The ABO blood group locus and a chromosome 3 gene cluster associate with SARS-CoV-2 respiratory failure in an Italian-Spanish genome-wide association analysis

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=1.14×10−10 and OR 1.32 (95% CI, 1.20 to 1.47; P=4.95×10−8), respectively. Among six genes at 3p21.31, SLC6A20 encodes a known interaction partner with angiotensin converting enzyme 2 (ACE2). The association signal at 9q34 was located at the ABO blood 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The IKMB's core facilities received infrastructure support by the Deutsche Forschungsgemeinschaft (DFG) Cluster of Excellence "Precision Medicine in Chronic Inflammation" (PMI, EXC2167). The project also received support through a philanthropic donation by Stein Erik Hagen and Canica AS. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The following ethical approvals of the project were obtained from the relevant ethics committees: Germany: Kiel (reference number D464/20); Italy: Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico (reference number 342_2020 and 334-2020 for cases and controls, respectively), Humanitas Clinical and Research Center, IRCCS (reference number 316/20), San Gerardo Hospital School of Medicine, Monza (the ethics committee of the National Institute of Infectious Diseases Lazzarro Spallanzani reference number 84/2020); Norway: Regional Committee for Medical and Health Research Ethics in South-Eastern Norway (reference number 132550); Spain: Hospital Clinic and IDIBAPS, Barcelona (reference number HCB/2020/0405), Hospital Universitario Vall d'Hebron, Barcelona (reference PR[AG]244/2020), Hospital Universitario Ramon y Cajal, Madrid (reference number 093/20), Donostia University Hospital, San Sebastian (reference number PI2020064). All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Summary statistics will be made available upon request and after signing of appropriate institutional data transfer agreements, after acceptance of the peer-reviewed manuscript.