Genomewide Association Study of Severe Covid-19 with Respiratory Failure

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

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.)