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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
general
GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19
Nature, Volume 617, No. 7962, Year 2023
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Description
Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A). © 2023, The Author(s).
Authors & Co-Authors
Pairo-Castineira, Erola
United Kingdom, Edinburgh
University of Edinburgh, College of Medicine and Veterinary Medicine
United Kingdom, Edinburgh
Western General Hospital
United Kingdom, Edinburgh
The University of Edinburgh
Rawlik, Konrad C.
United Kingdom, Edinburgh
University of Edinburgh, College of Medicine and Veterinary Medicine
Bretherick, Andrew D.
United Kingdom, Edinburgh
University of Edinburgh, College of Medicine and Veterinary Medicine
United Kingdom, Edinburgh
Western General Hospital
United Kingdom, Dundee
University of Dundee School of Medicine
Qi, Ting
China, Hangzhou
Westlake University
Wu, Yang
Australia, Brisbane
The University of Queensland
Nassiri, Isar
United Kingdom, Oxford
University of Oxford
Griffiths, Fiona
United Kingdom, Edinburgh
University of Edinburgh, College of Medicine and Veterinary Medicine
United Kingdom, Edinburgh
The University of Edinburgh
Oosthuyzen, Wilna
United Kingdom, Edinburgh
University of Edinburgh, College of Medicine and Veterinary Medicine
United Kingdom, Edinburgh
The University of Edinburgh
Kousathanas, Athanasios
United Kingdom, London
Genomics England Limited
Richmond, Anne
United Kingdom, Edinburgh
Western General Hospital
Millar, Jonathan E.
United Kingdom, Edinburgh
University of Edinburgh, College of Medicine and Veterinary Medicine
United Kingdom, Edinburgh
The University of Edinburgh
United Kingdom, Edinburgh
Royal Infirmary of Edinburgh
Thwaites, Ryan S.
United Kingdom, London
Imperial College London
Maslove, David M.
Canada, Kingston
Queen’s University
Nichol, Alistair
Ireland, Dublin
University College Dublin
Semple, Malcolm Gracie
United Kingdom, Liverpool
University of Liverpool
United Kingdom, Liverpool
Alder Hey Children's Hospital
Summers, Charlotte
United Kingdom, Cambridge
University of Cambridge
Horby, Peter W.
United Kingdom, Oxford
University of Oxford
Ling, Lowell
Hong Kong, Hong Kong
Chinese University of Hong Kong
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
Walsh, Timothy Simon
United Kingdom, Edinburgh
Royal Infirmary of Edinburgh
Tenesa, Albert
United Kingdom, Edinburgh
Western General Hospital
United Kingdom, Edinburgh
The University of Edinburgh
United Kingdom, Edinburgh
Edinburgh Medical School
Flores, Carlos M.
Spain, Granadilla de Abona
Instituto Tecnológico y de Energías Renovables, S.a.
Spain, Santa Cruz de Tenerife
Hospital Universitario Nuestra Senora de Candelaria
Spain, Madrid
Instituto de Salud Carlos Iii
Spain, Santa Maria de Guia de Gran Canaria
Universidad Fernando Pessoa Canarias
Riancho, José Antonio
Spain, Santander
Idival
Spain, Santander
Universidad de Cantabria
Spain, Santander
Hospital Universitario Marqués de Valdecilla
Rojas-Martinez, Augusto
Mexico, Monterrey
Tecnológico de Monterrey
Clohisey, Sara M.R.
United Kingdom, Edinburgh
The University of Edinburgh
Shankar-Hari, Manu
United Kingdom, Edinburgh
University of Edinburgh, College of Medicine and Veterinary Medicine
United Kingdom, London
Guy's and st Thomas' Nhs Foundation Trust
Armstrong, Ruth
United Kingdom, Edinburgh
The University of Edinburgh
Baillie, J. Kenneth
United Kingdom, Edinburgh
The University of Edinburgh
United Kingdom, Edinburgh
Royal Infirmary of Edinburgh
Gilchrist, Tammy
United Kingdom, Edinburgh
Western General Hospital
Moore, Shona C.
United Kingdom, Liverpool
University of Liverpool
Odam, Miranda
United Kingdom, Edinburgh
The University of Edinburgh
United Kingdom, Livingston
St John's Hospital
Parkinson, Nicholas J.
United Kingdom, Edinburgh
The University of Edinburgh
Schon, Katherine R.
United Kingdom, Cambridge
Cambridge University Hospitals Nhs Foundation Trust
Wrobel, Nicola
United Kingdom, Edinburgh
Western General Hospital
Ostermann, Marlies Elizabeth
United Kingdom, London
Guy's and st Thomas' Nhs Foundation Trust
Henning, Jeremy D.R.
United Kingdom, Middlesbrough
The James Cook University Hospital
Jones, Jessica E.
United Kingdom, Middlesbrough
The James Cook University Hospital
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
Mitchelmore, Oliver
United Kingdom, London
Barts Health Nhs Trust
Wood, Suzanne M.
United Kingdom, London
Barts Health Nhs Trust
Collier, David Andrew
United Kingdom, London
Barts Health Nhs Trust
Thompson, Chris Vaun
United Kingdom, Stoke-on-trent
Royal Stoke 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
Darnell, Sarah
United Kingdom, London
St Mary's Hospital
Hamilton, David Oliver
United Kingdom, Liverpool
Royal Liverpool University Hospital
Welters, Ingeborg Dorothea M.
