Tomoko Nakanishi1,2,3,4,5, Sara Pigazzini1,6, Frauke Degenhardt7,8, Mattia Cordioli1, Guillaume Butler-Laporte3,9, Douglas Maya-Miles10,11, Beatriz Nafría-Jiménez12, Youssef Bouysran13, Mari Niemi1, Adriana Palom14,15,16, David Ellinghaus7,17, Atlas Khan18, Manuel Martínez-Bueno19, Selina Rolker20, Sara Amitano21, Luisa Roade Tato11,14,15, Francesca Fava21,22,23, Christoph D Spinner24, Daniele Prati25, David Bernardo11,26, Federico Garcia27,28, Gilles Darcis29,30, Israel Fernández-Cadenas31, Jan Cato Holter32,33, Jesus Banales34, Robert Frithiof35, Krzysztof Kiryluk18, Stefano Duga36,37, Rosanna Asselta36,37, Alexandre C Pereira38, Manuel Romero-Gómez10,11, Luis Bujanda34, Johannes R Hov33,39,40, Isabelle Migeotte13,41, Alessandra Renieri21,22,23, Anna M Planas42,43, Kerstin U Ludwig20, Maria Buti11,14,15, Souad Rahmouni29, Marta E Alarcón-Riquelme19,44, Eva C Schulte45,46,47, Andre Franke7,8, Tom H Karlsen33,39,40, Luca Valenti48,49, Hugo Zeberg50,51, J Brent Richards2,3,9,52, Andrea Ganna1,53. 1. Institute for Molecular Medicine Finland, Univerisity of Helsinki, Helsinki, Finland. 2. Department of Human Genetics, McGill University, Montréal, Québec, Canada. 3. Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada. 4. Kyoto-McGill International Collaborative School in Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan. 5. Research Fellow, Japan Society for the Promotion of Science, Tokyo, Japan. 6. University of Milano-Bicocca, Milano, Italy. 7. Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany. 8. University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. 9. Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal, Québec, Canada. 10. Digestive Diseases Unit, Virgen del Rocio University Hospital, Institute of Biomedicine of Seville, University of Seville, Seville, Spain. 11. Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. 12. Osakidetza Basque Health Service, Donostialdea Integrated Health Organisation. Clinical Biochemistry Department, Sebastian, Spain. 13. Centre de Génétique Humaine, Hopital Erasme, Université Libre de Bruxelles, Brussels, Belgium. 14. Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain. 15. Universitat Autònoma de Barcelona. Departament de Medicina.Bellatera, Barcelona, Spain. 16. Vall d'Hebron Institut de Recerca (VHIR). Liver Diseases. 17. Novo Nordisk Foundation Center for Protein Research, Disease Systems Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen. 18. Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY. 19. GENYO. Centre for Genomics and Oncological Research: Pfizer / University of Granada / Andalusian Regional Government, Granada, Spain. 20. Institute of Human Genetics, University Hospital Bonn, Medical Faculty University of Bonn, Bonn, Germany. 21. Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Italy. 22. Medical Genetics, University of Siena, Italy. 23. Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy. 24. Technical University of Munich, School of Medicine, University Hospital rechts der Isar, Department of Internal Medicine II, Munich, Germany. 25. Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milano, Italy. 26. Mucosal Immunology Lab, Institute of Biomedicine and Molecular Genetics (IBGM), University of Valladolid-CSIC. Valladolid, Spain. 27. Hospital Universitario Clinico San Cecilio, Granada, Spain. 28. Instituto de Investigación Ibs.Granada. Granada, Spain. 29. University of Liege, GIGA-Insitute, Liege, Belgium. 30. Liege University Hospital (CHU of Liege), Liege, Belgium. 31. Stroke Pharmacogenomics and Genetics Group, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain. 32. Department of Microbiology, Oslo University Hospital, Oslo, Norway. 33. Institute of Clinical Medicine, University of Oslo, Oslo, Norway. 34. Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), CIBERehd, Ikerbasque, San Sebastian, Spain. 35. Department of Surgical Sciences, Anaesthesiology and Intensive Care Medicine, Uppsala University, Uppsala, Sweden. 36. Department of Biomedical Sciences, Humanitas University, Milan, Italy. 37. IRCCS Humanitas Research Hospital, Milan, Italy. 38. Heart Institute (InCor)/Univ São Paulo Med Sch, São Paulo, Brazil. 39. Norwegian PSC Research Center and Section of Gastroenterology, Dept Transplantation Medicine, Oslo University Hospital, Oslo, Norway. 40. Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway. 41. Fonds de la Recherche Scientifique (FNRS), Brussels, Belgium. 42. Institute for Biomedical Researhc of Barcelona (IIBB), National Spanish Research Council (CSIC), Barcelona, Spain. 43. Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. 44. Institute for Environmental Medicine, Karolinska Institutet, 17167, Solna, Sweden. 45. Institute of Virology, Technical University Munich/Helmholtz Zentrum München, Munich, Germany. 46. Institute of Psychiatric Phenomics and Genomics, University Hospital, LMU Munich University, Munich, Germany. 47. Department of Psychiatry, University Hospital, LMU Munich University, Munich, Germany. 48. Department of Pathopgysiology and Transplantation, Università degli Studi di Milano, Milano, Italy. 49. Department of Transfusion Medicine and Hematology, Precision Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy. 50. Department of Neuroscience, Karolinska Institutet, Sweden. 51. Max-Planck Institute for Evolutionary Anthropology, Leipzig, Germany. 52. Department of Twin Research, King's College London, London, United Kingdom. 53. Massachusetts General Hospital, Harvard Medical School.
