Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care(1) or hospitalization(2-4) 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. © 2022, The Author(s).

Kousathanas, A., Pairo-Castineira, E., Rawlik, K., Stuckey, A., Odhams, C.A., Walker, S., et al. (2022). Whole-genome sequencing reveals host factors underlying critical COVID-19. NATURE, 607(7917), 97-103 [10.1038/s41586-022-04576-6].

Whole-genome sequencing reveals host factors underlying critical COVID-19

Renieri, A.
Membro del Collaboration Group
;
Mari, F.
Membro del Collaboration Group
;
Fallerini, C.
Membro del Collaboration Group
;
Daga, S.
Membro del Collaboration Group
;
Benetti, E.
Membro del Collaboration Group
;
Baldassarri, M.
Membro del Collaboration Group
;
Fava, F.
Membro del Collaboration Group
;
Frullanti, E.
Membro del Collaboration Group
;
Amitrano, S.
Membro del Collaboration Group
;
Bruttini, M.
Membro del Collaboration Group
;
Croci, S.
Membro del Collaboration Group
;
Meloni, I.
Membro del Collaboration Group
;
Mencarelli, M. A.
Membro del Collaboration Group
;
Pinto, A. M.
Membro del Collaboration Group
;
Beligni, G.
Membro del Collaboration Group
;
Di Sarno, L.
Membro del Collaboration Group
;
Palmieri, M.
Membro del Collaboration Group
;
Carriero, M. L.
Membro del Collaboration Group
;
Alaverdian, D.
Membro del Collaboration Group
;
Gori, M.
Membro del Collaboration Group
;
Montagnani, F.
Membro del Collaboration Group
;
Fabbiani, M.
Membro del Collaboration Group
;
Rossetti, B.
Membro del Collaboration Group
;
Bargagli, E.
Membro del Collaboration Group
;
Bergantini, L.
Membro del Collaboration Group
;
D’Alessandro, M.
Membro del Collaboration Group
;
Cameli, P.
Membro del Collaboration Group
;
Bennett, D.
Membro del Collaboration Group
;
Anedda, F.
Membro del Collaboration Group
;
Marcantonio, S.
Membro del Collaboration Group
;
Scolletta, S.
Membro del Collaboration Group
;
Franchi, F.
Membro del Collaboration Group
;
Mazzei, M. A.
Membro del Collaboration Group
;
Guerrini, S.
Membro del Collaboration Group
;
Conticini, E.
Membro del Collaboration Group
;
Cantarini, L.
Membro del Collaboration Group
;
Frediani, B.
Membro del Collaboration Group
;
Valente, S.
Membro del Collaboration Group
;
Mandalà, M.;Giorli, A.
Membro del Collaboration Group
;
Salerni, L.
Membro del Collaboration Group
;
Tumbarello, M.
Membro del Collaboration Group
2022

Abstract

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care(1) or hospitalization(2-4) 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. © 2022, The Author(s).
Kousathanas, A., Pairo-Castineira, E., Rawlik, K., Stuckey, A., Odhams, C.A., Walker, S., et al. (2022). Whole-genome sequencing reveals host factors underlying critical COVID-19. NATURE, 607(7917), 97-103 [10.1038/s41586-022-04576-6].
File in questo prodotto:
File Dimensione Formato  
Whole-genome sequencing reveals host factors-Kousathanas-Nature-2020.pdf

accesso aperto

Tipologia: PDF editoriale
Licenza: Creative commons
Dimensione 8 MB
Formato Adobe PDF
8 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/1216994