Genomewide Association Study of Severe Covid-19 with Respiratory Failure

There is considerable variation in disease behavior among patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19). Genomewide association analysis may allow for the identification of potential genetic factors involved in the development of Covid-19.

2020-06-17

Ellinghaus, David, Frauke Degenhardt, Luis Bujanda, Maria Buti, Agustín Albillos, Pietro Invernizzi, Javier Fernández, Daniele Prati, Guido Baselli, Rosanna Asselta, Marit M. Grimsrud, Chiara Milani, Fátima Aziz, Jan Kässens, Sandra May, Mareike Wendorff, Lars Wienbrandt, Florian Uellendahl-Werth, Tenghao Zheng, Xiaoli Yi, Raúl de Pablo, Adolfo G. Chercoles, Adriana Palom, Alba-Estela Garcia-Fernandez, Francisco Rodriguez-Frias, Alberto Zanella, Alessandra Bandera, Alessandro Protti, Alessio Aghemo, Ana Lleo, Andrea Biondi, Andrea Caballero-Garralda, Andrea Gori, Anja Tanck, Anna Carreras Nolla, Anna Latiano, Anna Ludovica Fracanzani, Anna Peschuck, Antonio Julià, Antonio Pesenti, Antonio Voza, David Jiménez, Beatriz Mateos, Beatriz Nafria Jimenez, Carmen Quereda, Cinzia Paccapelo, Christoph Gassner, Claudio Angelini, Cristina Cea, Aurora Solier, David Pestaña, Eduardo Muñiz-Diaz, Elena Sandoval, Elvezia M. Paraboschi, Enrique Navas, Félix García Sánchez, Ferruccio Ceriotti, Filippo Martinelli-Boneschi, Flora Peyvandi, Francesco Blasi, Luis Téllez, Albert Blanco-Grau, Georg Hemmrich-Stanisak, Giacomo Grasselli, Giorgio Costantino, Giulia Cardamone, Giuseppe Foti, Serena Aneli, Hayato Kurihara, Hesham ElAbd, Ilaria My, Iván Galván-Femenia, Javier Martín, Jeanette Erdmann, Jose Ferrusquía-Acosta, Koldo Garcia-Etxebarria, Laura Izquierdo-Sanchez, Laura R. Bettini, Lauro Sumoy, Leonardo Terranova, Leticia Moreira, Luigi Santoro, Luigia Scudeller, Francisco Mesonero, Luisa Roade, Malte C. Rühlemann, Marco Schaefer, Maria Carrabba, Mar Riveiro-Barciela, Maria E. Figuera Basso, Maria G. Valsecchi, María Hernandez-Tejero, Marialbert Acosta-Herrera, Mariella D’Angiò, Marina Baldini, Marina Cazzaniga, Martin Schulzky, Maurizio Cecconi, Michael Wittig, Michele Ciccarelli, Miguel Rodríguez-Gandía, Monica Bocciolone, Monica Miozzo, Nicola Montano, Nicole Braun, Nicoletta Sacchi, Nilda Martínez, Onur Özer, Orazio Palmieri, Paola Faverio, Paoletta Preatoni, Paolo Bonfanti, Paolo Omodei, Paolo Tentorio, Pedro Castro, Pedro M. Rodrigues, Aaron Blandino Ortiz, Rafael de Cid, Ricard Ferrer, Roberta Gualtierotti, Rosa Nieto, Siegfried Goerg, Salvatore Badalamenti, Sara Marsal, Giuseppe Matullo, Serena Pelusi, Simonas Juzenas, Stefano Aliberti, Valter Monzani, Victor Moreno, Tanja Wesse, Tobias L. Lenz, Tomas Pumarola, Valeria Rimoldi, Silvano Bosari, Wolfgang Albrecht, Wolfgang Peter, Manuel Romero-Gómez, Mauro D’Amato, Stefano Duga, Jesus M. Banales, Johannes R. Hov, Trine Folseraas, Luca Valenti, Andre Franke, and Tom H. Karlsen. 2020. "Genomewide Association Study of Severe Covid-19 with Respiratory Failure." New England Journal of Medicine.

Background

There is considerable variation in disease behavior among patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19). Genomewide association analysis may allow for the identification of potential genetic factors involved in the development of Covid-19.

Methods

We conducted a genomewide association study involving 1980 patients with Covid-19 and severe disease (defined as respiratory failure) at seven hospitals in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe. After quality control and the exclusion of population outliers, 835 patients and 1255 control participants from Italy and 775 patients and 950 control participants from Spain were included in the final analysis. In total, we analyzed 8,582,968 single-nucleotide polymorphisms and conducted a meta-analysis of the two case–control panels.

Results

We detected cross-replicating associations with rs11385942 at locus 3p21.31 and with rs657152 at locus 9q34.2, which were significant at the genomewide level (P<5×10⁻⁸) in the meta-analysis of the two case–control panels (odds ratio, 1.77; 95% confidence interval [CI], 1.48 to 2.11; P=1.15×10⁻¹⁰; and odds ratio, 1.32; 95% CI, 1.20 to 1.47; P=4.95×10⁻⁸, respectively). At locus 3p21.31, the association signal spanned the genes SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6 and XCR1. The association signal at locus 9q34.2 coincided with the ABO blood group locus; in this cohort, a blood-group–specific analysis showed a higher risk in blood group A than in other blood groups (odds ratio, 1.45; 95% CI, 1.20 to 1.75; P=1.48×10⁻⁴) and a protective effect in blood group O as compared with other blood groups (odds ratio, 0.65; 95% CI, 0.53 to 0.79; P=1.06×10⁻⁵).

Conclusions

We identified a 3p21.31 gene cluster as a genetic susceptibility locus in patients with Covid-19 with respiratory failure and confirmed a potential involvement of the ABO blood-group system. (Funded by Stein Erik Hagen and others.)

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