s41586-022-04576-6.pdf (7.81 MB)
Whole-genome sequencing reveals host factors underlying critical COVID-19
journal contribution
posted on 2022-11-15, 15:29 authored by A Kousathanas, E Pairo-Castineira, K Rawlik, A Stuckey, CA Odhams, S Walker, CD Russell, T Malinauskas, Y Wu, J Millar, X Shen, KS Elliott, F Griffiths, W Oosthuyzen, K Morrice, S Keating, B Wang, D Rhodes, L Klaric, M Zechner, N Parkinson, A Siddiq, P Goddard, S Donovan, D Maslove, A Nichol, MG Semple, T Zainy, F Maleady-Crowe, L Todd, S Salehi, J Knight, G Elgar, G Chan, P Arumugam, C Patch, A Rendon, D Bentley, C Kingsley, JA Kosmicki, JE Horowitz, A Baras, GR Abecasis, MAR Ferreira, A Justice, T Mirshahi, M Oetjens, DJ Rader, MD Ritchie, A Verma, TA Fowler, M Shankar-Hari, C Summers, C Hinds, P Horby, L Ling, D McAuley, H Montgomery, PJM Openshaw, P Elliott, T Walsh, A Tenesa, GenOMICC investigators, 23andMe investigators, COVID-19 Human Genetics Initiative, 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, Chiara Batini, Paul H. Lee, nick Shrine, Alexander
T. Williams, Martin D. Tobin, Anna L. Guyatt, Catherine John, Richard J Packer, Altaf Ali, Xueyang Wang, Louise V. Wain, Laura D Venn, Catherine E Bee, Emma L Adams, Robert C. Free, Edward J HolloxCritical 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.
History
Author affiliation
Department of Health Sciences, University of LeicesterVersion
- VoR (Version of Record)
Published in
NatureVolume
607Issue
7917Pagination
97 - 103Publisher
Springer Science and Business Media LLCissn
0028-0836eissn
1476-4687Copyright date
2022Available date
2022-11-15Publisher DOI
Spatial coverage
EnglandLanguage
engPublisher version
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Keywords
GenOMICC investigators23andMe investigatorsCOVID-19 Human Genetics InitiativeHumansCritical IllnessFucosyltransferasesFactor VIIIATP-Binding Cassette TransportersPhospholipid Transfer ProteinsCell Adhesion MoleculesE-SelectinLectins, C-TypeReceptors, Cell SurfaceNerve Tissue ProteinsRepressor ProteinsCritical CareGenome, HumanInterleukin-10 Receptor beta SubunitHost-Pathogen InteractionsMucin-1Genome-Wide Association StudyWhole Genome SequencingCOVID-19SARS-CoV-2