Abstract
BACKGROUND: There is considerable variability in COVID-19 outcomes amongst younger adults-and some of this variation may be due to genetic predisposition. We characterized the clinical implications of the major genetic risk factor for COVID-19 severity, and its age-dependent effect, using individual-level data in a large international multi-centre consortium. METHOD: The major common COVID-19 genetic risk factor is a chromosome 3 locus, tagged by the marker rs10490770. We combined individual level data for 13,424 COVID-19 positive patients (N=6,689 hospitalized) from 17 cohorts in nine countries to assess the association of this genetic marker with mortality, COVID-19-related complications and laboratory values. We next examined if the magnitude of these associations varied by age and were independent from known clinical COVID-19 risk factors. FINDINGS: We found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (hazard ratio [HR] 1·4, 95% confidence interval [CI] 1·2-1·6) and COVID-19 related mortality (HR 1·5, 95%CI 1·3-1·8). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (odds ratio [OR] 2·0, 95%CI 1·6-2·6), venous thromboembolism (OR 1·7, 95%CI 1·2-2·4), and hepatic injury (OR 1·6, 95%CI 1·2-2·0). Risk allele carriers ≤ 60 years had higher odds of death or severe respiratory failure (OR 2·6, 95%CI 1·8-3·9) compared to those > 60 years OR 1·5 (95%CI 1·3-1·9, interaction p-value=0·04). Amongst individuals ≤ 60 years who died or experienced severe respiratory COVID-19 outcome, we found that 31·8% (95%CI 27·6-36·2) were risk variant carriers, compared to 13·9% (95%CI 12·6-15·2%) of those not experiencing these outcomes. Prediction of death or severe respiratory failure among those ≤ 60 years improved when including the risk allele (AUC 0·82 vs 0·84, p=0·016) and the prediction ability of rs10490770 risk allele was similar to, or better than, most established clinical risk factors. INTERPRETATION: The major common COVID-19 risk locus on chromosome 3 is associated with increased risks of morbidity and mortality-and these are more pronounced amongst individuals ≤ 60 years. The effect on COVID-19 severity was similar to, or larger than most established risk factors, suggesting potential implications for clinical risk management. FUNDING: Funding was obtained by each of the participating cohorts individually.
BACKGROUND: There is considerable variability in COVID-19 outcomes amongst younger adults-and some of this variation may be due to genetic predisposition. We characterized the clinical implications of the major genetic risk factor for COVID-19 severity, and its age-dependent effect, using individual-level data in a large international multi-centre consortium. METHOD: The major common COVID-19 genetic risk factor is a chromosome 3 locus, tagged by the marker rs10490770. We combined individual level data for 13,424 COVID-19 positive patients (N=6,689 hospitalized) from 17 cohorts in nine countries to assess the association of this genetic marker with mortality, COVID-19-related complications and laboratory values. We next examined if the magnitude of these associations varied by age and were independent from known clinical COVID-19 risk factors. FINDINGS: We found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (hazard ratio [HR] 1·4, 95% confidence interval [CI] 1·2-1·6) and COVID-19 related mortality (HR 1·5, 95%CI 1·3-1·8). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (odds ratio [OR] 2·0, 95%CI 1·6-2·6), venous thromboembolism (OR 1·7, 95%CI 1·2-2·4), and hepatic injury (OR 1·6, 95%CI 1·2-2·0). Risk allele carriers ≤ 60 years had higher odds of death or severe respiratory failure (OR 2·6, 95%CI 1·8-3·9) compared to those > 60 years OR 1·5 (95%CI 1·3-1·9, interaction p-value=0·04). Amongst individuals ≤ 60 years who died or experienced severe respiratory COVID-19 outcome, we found that 31·8% (95%CI 27·6-36·2) were risk variant carriers, compared to 13·9% (95%CI 12·6-15·2%) of those not experiencing these outcomes. Prediction of death or severe respiratory failure among those ≤ 60 years improved when including the risk allele (AUC 0·82 vs 0·84, p=0·016) and the prediction ability of rs10490770 risk allele was similar to, or better than, most established clinical risk factors. INTERPRETATION: The major common COVID-19 risk locus on chromosome 3 is associated with increased risks of morbidity and mortality-and these are more pronounced amongst individuals ≤ 60 years. The effect on COVID-19 severity was similar to, or larger than most established risk factors, suggesting potential implications for clinical risk management. FUNDING: Funding was obtained by each of the participating cohorts individually.
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