Whole-genome sequencing reveals host factors underlying critical COVID-19.
Authors
Stuckey, Alex
Odhams, Christopher A
Russell, Clark D
Millar, Jonathan
Griffiths, Fiona
Oosthuyzen, Wilna
Morrice, Kirstie
Rhodes, Daniel
Zechner, Marie
Siddiq, Afshan
Goddard, Peter
Donovan, Sally
Maslove, David
Zainy, Tala
Maleady-Crowe, Fiona
Todd, Linda
Chan, Georgia
Arumugam, Prabhu
Rendon, Augusto
Bentley, David
Kingsley, Clare
Kosmicki, Jack A
Horowitz, Julie E
Justice, Anne
Mirshahi, Tooraj
Oetjens, Matthew
Verma, Anurag
Fowler, Tom A
Horby, Peter
Ling, Lowell
Openshaw, Peter JM
Walsh, Timothy
GenOMICC investigators
23andMe investigators
COVID-19 Human Genetics Initiative
Fawkes, Angie
Scott, Richard H
Publication Date
2022-03-07Journal Title
Nature
ISSN
0028-0836
Publisher
Springer Science and Business Media LLC
Type
Article
This Version
AM
Metadata
Show full item recordCitation
Kousathanas, A., Pairo-Castineira, E., Rawlik, K., Stuckey, A., Odhams, C. A., Walker, S., Russell, C. D., et al. (2022). Whole-genome sequencing reveals host factors underlying critical COVID-19.. Nature https://doi.org/10.1038/s41586-022-04576-6
Abstract
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.
Sponsorship
Medical Research Council (MC_PC_14089)
Identifiers
External DOI: https://doi.org/10.1038/s41586-022-04576-6
This record's URL: https://www.repository.cam.ac.uk/handle/1810/334396
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