Whole-genome sequencing reveals host factors underlying critical COVID-19
Whole-genome sequencing reveals host factors underlying critical COVID-19
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.
97-103
Kousathanas, Athanasios
9353ab9f-1be6-421a-939c-fce6be8b5646
Pairo-Castineira, Erola
6eb6049a-c4b3-4fd5-a706-b1bd6b6e0c2b
Rawlik, Konrad
ef0c858d-8bc4-47bf-aa05-5d7a11f82331
Cusack, Rebecca
dfb1595f-2792-4f76-ac6d-da027cf40146
Lee, Paul H.
02620eab-ae7f-4a1c-bad1-8a50e7e48951
COVID-19 Human Genetics Initiative
7 July 2022
Kousathanas, Athanasios
9353ab9f-1be6-421a-939c-fce6be8b5646
Pairo-Castineira, Erola
6eb6049a-c4b3-4fd5-a706-b1bd6b6e0c2b
Rawlik, Konrad
ef0c858d-8bc4-47bf-aa05-5d7a11f82331
Cusack, Rebecca
dfb1595f-2792-4f76-ac6d-da027cf40146
Lee, Paul H.
02620eab-ae7f-4a1c-bad1-8a50e7e48951
Kousathanas, Athanasios, Pairo-Castineira, Erola and Rawlik, Konrad
,
et al., GenOMICC investigators, 23andMe investigators and COVID-19 Human Genetics Initiative
(2022)
Whole-genome sequencing reveals host factors underlying critical COVID-19.
Nature, 607 (7917), .
(doi: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.
Text
s41586-022-04576-6
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Accepted/In Press date: 23 February 2022
e-pub ahead of print date: 7 March 2022
Published date: 7 July 2022
Identifiers
Local EPrints ID: 490687
URI: http://eprints.soton.ac.uk/id/eprint/490687
ISSN: 0028-0836
PURE UUID: 2eada2a0-014e-45e5-89fd-01818fdeaec3
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Date deposited: 03 Jun 2024 17:12
Last modified: 04 Jun 2024 02:05
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Contributors
Author:
Athanasios Kousathanas
Author:
Erola Pairo-Castineira
Author:
Konrad Rawlik
Author:
Rebecca Cusack
Author:
Paul H. Lee
Corporate Author: et al.
Corporate Author: GenOMICC investigators
Corporate Author: 23andMe investigators
Corporate Author: COVID-19 Human Genetics Initiative
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