United Kingdom, Liverpool
Royal Liverpool University Hospital
Hutton, Paula J.
United Kingdom, Oxford
John Radcliffe Hospital
McKechnie, Stuart R.
United Kingdom, Oxford
John Radcliffe 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
Hurt, William James
United Kingdom, London
St George's Hospital
Leaver, Susannah K.
United Kingdom, London
St George's Hospital
Patel, Kamal Vijaykant
United Kingdom, London
St George's Hospital
Smith, Helen V.
United Kingdom, Ilford
King George Hospital
Phull, Mandeep Kaur
United Kingdom, Ilford
King George Hospital
Flower, Luke
United Kingdom, Ilford
King George Hospital
Baillie, Kenneth J.
United Kingdom, Edinburgh
Royal Infirmary of Edinburgh
Hope, David T.
United Kingdom, Edinburgh
Royal Infirmary of Edinburgh
Swain, Andrew H.
United Kingdom, Kingston Upon Thames
Kingston Hospital Nhs Foundation Trust
Rose, Steve
United Kingdom, Portsmouth
Queen Alexandra Hospital
Pogson, David G.
United Kingdom, Portsmouth
Queen Alexandra Hospital
Gribbin, Andrew
United Kingdom, Portsmouth
Queen Alexandra Hospital
Szakmany, Tamas
United Kingdom, Newport
Royal Gwent Hospital
Hopkins, Susan M.
United Kingdom, Stockport
Stepping Hill Hospital
Faulkner, Maria
United Kingdom, Chester
Countess of Chester Hospital Nhs Foundation Trust
Radhakrishnan, Jayachandran
United Kingdom, Chelmsford
Broomfield Hospital
Scriven, James E.
United Kingdom, Birmingham
Heartlands Hospital
United Kingdom, Birmingham
Queen Elizabeth Hospital Birmingham
United Kingdom, Birmingham
University Hospitals Birmingham Nhs Foundation Trust
de Gordoa, Laura Ortiz Ruiz
United Kingdom, Brighton
Royal Sussex County Hospital
Felton, Tim W.
United Kingdom, Manchester
Wythenshawe Hospital
Shaw, Jane Alexandra
United Kingdom, Manchester
Wythenshawe Hospital
Smith, Chris
United Kingdom, Manchester
Wythenshawe Hospital
Kaye, Callum T.
United Kingdom, Aberdeen
Aberdeen Royal Infirmary
Benyon, Sarah Louise
United Kingdom, Exeter
Royal Devon and Exeter Hospital
Puxty, Alex
United Kingdom, Glasgow
Glasgow Royal Infirmary
Preston, Stephen D.
United Kingdom, Blackpool
Blackpool Victoria Hospital
Cupitt, Jason M.
United Kingdom, Blackpool
Blackpool Victoria Hospital
Bolger, Clare
United Kingdom, Southampton
Southampton General Hospital
Camsooksai, Julie
United Kingdom, Poole
University Hospitals Dorset Nhs Foundation Trust
Rooney, Kevin Donal
United Kingdom, Paisley
Royal Alexandra Hospital
Nune, Arvind
United Kingdom, Southport
Southport and Ormskirk Hospital Nhs Trust
Davey, Miriam
United Kingdom, Maidstone
Maidstone Hospital
Collins, Amy
Unknown Affiliation
Khaliq, Waqas
United Kingdom, London
University Hospital Lewisham
Hey, Samuel
United Kingdom, Manchester
North Manchester General Hospital
Lamb, Thomas
United Kingdom, Manchester
North Manchester General Hospital
Duncan, Tracy
United Kingdom, Manchester
North Manchester General Hospital
Hanson, Helen L.
United Kingdom, Newcastle
Royal Victoria Infirmary
Robinson, Philip A.
United Kingdom, Newcastle
Royal Victoria 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
Jude, Edward B.
United Kingdom, Ashton-under-lyne
Tameside General Hospital
Walker, Danielle Carey
United Kingdom, Salford
Salford Royal Hospital
Dark, Paul M.
United Kingdom, Salford
Salford Royal Hospital
Bamford, A. R.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
Ray, Samiran
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
Bell, Michael J.
United Kingdom, London
Great Ormond Street Hospital for Children Nhs Foundation Trust
Jacob, Reni
United Kingdom, Wirral
Arrowe Park Hospital
Shafique, Huma
United Kingdom, Bradford
Bradford Royal Infirmary
Lawton, Tom O.
United Kingdom, Bradford
Bradford Royal Infirmary
Davies, Jennifer C.
United Kingdom, Rhyl
Glan Clwyd Hospital
Nigel White, Nigel A.
United Kingdom, Bournemouth
Royal Bournemouth Hospital
Grimmer, Lisa
United Kingdom, Bristol
Bristol Royal Infirmary
Bewley, Jeremy S.
United Kingdom, Bristol
Bristol Royal Infirmary
Webster, Denise
United Kingdom, Bristol
Bristol Royal Infirmary
Statistics
Citations: 15
Authors: 114
Affiliations: 123
Identifiers
Doi:
10.1038/s41586-023-06034-3
ISSN:
00280836
Research Areas
Covid
Genetics And Genomics
Study Design
Randomised Control Trial
Study Approach
Systematic review