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New susceptibility loci for severe COVID-19 by detailed GWAS analysis in European populations

By Frauke Degenhardt, David Ellinghaus, Simonas Juzenas, Jon Lerga-Jaso, Mareike Wendorff, Douglas Maya-Miles, Florian Uellendahl-Werth, Hesham ElAbd, Malte C Ruhlemann, Jatin Arora, Onur Oezer, Ole Bernt Lenning, Ronny Myhre, May Sissel Vadla, Eike Matthias Wacker, Lars Wienbrandt, Aaron Blandino Ortiz, Adolfo de Salazar, Adolfo Garrido Chercoles, Adriana Palom, Agustin Ruiz, Alba-Estela Garcia-Fernandez, Albert Blanco-Grau, Alberto Mantovani, Alberto Zanella, Aleksander Rygh Holten, Alena Mayer, Alessandra Bandera, Alessandro Cherubini, Alessandro Protti, Alessio Aghemo, Alessio Gerussi, Alfredo Ramirez, Alice Braun, Almut Nebel, Ana Barreira, Ana Lleo, Ana Teles, Anders Kildal, Andrea Biondi, Andrea Caballero-Garralda, andrea ganna, Andrea Gori, Andreas Glueck, Andreas Lind, Anja Tanck, Anke Hinney, Anna Carreras Carreras Nolla, Anna Ludovica Fracanzani, Anna Peschuck, Annalisa Cavallero, Anne Ma Dyrhol-Riise, Antonella Ruello, Antonio Julia, Antonio Muscatello, Antonio Pesenti, Antonio Voza, Ariadna Rando-Segura, Aurora Solier, Axel Schmidt, Beatriz Cortes, Beatriz Mateos, Beatriz Nafria-Jimenez, Benedikt Schaefer, Bjoern Jensen, Carla Bellinghausen, Carlo Maj, Carlos Ferrando, Carmen de la Horra, Carmen Quereda, Carsten Skurk, Charlotte Thiebeault, Chiara Scollo, Christian Herr, Christoph D. Spinner, Christoph Gassner, Christoph Lange, Cinzia Hu, Cinzia Paccapelo, Clara Lehmann, Claudio Angelini, Claudio Cappadona, Clinton Azuure, Cristiana Bianco, Cristina Cea, Cristina Sancho, Dag Arne Lihaug Hoff, Daniela Galimberti, Daniele Prati, David Haschka, David Sebastian Jimenez, David Pestana, David Toapanta, Eduardo Muniz-Diaz, Elena Azzolini, Elena Sandoval, Eleonora Binatti, Elio Scarpini, Elisa T. Helbig, Elisabetta Casalone, Eloisa Urrechaga, Elvezia Maria Paraboschi, Emanuele Pontali, Enric Reverter, Enrique J. Calderon, Enrique Navas, Erik Solligaard, Ernesto Contro, Eunate Arana-Arri, Fatima Aziz, Federico Garcia, Felix Garcia Sanchez, Ferruccio Ceriotti, Filippo Martinelli-Boneschi, Flora Peyvandi, Florian Kurth, Francesco Blasi, Francesco Malvestiti, Francisco J. Medrano, Francisco Mesonero, Francisco Rodriguez-Frias, Frank Hanses, Fredrik Mueller, Georg Hemmrich-Stanisak, Giacomo Bellani, Giacomo Grasselli, Gianni Pezzoli, Giorgio Costantino, Giovanni Albano, Giulia Cardamone, Giuseppe Bellelli, Giuseppe Citerio, Giuseppe Foti, Giuseppe Lamorte, Giuseppe Matullo, Guido Baselli, Hayato Kurihara, Holger Neb, Ilaria My, Ingo Kurth, Isabel Hernandez, Isabell Pink, Itziar de Rojas, Ivan Galvan-Femenia, Jan Cato Holter, Jan Egil Afset, Jan Heyckendorf, Jan Kaessens, Jan Kristian Damaas, Jan Rybniker, Janine Altmüller, Javier Ampuero, Javier Martin, Jeanette Erdmann, Jesus M Banales, Joan Ramon Badia, Joaquin Dopazo, Jochen Schneider, Jonas Bergan, Jordi Barretina, Joern Walter, Jose Hernandez Quero, Josune Goikoetxea, Juan Delgado, Juan M. Guerrero, Julia Fazaal, Julia Kraft, Julia Schroeder, Kari Risnes, Karina Banasik, Karl Erik Mueller, Karoline I. Gaede, Koldo Garcia-Etxebarria, Kristian Tonby, Lars Heggelund, Laura Izquierdo-Sanchez, Laura Rachele