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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
general
Whole-genome sequencing reveals host factors underlying critical COVID-19
Nature, Volume 607, No. 7917, Year 2022
Notification
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Description
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. © 2022, The Author(s).
Authors & Co-Authors
Kousathanas, Athanasios
United Kingdom, London
Genomics England Limited
Pairo-Castineira, Erola
United Kingdom, Edinburgh
The University of Edinburgh
United Kingdom, Edinburgh
Western General Hospital
Rawlik, Konrad C.
United Kingdom, Edinburgh
The University of Edinburgh
Stuckey, Alexander
United Kingdom, London
Genomics England Limited
Odhams, Christopher A.
United Kingdom, London
Genomics England Limited
Walker, Susan
United Kingdom, London
Genomics England Limited
Russell, Clark Donald
United Kingdom, Edinburgh
The University of Edinburgh
United Kingdom, Edinburgh
University of Edinburgh, College of Medicine and Veterinary Medicine
Wu, Yang
Australia, Brisbane
The University of Queensland
Millar, Jonathan E.
United Kingdom, Edinburgh
The University of Edinburgh
Griffiths, Fiona
United Kingdom, Edinburgh
The University of Edinburgh
Oosthuyzen, Wilna
United Kingdom, Edinburgh
The University of Edinburgh
Rhodes, Daniel
United Kingdom, London
Genomics England Limited
Parkinson, Nicholas J.
United Kingdom, Edinburgh
The University of Edinburgh
Siddiq, Afshan
United Kingdom, London
Genomics England Limited
Maslove, David M.
Canada, Kingston
Queen’s University
Nichol, Alistair D.
Ireland, Dublin
University College Dublin
Semple, Malcolm Gracie
United Kingdom, Liverpool
University of Liverpool
United Kingdom, Liverpool
Alder Hey Children's Hospital
Maleady-Crowe, Fiona
United Kingdom, London
Genomics England Limited
Knight, Julian C.
United Kingdom, Oxford
University of Oxford
Elgar, Greg S.
United Kingdom, London
Genomics England Limited
Chan, Georgia C.
United Kingdom, London
Genomics England Limited
Arumugam, Prabhu
United Kingdom, London
Genomics England Limited
Patch, Christine
United Kingdom, London
Genomics England Limited
Rendon, Augusto
United Kingdom, London
Genomics England Limited
Bentley, David R.
Unknown Affiliation
Kosmicki, Jack A.
United States, Tarrytown
Regeneron Genetics Center
Horowitz, Julie E.
United States, Tarrytown
Regeneron Genetics Center
Baras, Aris
United States, Tarrytown
Regeneron Genetics Center
Abecasis, Gonçalo R.
United States, Tarrytown
Regeneron Genetics Center
Ferreira, Manuel Allen Revez
United States, Tarrytown
Regeneron Genetics Center
Justice, Anne E.
United States, Danville
Geisinger
Rader, Daniel J.
United States, Philadelphia
University of Pennsylvania
Ritchie, Marylyn D.
United States, Philadelphia
University of Pennsylvania
Verma, Anurag
United States, Philadelphia
University of Pennsylvania
Fowler, Tom A.
United Kingdom, London
Genomics England Limited
Shankar-Hari, Manu
United Kingdom, London
Guy's and st Thomas' Nhs Foundation Trust
Summers, Charlotte
United Kingdom, Cambridge
University of Cambridge
Horby, Peter W.
United Kingdom, Oxford
University of Oxford
McAuley, Daniel F.
United Kingdom, Belfast
Queen's University Belfast
United Kingdom, Belfast
Royal Victoria Hospital Belfast
Montgomery, Hugh E.
United Kingdom, London
University College London
Openshaw, Peter J.M.
United Kingdom, London
Imperial College London
United Kingdom, London
Imperial College Healthcare Nhs Trust
Elliott, Paul E.
United Kingdom, London
Imperial College London
Walsh, Timothy Simon
United Kingdom, Edinburgh
Royal Infirmary of Edinburgh
Tenesa, Albert
United Kingdom, Edinburgh
The University of Edinburgh
United Kingdom, Edinburgh
Western General Hospital
United Kingdom, Edinburgh
Edinburgh Medical School
Fawkes, Angie
United Kingdom, Edinburgh
Western General Hospital
Murphy, Lee D.
United Kingdom, Edinburgh
Western General Hospital
Rowan, Kathryn M.
Unknown Affiliation
Ponting, Chris Paul
United Kingdom, Edinburgh
Western General Hospital
Vitart, Véronique
United Kingdom, Edinburgh
Western General Hospital
Wilson, James F.
United Kingdom, Edinburgh
Western General Hospital
United Kingdom, Edinburgh
Edinburgh Medical School
Yang, Jian
China, Hangzhou
Westlake University
Bretherick, Andrew D.
