Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 1522-1534 |
| Number of pages | 13 |
| Journal | The New England Journal of Medicine |
| Volume | 383 |
| Issue number | 16 |
| DOIs | |
| Publication status | Published - 15 Oct 2020 |
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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; Nolla, Anna Carreras; Latiano, Anna; Fracanzani, Anna Ludovica; Peschuck, Anna; Julià, Antonio; Pesenti, Antonio; Voza, Antonio; Jiménez, David; Mateos, Beatriz; Jimenez, Beatriz Nafria; Quereda, Carmen; Paccapelo, Cinzia; Gassner, Christoph; Angelini, Claudio; Cea, Cristina; Solier, Aurora; Pestaña, David; Muñiz-Diaz, Eduardo; Sandoval, Elena; Paraboschi, Elvezia M.; Navas, Enrique; Sánchez, Félix García; 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; Basso, Maria E.Figuera; 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.; Ortiz, Aaron Blandino; 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.
In: The New England Journal of Medicine, Vol. 383, No. 16, 15.10.2020, p. 1522-1534.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Genomewide association study of severe COVID-19 with respiratory failure
AU - Ellinghaus, David
AU - Degenhardt, Frauke
AU - Bujanda, Luis
AU - Buti, Maria
AU - Albillos, Agustín
AU - Invernizzi, Pietro
AU - Fernández, Javier
AU - Prati, Daniele
AU - Baselli, Guido
AU - Asselta, Rosanna
AU - Grimsrud, Marit M.
AU - Milani, Chiara
AU - Aziz, Fátima
AU - Kässens, Jan
AU - May, Sandra
AU - Wendorff, Mareike
AU - Wienbrandt, Lars
AU - Uellendahl-Werth, Florian
AU - Zheng, Tenghao
AU - Yi, Xiaoli
AU - de Pablo, Raúl
AU - Chercoles, Adolfo G.
AU - Palom, Adriana
AU - Garcia-Fernandez, Alba Estela
AU - Rodriguez-Frias, Francisco
AU - Zanella, Alberto
AU - Bandera, Alessandra
AU - Protti, Alessandro
AU - Aghemo, Alessio
AU - Lleo, Ana
AU - Biondi, Andrea
AU - Caballero-Garralda, Andrea
AU - Gori, Andrea
AU - Tanck, Anja
AU - Nolla, Anna Carreras
AU - Latiano, Anna
AU - Fracanzani, Anna Ludovica
AU - Peschuck, Anna
AU - Julià, Antonio
AU - Pesenti, Antonio
AU - Voza, Antonio
AU - Jiménez, David
AU - Mateos, Beatriz
AU - Jimenez, Beatriz Nafria
AU - Quereda, Carmen
AU - Paccapelo, Cinzia
AU - Gassner, Christoph
AU - Angelini, Claudio
AU - Cea, Cristina
AU - Solier, Aurora
AU - Pestaña, David
AU - Muñiz-Diaz, Eduardo
AU - Sandoval, Elena
AU - Paraboschi, Elvezia M.
AU - Navas, Enrique
AU - Sánchez, Félix García
AU - Ceriotti, Ferruccio
AU - Martinelli-Boneschi, Filippo
AU - Peyvandi, Flora
AU - Blasi, Francesco
AU - Téllez, Luis
AU - Blanco-Grau, Albert
AU - Hemmrich-Stanisak, Georg
AU - Grasselli, Giacomo
AU - Costantino, Giorgio
AU - Cardamone, Giulia
AU - Foti, Giuseppe
AU - Aneli, Serena
AU - Kurihara, Hayato
AU - ElAbd, Hesham
AU - My, Ilaria
AU - Galván-Femenia, Iván
AU - Martín, Javier
AU - Erdmann, Jeanette
AU - Ferrusquía-Acosta, Jose
AU - Garcia-Etxebarria, Koldo
AU - Izquierdo-Sanchez, Laura
AU - Bettini, Laura R.
AU - Sumoy, Lauro
AU - Terranova, Leonardo
AU - Moreira, Leticia
AU - Santoro, Luigi
AU - Scudeller, Luigia
AU - Mesonero, Francisco
AU - Roade, Luisa
AU - Rühlemann, Malte C.
AU - Schaefer, Marco
AU - Carrabba, Maria
AU - Riveiro-Barciela, Mar
AU - Basso, Maria E.Figuera
AU - Valsecchi, Maria G.
AU - Hernandez-Tejero, María
AU - Acosta-Herrera, Marialbert
AU - D'Angiò, Mariella
AU - Baldini, Marina
AU - Cazzaniga, Marina
AU - Schulzky, Martin
AU - Cecconi, Maurizio
AU - Wittig, Michael
AU - Ciccarelli, Michele
AU - Rodríguez-Gandía, Miguel
AU - Bocciolone, Monica
AU - Miozzo, Monica
AU - Montano, Nicola
AU - Braun, Nicole
AU - Sacchi, Nicoletta
AU - Martínez, Nilda
AU - Özer, Onur
AU - Palmieri, Orazio
AU - Faverio, Paola
AU - Preatoni, Paoletta
AU - Bonfanti, Paolo
AU - Omodei, Paolo
AU - Tentorio, Paolo
AU - Castro, Pedro
AU - Rodrigues, Pedro M.
AU - Ortiz, Aaron Blandino
AU - de Cid, Rafael
AU - Ferrer, Ricard
AU - Gualtierotti, Roberta
AU - Nieto, Rosa
AU - Goerg, Siegfried
AU - Badalamenti, Salvatore
AU - Marsal, Sara
AU - Matullo, Giuseppe
AU - Pelusi, Serena
AU - Juzenas, Simonas
AU - Aliberti, Stefano
AU - Monzani, Valter
AU - Moreno, Victor
AU - Wesse, Tanja
AU - Lenz, Tobias L.
AU - Pumarola, Tomas
AU - Rimoldi, Valeria
AU - Bosari, Silvano
AU - Albrecht, Wolfgang
AU - Peter, Wolfgang
AU - Romero-Gómez, Manuel
AU - D'Amato, Mauro
AU - Duga, Stefano
AU - Banales, Jesus M.
AU - Hov, Johannes R.
AU - Folseraas, Trine
AU - Valenti, Luca
AU - Franke, Andre
AU - Karlsen, Tom H.
PY - 2020/10/15
Y1 - 2020/10/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85087699779&partnerID=8YFLogxK
U2 - 10.1056/NEJMoa2020283
DO - 10.1056/NEJMoa2020283
M3 - Article
C2 - 32558485
AN - SCOPUS:85087699779
VL - 383
SP - 1522
EP - 1534
JO - The New England Journal of Medicine
JF - The New England Journal of Medicine
SN - 0028-4793
IS - 16
ER -