Bettini, Lauro Sumoy, Leif E. Sander, Lena J. Lippert, Leonardo Terranova, Lindokuhle Nkambule, Lisa Knopp, Lise Tuset Gustad, Lucia Garbarino, Luigi Santoro, Luis Tellez, Luisa Roade, Mahnoosh Ostadreza, Maider Intxausti, Manolis Kogevinas, Mar Riveiro-Barciela, Marc M. Berger, Marco Schaefer, Mari E.K. Niemi, Maria A. Gutierrez-Stampa, Maria Carrabba, Maria E Figuera Basso, Maria Grazia Valsecchi, Maria Hernandez-Tejero, Maria J.G.T. Vehreschild, Maria Manunta, Marialbert Acosta-Herrera, Mariella D'Angio, Marina Baldini, Marina Cazzaniga, Marit M. Grimsrud, Markus Cornberg, Markus M. Noethen, Marta Marquie, Massimo Castoldi, Mattia Cordioli, Maurizio Cecconi, Mauro D'Amato, Max Augustin, Melissa Tomasi, Merce Boada, Michael Dreher, Michael J. Seilmaier, Michael Joannidis, Michael Wittig, Michela Mazzocco, Michele Ciccarelli, Miguel Rodriguez-Gandia, Monica Bocciolone, Monica Miozzo, Natale Imaz-Ayo, Natalia Blay, Natalia Chueca, Nicola Montano, Nicole Braun, Nicole Ludwig, Nikolaus Marx, Nilda Martinez, Oliver Andreas Cornely, Oliver Witzke, Orazio Palmieri, Paola Faverio, Paoletta Preatoni, Paolo Bonfanti, Paolo Omodei, Paolo Tentorio, Pedro Castro, Pedro M. Rodrigues, Pedro Pablo Espana, Per Hoffmann, Philip Rosenstiel, Philipp Schommers, Phillip Suwalski, Raul de Pablo, Ricard Ferrer, Robert Bals, Roberta Gualtierotti, Rocio Gallego-Duran, Rosa Nieto, Rossana Carpani, Ruben Morilla, Salvatore Badalamenti, Sammra Haider, Sandra Ciesek, Sandra May, Sara Bombace, Sara Marsal, Sara Pigazzini, Sebastian Klein, Serena Pelusi, Sibylle Wilfling, Silvano Bosari, Sonja Volland, Soren Brunak, Soumya Raychaudhuri, Stefan Schreiber, Stefanie Heilmann-Heimbach, Stefano Aliberti, Stephan Ripke, Susanne Dudman, Tanja Wesse, Tenghao Zheng, Thomas Bahmer, Thomas Eggermann, Thomas Illig, Thorsten Brenner, Tomas Pumarola, Torsten Feldt, Trine Folseraas, Trinidad Gonzalez Cejudo, Ulf Landmesser, Ulrike A. Protzer, Ute Hehr, Valeria Rimoldi, Valter Monzani, Vegard Skogen, Verena Keitel, Verena Kopfnagel, Vicente Friaza, Victor Andrade, Victor J Moreno, Wolfgang Albrecht, Wolfgang Peter, Wolfgang Poller, Xavier Farre, Xiaoli Yi, Xiaomin Wang, Yascha Khodamoradi, Zehra Karadeniz, Anna Latiano, Siegfried Goerg, Petra Bacher, Philipp Koehler, Florian Tran, Heinz Zoller, Eva C Schulte, Bettina Heidecker, Kerstin U Ludwig, Javier Fernandez, Manuel Romero-Gomez, Agustin Albillos, Pietro Invernizzi, Maria Buti, Stefano Duga, Luis Bujanda, Johannes R. Hov, Tobias L. Lenz, Rosanna Asselta, Rafael de Cid, Luca Valenti, Tom Hemming Karlsen, Mario Caceres, Andre Franke, COVICAT study group, Covid-19 Aachen Study (COVAS), Pa COVID-19 Study Group, The Humanitas COVID-19 Task Force, The Humanitas Gavazzeni COVID-19 Task Force, Norwegian SARS-CoV-2 Study group

Posted 23 Jul 2021
medRxiv DOI: 10.1101/2021.07.21.21260624

Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of a well-characterized cohort of 3,260 COVID-19 patients with respiratory failure and 12,483 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen (HLA) region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a highly pleiotropic ~0.9-Mb inversion polymorphism and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.

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