United Kingdom, Edinburgh
Western General Hospital
Scott, Richard H.
United Kingdom, London
Genomics England Limited
United Kingdom, London
Great Ormond Street Hospital for Children Nhs Foundation Trust
Moutsianas, Loukas
United Kingdom, London
Genomics England Limited
Law, Andrew S.
United Kingdom, Edinburgh
The University of Edinburgh
Caulfield, Mark J.
United Kingdom, London
Genomics England Limited
United Kingdom, London
Queen Mary University of London
Baillie, John Kenneth
United Kingdom, Edinburgh
The University of Edinburgh
United Kingdom, Edinburgh
Western General Hospital
United Kingdom, Edinburgh
University of Edinburgh, College of Medicine and Veterinary Medicine
United Kingdom, Edinburgh
Royal Infirmary of Edinburgh
Ling, Lowell
Hong Kong, Hong Kong
Chinese University of Hong Kong
Pereira, Alexandre Da Costa
Brazil, Sao Paulo
Universidade de São Paulo
Armstrong, Ruth
United Kingdom, Edinburgh
The University of Edinburgh
Gilchrist, Tammy
United Kingdom, Edinburgh
Western General Hospital
Moore, Shona C.
United Kingdom, Liverpool
University of Liverpool
Schon, Katherine R.
United Kingdom, Cambridge
Cambridge University Hospitals Nhs Foundation Trust
Turtle, Lance C.W.
United Kingdom, Liverpool
University of Liverpool
Wrobel, Nicola
United Kingdom, Edinburgh
Western General Hospital
Ostermann, Marlies Elizabeth
United Kingdom, London
Guy's and st Thomas' Nhs Foundation Trust
Alldis, Zoe
United Kingdom, London
Barts Health Nhs Trust
Bibi, Fatima
United Kingdom, London
Barts Health Nhs Trust
Bowles, Ruth
United Kingdom, London
Barts Health Nhs Trust
Burton, Maudrian
United Kingdom, London
Barts Health Nhs Trust
Collier, David Andrew
United Kingdom, London
Barts Health Nhs Trust
Mitchelmore, Oliver
United Kingdom, London
Barts Health Nhs Trust
Wood, Suzanne M.
United Kingdom, London
Barts Health Nhs Trust
Jones, Jessica E.
United Kingdom, Middlesbrough
The James Cook University Hospital
Thompson, Chris Vaun
United Kingdom, Stoke-on-trent
Royal Stoke University Hospital
Hamilton, David Oliver
United Kingdom, Liverpool
Royal Liverpool University Hospital
Welters, Ingeborg Dorothea M.
United Kingdom, Liverpool
Royal Liverpool University Hospital
Jerome, Ellen
United Kingdom, London
King's College Hospital
Brett, Stephen J.
United Kingdom, London
St Mary's Hospital
Gordon, Anthony C.
United Kingdom, London
St Mary's Hospital
Hutton, Paula J.
United Kingdom, Oxford
John Radcliffe Hospital
McKechnie, Stuart R.
United Kingdom, Oxford
John Radcliffe Hospital
Swain, Andrew H.
United Kingdom, Kingston Upon Thames
Kingston Hospital Nhs Foundation Trust
Hope, David T.
United Kingdom, Edinburgh
Royal Infirmary of Edinburgh
Pogson, David G.
United Kingdom, Portsmouth
Queen Alexandra Hospital
Rose, Steve
United Kingdom, Portsmouth
Queen Alexandra Hospital
Agrawal, Shruti
United Kingdom, Cambridge
Addenbrooke's Hospital
Pathan, Nazima
United Kingdom, Cambridge
Addenbrooke's Hospital
White, Deborah K.
United Kingdom, Cambridge
Addenbrooke's Hospital
Phull, Mandeep Kaur
United Kingdom, Ilford
King George Hospital
de Gordoa, Laura Ortiz Ruiz
United Kingdom, Brighton
Royal Sussex County Hospital
Collins, Amy
Unknown Affiliation
Khaliq, Waqas
Unknown Affiliation
Leaver, Susannah K.
United Kingdom, London
St George's Hospital
Hurt, William James
United Kingdom, London
St George's Hospital
Patel, Kamal Vijaykant
United Kingdom, London
St George's Hospital
Faulkner, Maria
United Kingdom, Chester
Countess of Chester Hospital Nhs Foundation Trust
Davey, Miriam
United Kingdom, Maidstone
Maidstone Hospital
Szakmany, Tamas
United Kingdom, Newport
Royal Gwent Hospital
Radhakrishnan, Jayachandran
United Kingdom, Chelmsford
Broomfield Hospital
Baird, Yolanda
United Kingdom, Worthing
Worthing Hospital
United Kingdom, Chichester
St Richard's Hospital
Anderson, Peter L.
