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Whole-genome sequencing reveals host factors underlying critical COVID-19

Athanasios Kousathanas, Erola Pairo-Castineira, Konrad Rawlik, Alex Stuckey, Christopher A. Odhams, Susan Walker, Clark D. Russell, Tomas Malinauskas, Yang Wu, Jonathan Millar, Xia Shen, Katherine S. Elliott, Fiona Griffiths, Wilna Oosthuyzen, Kirstie Morrice, Sean Keating, Bo Wang, Daniel Rhodes, Lucija Klaric, Marie Zechner, Nick Parkinson, Afshan Siddiq, Peter Goddard, Sally Donovan, David Maslove, Alistair Nichol, Malcolm G. Semple, Tala Zainy, Fiona Maleady-Crowe, Linda Todd, Shahla Salehi, Julian Knight, Greg Elgar, Georgia Chan, Prabhu Arumugam, Christine Patch, Augusto Rendon, David Bentley, Clare Kingsley, Jack A. Kosmicki, Julie E. Horowitz, Aris Baras, Goncalo R. Abecasis, Manuel A. R. Ferreira, Anne Justice, Tooraj Mirshahi, Matthew Oetjens, Daniel J. Rader, Marylyn D. Ritchie, Anurag Verma, Tom A. Fowler, Manu Shankar-Hari, Charlotte Summers, Charles Hinds, Peter Horby, Lowell Ling, Danny McAuley, Hugh Montgomery, Peter J. M. Openshaw, Paul Elliott, Timothy Walsh, Albert Tenesa, Angie Fawkes, Lee Murphy, Kathy Rowan, Chris P. Ponting, Veronique Vitart, James F. Wilson, Jian Yang, Andrew D. Bretherick, Richard H. Scott, Sara Clohisey Hendry, Loukas Moutsianas, Andy Law, Mark J. Caulfield () and J. Kenneth Baillie ()
Additional contact information
Athanasios Kousathanas: Genomics England
Erola Pairo-Castineira: University of Edinburgh
Konrad Rawlik: University of Edinburgh
Alex Stuckey: Genomics England
Christopher A. Odhams: Genomics England
Susan Walker: Genomics England
Clark D. Russell: University of Edinburgh
Tomas Malinauskas: University of Oxford
Yang Wu: The University of Queensland
Jonathan Millar: University of Edinburgh
Xia Shen: Fudan University
Katherine S. Elliott: University of Oxford
Fiona Griffiths: University of Edinburgh
Wilna Oosthuyzen: University of Edinburgh
Kirstie Morrice: Western General Hospital, University of Edinburgh
Sean Keating: Royal Infirmary of Edinburgh
Bo Wang: University of Edinburgh
Daniel Rhodes: Genomics England
Lucija Klaric: University of Edinburgh, Western General Hospital
Marie Zechner: University of Edinburgh
Nick Parkinson: University of Edinburgh
Afshan Siddiq: Genomics England
Peter Goddard: Genomics England
Sally Donovan: Genomics England
David Maslove: Queen’s University and Kingston Health Sciences Centre
Alistair Nichol: University College Dublin
Malcolm G. Semple: University of Liverpool
Tala Zainy: Genomics England
Fiona Maleady-Crowe: Genomics England
Linda Todd: Genomics England
Shahla Salehi: Genomics England
Julian Knight: University of Oxford
Greg Elgar: Genomics England
Georgia Chan: Genomics England
Prabhu Arumugam: Genomics England
Christine Patch: Genomics England
Augusto Rendon: Genomics England
David Bentley: Illumina Cambridge
Clare Kingsley: Illumina Cambridge
Jack A. Kosmicki: Regeneron Genetics Center
Julie E. Horowitz: Regeneron Genetics Center
Aris Baras: Regeneron Genetics Center
Goncalo R. Abecasis: Regeneron Genetics Center
Manuel A. R. Ferreira: Regeneron Genetics Center
Anne Justice: Geisinger
Tooraj Mirshahi: Geisinger
Matthew Oetjens: Geisinger
Daniel J. Rader: University of Pennsylvania
Marylyn D. Ritchie: University of Pennsylvania
Anurag Verma: University of Pennsylvania
Tom A. Fowler: Genomics England
Manu Shankar-Hari: Guy’s and St Thomas’ NHS Foundation Trust
Charlotte Summers: University of Cambridge
Charles Hinds: Queen Mary University of London
Peter Horby: University of Oxford
Lowell Ling: The Chinese University of Hong Kong, Prince of Wales Hospital
Danny McAuley: Queen’s University Belfast
Hugh Montgomery: UCL Centre for Human Health and Performance
Peter J. M. Openshaw: Imperial College London
Paul Elliott: Imperial College
Timothy Walsh: Royal Infirmary of Edinburgh
Albert Tenesa: University of Edinburgh
Angie Fawkes: Western General Hospital, University of Edinburgh
Lee Murphy: Western General Hospital, University of Edinburgh
Kathy Rowan: Intensive Care National Audit and Research Centre
Chris P. Ponting: University of Edinburgh, Western General Hospital
Veronique Vitart: University of Edinburgh, Western General Hospital
James F. Wilson: University of Edinburgh, Western General Hospital
Jian Yang: Westlake University
Andrew D. Bretherick: University of Edinburgh, Western General Hospital
Richard H. Scott: Genomics England
Sara Clohisey Hendry: University of Edinburgh
Loukas Moutsianas: Genomics England
Andy Law: University of Edinburgh
Mark J. Caulfield: Genomics England
J. Kenneth Baillie: University of Edinburgh

Nature, 2022, vol. 607, issue 7917, 97-103

Abstract: Abstract 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.

Date: 2022
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Citations: View citations in EconPapers (5)

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DOI: 10.1038/s41586-022-04576-6

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