TY - JOUR
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 E.
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, Nicholas
AU - Siddiq, Afshan
AU - Goddard, Peter
AU - Donovan, Sally
AU - Maslove, David M.
AU - Nichol, Alistair D.
AU - Semple, Malcolm G.
AU - Zainy, Tala
AU - Maleady-Crowe, Fiona
AU - Todd, Linda
AU - Salehi, Shahla
AU - Knight, Julian C.
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
AU - Ritchie, Marylyn D.
AU - Verma, Anurag
AU - Fowler, Tom
AU - Shankar-Hari, Manu
AU - Summers, Charlotte
AU - Hinds, Charles J.
AU - Horby, Peter W.
AU - Ling, Lowell
AU - McAuley, Daniel F.
AU - Montgomery, Hugh
AU - Openshaw, Peter J.M.
AU - Elliott, Paul
AU - Walsh, Timothy
AU - Tenesa, Albert
AU - The GenOMICC Investigators
AU - 23andMe
AU - The Covid-19 Human Genetics Initiative
AU - Fawkes, Angie
AU - Murphy, Lee
AU - Rowan, Kathryn M.
AU - Ponting, Chris P.
AU - Vitart, Veronique
AU - Wilson, James F.
AU - Yang, Jian
AU - Bretherick, Andrew D.
AU - Scott, Richard H.
AU - Hendry, Sara Clohisey
AU - Moutsianas, Loukas
AU - Law, Andy
AU - Caulfield, Mark J.
AU - Baillie, J. Kenneth
PY - 2022
DA - March
TI - Whole genome sequencing reveals host factors underlying critical Covid-19
JO - Nature
DO - https://doi.org/10.1038/s41586-022-04576-6
AB - Critical Covid-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalisation2-4 following SARS-CoV-2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from critically-ill cases with population controls in order to find underlying disease mechanisms. Here, we use whole genome sequencing in 7,491 critically-ill cases 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 involved in interferon signalling (IL10RB, PLSCR1), leucocyte differentiation (BCL11A), and blood type antigen secretor status (FUT2). Using transcriptome-wide association and colocalisation to infer the effect of gene expression on disease severity, we find evidence implicating multiple genes, including reduced expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1), in critical disease. Mendelian randomisation provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5, CD209) and 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 critically-ill cases and population controls is highly efficient for detection of therapeutically-relevant mechanisms of disease.
PB - Springer Nature
UR - https://www.research.ed.ac.uk/en/publications/8b1d3897-21b1-4dd3-bd26-f7291559786d
KW - Coronavirus (COVID-19)
ER