Whole genome sequencing reveals host factors underlying critical Covid-19

GenOMICC Investigators, 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 KlaricMarie 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, J Kenneth Baillie

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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 (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.

Original languageEnglish
Pages (from-to)97-103
Early online date7 Mar 2022
Publication statusPublished - 7 Jul 2022

Keywords / Materials (for Non-textual outputs)

  • ATP-Binding Cassette Transporters
  • COVID-19/genetics
  • Cell Adhesion Molecules
  • Critical Care
  • Critical Illness/mortality
  • E-Selectin
  • Factor VIII
  • Fucosyltransferases
  • Genome, Human/genetics
  • Genome-Wide Association Study
  • Host-Pathogen Interactions/genetics
  • Humans
  • Interleukin-10 Receptor beta Subunit
  • Lectins, C-Type
  • Mucin-1
  • Nerve Tissue Proteins
  • Phospholipid Transfer Proteins
  • Receptors, Cell Surface
  • Repressor Proteins
  • SARS-CoV-2/pathogenicity
  • Whole Genome Sequencing


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