Authors: Athanasios Kousathanas, Erola Pairo-Castineira, J. Kenneth BaillieArticle

Published: 07 March 2022 nature  articles  article

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Abstract

Critical Covid-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care¹ or hospitalisation^2–4 following SARS-CoV-2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from critically-ill cases with population controls in order to find underlying disease mechanisms. Here, we use whole genome sequencing in 7,491 critically-ill cases 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 involved in interferon signalling (IL10RB, PLSCR1), leucocyte differentiation (BCL11A), and blood type antigen secretor status (FUT2). Using transcriptome-wide association and colocalisation to infer the effect of gene expression on disease severity, we find evidence implicating multiple genes, including reduced expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1), in critical disease. Mendelian randomisation provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5, CD209) and 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 critically-ill cases and population controls is highly efficient for detection of therapeutically-relevant mechanisms of disease.

Author information

Author notes

1. These authors contributed equally: Athanasios Kousathanas, Erola Pairo-Castineira
2. These authors jointly supervised this work: Sara Clohisey Hendry, Loukas Moutsianas, Andy Law, Mark J Caulfield, J. Kenneth Baillie
3. A list of authors and their affiliations appears in the Supplementary Information

Affiliations

1. Genomics England, London, UKAthanasios Kousathanas, Alex Stuckey, Christopher A. Odhams, Susan Walker, Daniel Rhodes, Afshan Siddiq, Peter Goddard, Sally Donovan, Tala Zainy, Fiona Maleady-Crowe, Linda Todd, Shahla Salehi, Greg Elgar, Georgia Chan, Prabhu Arumugam, Christine Patch, Augusto Rendon, Tom A. Fowler, Richard H. Scott, Loukas Moutsianas & Mark J. Caulfield
2. Roslin Institute, University of Edinburgh, Easter Bush, Edinburgh, UKErola Pairo-Castineira, Konrad Rawlik, Clark D. Russell, Jonathan Millar, Fiona Griffiths, Wilna Oosthuyzen, Bo Wang, Marie Zechner, Nick Parkinson, Albert Tenesa, Sara Clohisey Hendry, Andy Law & J. Kenneth Baillie
3. MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, UKErola Pairo-Castineira, Lucija Klaric, Albert Tenesa, Chris P. Ponting, Veronique Vitart, James F. Wilson, Andrew D. Bretherick & J. Kenneth Baillie
4. Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UKClark D. Russell & J. Kenneth Baillie
5. Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UKTomas Malinauskas, Katherine S. Elliott & Julian Knight
6. Institute for Molecular Bioscience, The University of Queensland, Brisbane, AustraliaYang Wu
7. Biostatistics Group, Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Guangzhou, ChinaXia Shen
8. Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, Teviot Place, Edinburgh, UKXia Shen, Albert Tenesa & James F. Wilson
9. Edinburgh Clinical Research Facility, Western General Hospital, University of Edinburgh, Edinburgh, UKKirstie Morrice, Angie Fawkes & Lee Murphy
10. Intensive Care Unit, Royal Infirmary of Edinburgh, 54 Little France Drive, Edinburgh, UKSean Keating, Timothy Walsh & J. Kenneth Baillie
11. Department of Critical Care Medicine, Queen’s University and Kingston Health Sciences Centre, Kingston, ON, CanadaDavid Maslove
12. Clinical Research Centre at St Vincent’s University Hospital, University College Dublin, Dublin, IrelandAlistair Nichol
13. NIHR Health Protection Research Unit for Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences University of Liverpool, Liverpool, UKMalcolm G. Semple
14. Respiratory Medicine, Alder Hey Children’s Hospital, Institute in The Park, University of Liverpool, Alder Hey Children’s Hospital, Liverpool, UKMalcolm G. Semple
15. Illumina Cambridge, 19 Granta Park, Great Abington, Cambridge, UKDavid Bentley & Clare Kingsley
16. Regeneron Genetics Center, 777 Old Saw Mill River Rd., Tarrytown, USAJack A. Kosmicki, Julie E. Horowitz, Aris Baras, Goncalo R. Abecasis & Manuel A. R. Ferreira
17. Geisinger, Danville, PA, USAAnne Justice, Tooraj Mirshahi & Matthew Oetjens
18. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USADaniel J. Rader, Marylyn D. Ritchie & Anurag Verma
19. Test and Trace, the Health Security Agency, Department of Health and Social Care, Victoria St, London, UKTom A. Fowler
20. Department of Intensive Care Medicine, Guy’s and St. Thomas NHS Foundation Trust, London, UKManu Shankar-Hari
21. Department of Medicine, University of Cambridge, Cambridge, UKCharlotte Summers
22. William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UKCharles Hinds
23. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, UKPeter Horby
24. Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, ChinaLowell Ling
25. Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, Northern Ireland, UKDanny McAuley
26. Department of Intensive Care Medicine, Royal Victoria Hospital, Belfast, Northern Ireland, UKDanny McAuley
27. UCL Centre for Human Health and Performance, London, UKHugh Montgomery
28. National Heart and Lung Institute, Imperial College London, London, UKPeter J. M. Openshaw
29. Imperial College Healthcare NHS Trust: London, London, UKPeter J. M. Openshaw
30. Imperial College, London, UKPaul Elliott
31. Intensive Care National Audit & Research Centre, London, UKKathy Rowan
32. School of Life Sciences, Westlake University, Hangzhou, Zhejiang, ChinaJian Yang
33. Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, ChinaJian Yang
34. Great Ormond Street Hospital, London, UKRichard H. Scott
35. William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London, UKMark J. Caulfield

Consortia

GenOMICC Investigators

23andMe

Covid-19 Human Genetics Initiative

Corresponding authors

Correspondence to Mark J. Caulfield or J. Kenneth Baillie.

Supplementary information

Supplementary Information

This file contains Supplementary Figures; Supplementary Tables and Supplementary References