United Kingdom, Worcester
Worcestershire Royal Hospital
Cupitt, Jason M.
United Kingdom, Blackpool
Blackpool Victoria Hospital
Preston, Stephen D.
United Kingdom, Blackpool
Blackpool Victoria Hospital
Puxty, Alex
United Kingdom, Glasgow
Glasgow Royal Infirmary
Felton, Tim W.
United Kingdom, Manchester
Wythenshawe Hospital
Rooney, Kevin Donal
United Kingdom, Paisley
Royal Alexandra Hospital
Jude, Edward B.
United Kingdom, Ashton-under-lyne
Tameside General Hospital
Hanson, Helen L.
United Kingdom, Newcastle
Royal Victoria Infirmary
Robinson, Philip A.
United Kingdom, Newcastle
Royal Victoria Infirmary
Camsooksai, Julie
United Kingdom, Poole
University Hospitals Dorset Nhs Foundation Trust
Duncan, Tracy
United Kingdom, Manchester
North Manchester General Hospital
Hey, Samuel
United Kingdom, Manchester
North Manchester General Hospital
Lamb, Thomas
United Kingdom, Manchester
North Manchester General Hospital
Kaye, Callum T.
United Kingdom, Aberdeen
Aberdeen Royal Infirmary
Dark, Paul M.
United Kingdom, Salford
Salford Royal Hospital
Walker, Danielle Carey
United Kingdom, Salford
Salford Royal Hospital
Lawton, Tom O.
United Kingdom, Bradford
Bradford Royal Infirmary
Bewley, Jeremy S.
United Kingdom, Bristol
Bristol Royal Infirmary
Grimmer, Lisa
United Kingdom, Bristol
Bristol Royal Infirmary
Sweet, Katie
United Kingdom, Bristol
Bristol Royal Infirmary
Webster, Denise
United Kingdom, Bristol
Bristol Royal Infirmary
Randell, Georgina
United Kingdom, Norwich
Norfolk and Norwich University Hospitals Nhs Foundation Trust
Bokhari, Maria
United Kingdom, Tyne and Wear
Queen Elizabeth Hospital, Gateshead
Benyon, Sarah Louise
United Kingdom, Exeter
Royal Devon and Exeter Hospital
Čagová, Lenka
United Kingdom, Cambridge
Royal Papworth Hospital Nhs Foundation Trust
Vuylsteke, Alain
United Kingdom, Cambridge
Royal Papworth Hospital Nhs Foundation Trust
Bamford, A. R.J.
United Kingdom, London
Great Ormond Street Hospital for Children Nhs Foundation Trust
Bell, Michael J.
United Kingdom, London
Great Ormond Street Hospital for Children Nhs Foundation Trust
Meghari, Hamza
United Kingdom, London
Great Ormond Street Hospital for Children Nhs Foundation Trust
O’Neill, Lauran
United Kingdom, London
Great Ormond Street Hospital for Children Nhs Foundation Trust
Peters, Mark John
United Kingdom, London
Great Ormond Street Hospital for Children Nhs Foundation Trust
Ray, Samiran
United Kingdom, London
Great Ormond Street Hospital for Children Nhs Foundation Trust
Cole, Jade M.
United Kingdom, Cardiff
University Hospital of Wales
Hill, Helen C.
United Kingdom, Cardiff
University Hospital of Wales
Mupudzi, McDonald
United Kingdom, Basingstoke
Hampshire Hospitals Nhs Foundation Trust
Jacob, Reni
United Kingdom, Wirral
Arrowe Park Hospital
Mills, Gary H.
United Kingdom, Sheffield
Northern General Hospital
Rowland-Jones, Sarah Louise
United Kingdom, Sheffield
Northern General Hospital
Thompson, A. A.Roger
United Kingdom, Sheffield
Northern General Hospital
Hay, Alasdair W.
United Kingdom, Dumfries
Dumfries and Galloway Royal Infirmary
Nune, Arvind
United Kingdom, Southport
Southport and Ormskirk Hospital Nhs Trust
Nigel White, Nigel A.
United Kingdom, Bournemouth
Royal Bournemouth Hospital
Williams, Alexandra J.
United Kingdom, Preston
Royal Preston Hospital
Parmar, Chetan D.
United Kingdom, London
The Whittington Hospital
Statistics
Citations: 127
Authors: 145
Affiliations: 135
Identifiers
Doi:
10.1038/s41586-022-04576-6
ISSN:
00280836
Research Areas
Covid
Genetics And Genomics
Violence And Injury
Study Design
Randomised Control Trial
Cross Sectional Study