Whole genome sequencing reveals host factors underlying critical Covid-19

Authors: Athanasios KousathanasErola Pairo-CastineiraJ. Kenneth BaillieArticle

Published:  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 hospitalisation2–4 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 (IL10RBPLSCR1), 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 (SELEICAM5CD209) 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

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