo , Hollmann Markus , Horn Janneke , Hovius Joppe W. , de Jong Menno D. , Koning Rutger , Lim Endry H. T. , van Mourik Niels , Nellen Jeaninne , Nossent Esther J. , Paulus Frederique , Peters Edgar , Pina-Fuentes Dan A. I. , van der Poll Tom , Preckel Bennedikt , Prins Jan M. , Raasveld Jorinde , Reijnders Tom , de Rotte Maurits C. F. J. , Schinkel Michiel , Schultz Marcus J. , Schrauwen Femke A. P. , Schuurmans Alex , Schuurmans Jaap , Sigaloff Kim , Slim Marleen A. , Smeele Patrick , Smit Marry , Stijnis Cornelis S. , Stilma Willemke , Teunissen Charlotte , Thoral Patrick , Tsonas Anissa M. , Tuinman Pieter R. , van der Valk Marc , Veelo Denise , Volleman Carolien , de Vries Heder , Vught Lonneke A. , van Vugt Michèle , Wouters Dorien , Zwinderman A. H. , Brouwer Matthijs C. , Wiersinga W. Joost , Vlaar Alexander P. J. , van de Beek Diederik ,   NIAID-USUHS COVID Study Group, Tompkins Miranda F. , Alba Camille , Snow Andrew L. , Hupalo Daniel N. , Rosenberger John , Sukumar Gauthaman , Wilkerson Matthew D. , Zhang Xijun , Lack Justin , Oler Andrew J. , Dobbs Kerry , Danielson Jeffrey J. , Biondi Andrea , Bettini Laura Rachele , D’Angio’ Mariella , Beretta Ilaria , Imberti Luisa , Sottini Alessandra , Quaresima Virginia , Quiros-Roldan Eugenia , Rossi Camillo , 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 Aurélie 
Published: April 2023

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.