TheABOblood group locus and a chromosome 3 gene cluster associate with SARS-CoV-2 respiratory failure in an Italian-Spanish genome-wide association analysis
Authors: Ellinghaus David , Degenhardt Frauke , Bujanda Luis , Buti Maria , Albillos Agustín , Invernizzi Pietro , Fernández Javier , Prati Daniele , Baselli Guido , Asselta Rosanna , M Grimsrud Marit , Milani Chiara , Aziz Fátima , Kässens Jan , May Sandra , Wendorff Mareike , Wienbrandt Lars , Uellendahl-Werth Florian , Zheng Tenghao , Yi Xiaoli , Pablo Raúl de , Garrido Chercoles Adolfo ,   Graduate in Chemistry, 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 , Latiano Anna , Ludovica Fracanzani Anna , Peschuk Anna , Julià Antonio , Pesenti Antonio , Voza Antonio , Jiménez David , Mateos Beatriz , Nafria Jimenez Beatriz ,   Graduate in Biotechnology, Quereda Carmen , Angelini Claudio , Cea Cristina , Solier Aurora , Pestaña David , Sandoval Elena , Maria Paraboschi Elvezia , Navas Enrique , Ceriotti Ferruccio , Martinelli-Boneschi Filippo , Peyvandi Flora , Blasi Francesco , Téllez Luis , Blanco-Grau Albert , Grasselli Giacomo , Costantino Giorgio , Cardamone Giulia , Foti Giuseppe , Aneli Serena , Kurihara Hayato , ElAbd Hesham , My Ilaria , Martin Javier , Erdmann Jeanette , Ferrusquía-Acosta José , Garcia-Etxebarria Koldo , Izquierdo-Sanchez Laura ,   Graduate in Biochemistry, MS, Rachele Bettini Laura , Terranova Leonardo , Moreira Leticia , Santoro Luigi , Scudeller Luigia , Mesonero Francisco , Roade Luisa , Schaefer Marco , Carrabba Maria , Mar Riveiro Barciela Maria del , Eloina Figuera Basso Maria , Grazia Valsecchi Maria , 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 , Braun Nicole , Martínez Nilda , Palmieri Orazio , Faverio Paola , Preatoni Paoletta , Bonfanti Paolo , Omodei Paolo , Tentorio Paolo , Castro Pedro , Rodrigues Pedro M. , Blandino Ortiz Aaron , Roca Ricardo Ferrer , Gualtierotti Roberta , Nieto Rosa , Badalamenti Salvatore , Marsal Sara , Matullo Giuseppe , Pelusi Serena , Monzani Valter , Wesse Tanja , Pumarola Tomas , Rimoldi Valeria , Bosari Silvano , Albrecht Wolfgang , Peter Wolfgang , Romero Gómez Manuel , D’Amato Mauro , Duga Stefano , Banales Jesus M. , R Hov Johannes , Folseraas Trine , Valenti Luca , Franke Andre , Karlsen Tom H 
Published: June 2020

Background

Respiratory failure is a key feature of severe Covid-19 and a critical driver of mortality, but for reasons poorly defined affects less than 10% of SARS-CoV-2 infected patients.

Methods

We included 1,980 patients with Covid-19 respiratory failure at seven centers in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe (Milan, Monza, Madrid, San Sebastian and Barcelona) for a genome-wide association analysis. After quality control and exclusion of population outliers, 835 patients and 1,255 population-derived controls from Italy, and 775 patients and 950 controls from Spain were included in the final analysis. In total we analyzed 8,582,968 single-nucleotide polymorphisms (SNPs) and conducted a meta-analysis of both case-control panels.

Results

We detected cross-replicating associations with rs11385942 at chromosome 3p21.31 and rs657152 at 9q34, which were genome-wide significant (P<5×10−8) in the meta-analysis of both study panels, odds ratio [OR], 1.77; 95% confidence interval [CI], 1.48 to 2.11; P=1.14×10−10and OR 1.32 (95% CI, 1.20 to 1.47; P=4.95×10−8), respectively. Among six genes at 3p21.31,SLC6A20encodes a known interaction partner with angiotensin converting enzyme 2 (ACE2). The association signal at 9q34 was located at theABOblood group locus and a blood-group-specific analysis showed higher risk for A-positive individuals (OR=1.45, 95% CI, 1.20 to 1.75, P=1.48×10−4) and a protective effect for blood group O (OR=0.65, 95% CI, 0.53 to 0.79, P=1.06×10−5).

Conclusions

We herein report the first robust genetic susceptibility loci for the development of respiratory failure in Covid-19. Identified variants may help guide targeted exploration of severe Covid-19 pathophysiology.