[en] Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2-4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.
Disciplines :
Genetics & genetic processes
Author, co-author :
Kousathanas, Athanasios ; Genomics England, London, UK
Pairo-Castineira, Erola ; Roslin Institute, University of Edinburgh, Edinburgh, UK ; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK
Rawlik, Konrad ; Roslin Institute, University of Edinburgh, Edinburgh, UK
Stuckey, Alex; Genomics England, London, UK
Odhams, Christopher A; Genomics England, London, UK
Walker, Susan ; Genomics England, London, UK
Russell, Clark D; Roslin Institute, University of Edinburgh, Edinburgh, UK ; Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
Malinauskas, Tomas ; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
Wu, Yang ; Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
Millar, Jonathan; Roslin Institute, University of Edinburgh, Edinburgh, UK
Shen, Xia ; Biostatistics Group, Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Guangzhou, China ; Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, Edinburgh, UK
Elliott, Katherine S ; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
Griffiths, Fiona; Roslin Institute, University of Edinburgh, Edinburgh, UK
Oosthuyzen, Wilna; Roslin Institute, University of Edinburgh, Edinburgh, UK
Morrice, Kirstie; Edinburgh Clinical Research Facility, Western General Hospital, University of Edinburgh, Edinburgh, UK
Keating, Sean ; Intensive Care Unit, Royal Infirmary of Edinburgh, Edinburgh, UK
Wang, Bo ; Roslin Institute, University of Edinburgh, Edinburgh, UK
Rhodes, Daniel; Genomics England, London, UK
Klaric, Lucija ; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK
Zechner, Marie; Roslin Institute, University of Edinburgh, Edinburgh, UK
Parkinson, Nick ; Roslin Institute, University of Edinburgh, Edinburgh, UK
Siddiq, Afshan; Genomics England, London, UK
Goddard, Peter; Genomics England, London, UK
Donovan, Sally; Genomics England, London, UK
Maslove, David; Department of Critical Care Medicine, Queen's University and Kingston Health Sciences Centre, Kingston, Ontario, Canada
Nichol, Alistair ; Clinical Research Centre at St Vincent's University Hospital, University College Dublin, Dublin, Ireland
Semple, Malcolm G ; NIHR Health Protection Research Unit for Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK ; Respiratory Medicine and Institute in the Park, Alder Hey Children's Hospital and University of Liverpool, Liverpool, UK
Zainy, Tala; Genomics England, London, UK
Maleady-Crowe, Fiona; Genomics England, London, UK
Todd, Linda; Genomics England, London, UK
Salehi, Shahla ; Genomics England, London, UK
Knight, Julian ; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
Elgar, Greg ; Genomics England, London, UK
Chan, Georgia; Genomics England, London, UK
Arumugam, Prabhu; Genomics England, London, UK
Patch, Christine ; Genomics England, London, UK
Rendon, Augusto; Genomics England, London, UK
Bentley, David; Illumina Cambridge, Great Abington, UK
Kingsley, Clare; Illumina Cambridge, Great Abington, UK
Kosmicki, Jack A; Regeneron Genetics Center, Tarrytown, NY, USA
Horowitz, Julie E; Regeneron Genetics Center, Tarrytown, NY, USA
Baras, Aris ; Regeneron Genetics Center, Tarrytown, NY, USA
Abecasis, Goncalo R ; Regeneron Genetics Center, Tarrytown, NY, USA
Ferreira, Manuel A R ; Regeneron Genetics Center, Tarrytown, NY, USA
Justice, Anne; Geisinger, Danville, PA, USA
Mirshahi, Tooraj; Geisinger, Danville, PA, USA
Oetjens, Matthew; Geisinger, Danville, PA, USA
Rader, Daniel J ; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Ritchie, Marylyn D ; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Verma, Anurag; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Fowler, Tom A; Genomics England, London, UK ; Test and Trace, the Health Security Agency, Department of Health and Social Care, London, UK
Shankar-Hari, Manu ; Department of Intensive Care Medicine, Guy's and St Thomas' NHS Foundation Trust, London, UK
Summers, Charlotte ; Department of Medicine, University of Cambridge, Cambridge, UK
Hinds, Charles ; William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
Horby, Peter; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK
Ling, Lowell; Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
McAuley, Danny ; Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK ; Department of Intensive Care Medicine, Royal Victoria Hospital, Belfast, UK
Montgomery, Hugh ; UCL Centre for Human Health and Performance, London, UK
Openshaw, Peter J M; National Heart and Lung Institute, Imperial College London, London, UK ; Imperial College Healthcare NHS Trust: London, London, UK
Elliott, Paul ; Imperial College, London, UK
Walsh, Timothy; Intensive Care Unit, Royal Infirmary of Edinburgh, Edinburgh, UK
Tenesa, Albert ; Roslin Institute, University of Edinburgh, Edinburgh, UK ; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK ; Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, Edinburgh, UK
GenOMICC investigators
23andMe investigators
COVID-19 Human Genetics Initiative
Fawkes, Angie; Edinburgh Clinical Research Facility, Western General Hospital, University of Edinburgh, Edinburgh, UK
Murphy, Lee ; Edinburgh Clinical Research Facility, Western General Hospital, University of Edinburgh, Edinburgh, UK
Rowan, Kathy ; Intensive Care National Audit and Research Centre, London, UK
Ponting, Chris P ; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK
Vitart, Veronique ; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK
Wilson, James F ; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK ; Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, Edinburgh, UK
Yang, Jian ; School of Life Sciences, Westlake University, Hangzhou, China ; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
Bretherick, Andrew D ; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK
Scott, Richard H; Genomics England, London, UK ; Great Ormond Street Hospital, London, UK
Hendry, Sara Clohisey ; Roslin Institute, University of Edinburgh, Edinburgh, UK
Moutsianas, Loukas ; Genomics England, London, UK
Law, Andy ; Roslin Institute, University of Edinburgh, Edinburgh, UK
Caulfield, Mark J ; Genomics England, London, UK. m.j.caulfield@qmul.ac.uk ; William Harvey Research Institute, Queen Mary University of London, London, UK. m.j.caulfield@qmul.ac.uk
Baillie, J Kenneth ; Roslin Institute, University of Edinburgh, Edinburgh, UK. j.k.baillie@ed.ac.uk ; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK. j.k.baillie@ed.ac.uk ; Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK. j.k.baillie@ed.ac.uk ; Intensive Care Unit, Royal Infirmary of Edinburgh, Edinburgh, UK. j.k.baillie@ed.ac.uk
Rahmouni, Souad ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques
DARCIS, Gilles ; Centre Hospitalier Universitaire de Liège - CHU > > Service des maladies infectieuses - médecine interne ; Université de Liège - ULiège > Département des sciences cliniques
LAMBERMONT, Bernard ; Centre Hospitalier Universitaire de Liège - CHU > Frais communs médecine - Pool assistants
