TY - JOUR
T1 - Whole-genome sequencing reveals host factors underlying critical COVID-19
AU - 23andMe investigators
AU - COVID-Human Genetics Initiative
AU - GenOMICC investigators
AU - Kousathanas, Athanasios
AU - Pairo-Castineira, Erola
AU - Rawlik, Konrad
AU - Stuckey, Alex
AU - Odhams, Christopher A.
AU - Walker, Susan
AU - Russell, Clark D.
AU - Malinauskas, Tomas
AU - Wu, Yang
AU - Millar, Jonathan
AU - Shen, Xia
AU - Elliott, Katherine S.
AU - Griffiths, Fiona
AU - Oosthuyzen, Wilna
AU - Morrice, Kirstie
AU - Keating, Sean
AU - Wang, Bo
AU - Rhodes, Daniel
AU - Klaric, Lucija
AU - Zechner, Marie
AU - Parkinson, Nick
AU - Siddiq, Afshan
AU - Goddard, Peter
AU - Donovan, Sally
AU - Maslove, David
AU - Nichol, Alistair
AU - Semple, Malcolm G.
AU - Zainy, Tala
AU - Maleady-Crowe, Fiona
AU - Todd, Linda
AU - Salehi, Shahla
AU - Knight, Julian
AU - Elgar, Greg
AU - Chan, Georgia
AU - Arumugam, Prabhu
AU - Patch, Christine
AU - Rendon, Augusto
AU - Bentley, David
AU - Kingsley, Clare
AU - Kosmicki, Jack A.
AU - Horowitz, Julie E.
AU - Baras, Aris
AU - Abecasis, Goncalo R.
AU - Ferreira, Manuel A.R.
AU - Justice, Anne
AU - Mirshahi, Tooraj
AU - Oetjens, Matthew
AU - Rader, Daniel J.
AU - Ritchie, Marylyn D.
AU - Hottenga, Jouke Jan
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/7/7
Y1 - 2022/7/7
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85134361378
U2 - 10.1038/s41586-022-04576-6
DO - 10.1038/s41586-022-04576-6
M3 - Article
C2 - 35255492
AN - SCOPUS:85134361378
SN - 0028-0836
VL - 607
SP - 97
EP - 103
JO - Nature
JF - Nature
IS - 7917
ER -