Whole genome sequencing identifies multiple loci for critical illness caused by COVID-19

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Kousathanas, Athanasios ORCID: 0000-0001-6265-6521, Pairo-Castineira, Erola ORCID: 0000-0002-2423-3090, Rawlik, Konrad ORCID: 0000-0002-0010-370X, Stuckey, Alex ORCID: 0000-0001-8636-737X, Odhams, Christopher ORCID: 0000-0003-2396-6150, Walker, Susan, Russell, Clark ORCID: 0000-0002-9873-8243, Malinauskas, Tomas, Millar, Jonathan ORCID: 0000-0002-4853-9377, Elliott, Katherine et al (show 52 more authors) , Griffiths, Fiona, Oosthuyzen, Wilna, Morrice, Kirstie, Keating, Sean, Wang, Bo, Rhodes, Daniel, Klaric, Lucija, Zechner, Marie, Parkinson, Nick, Bretherick, Andrew ORCID: 0000-0001-9258-3140, Siddiq, Afshan, Goddard, Peter, Donovan, Sally, Maslove, David, Nichol, Alistair, Semple, Malcolm ORCID: 0000-0001-9700-0418, Zainy, Tala, Maleady-Crowe, Fiona, Todd, Linda, Salehi, Shahla, Knight, Julian ORCID: 0000-0002-0377-5536, Elgar, Greg, Chan, Georgia, Arumugam, Prabhu, Fowler, Tom ORCID: 0000-0002-7258-2279, Rendon, Augusto, Shankar-Hari, Manu, Summers, Charlotte ORCID: 0000-0002-7269-2873, Hinds, Charles, Horby, Peter, McAuley, Danny, Montgomery, Hugh, Openshaw, Peter JM, Wu, Yang, Yang, Jian, Elliott, Paul, Walsh, Timothy, GenOMICC Investigators, 23andMe, Covid-19 Human Genetics Initiative, Fawkes, Angie, Murphy, Lee, Rowan, Kathy, Ponting, Chris, Vitart, Veronique, Wilson, James, Scott, Richard, Clohisey, Sara, Moutsianas, Loukas, Law, Andy, Caulfield, Mark and Baillie, Kenneth (2021) Whole genome sequencing identifies multiple loci for critical illness caused by COVID-19. [Preprint]

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Abstract

Critical illness in COVID-19 is caused by inflammatory lung injury, mediated by the host immune system. We and others have shown that host genetic variation influences the development of illness requiring critical care 1 or hospitalisation 2;3;4 following SARS-Co-V2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study recruits critically-ill cases and compares their genomes with population controls in order to find underlying disease mechanisms. Here, we use whole genome sequencing and statistical fine mapping in 7,491 critically-ill cases compared with 48,400 population controls to discover and replicate 22 independent variants that significantly predispose to life-threatening COVID-19. We identify 15 new independent associations with critical COVID-19, 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 expression of multiple genes, including reduced expression of a membrane flippase ( ATP11A ), and increased mucin expression ( MUC1 ), in critical disease. We show that comparison between critically-ill cases and population controls is highly efficient for genetic association analysis and enables detection of therapeutically-relevant mechanisms of disease. Therapeutic predictions arising from these findings require testing in clinical trials.

Item Type:	Preprint
Uncontrolled Keywords:	GenOMICC Investigators, 23andMe, Covid-19 Human Genetics Initiative
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences
Depositing User:	Symplectic Admin
Date Deposited:	22 Oct 2021 07:02
Last Modified:	15 Aug 2024 13:49
DOI:	10.1101/2021.09.02.21262965
Open Access URL:	http://10.0.4.77/2021.09.02.21262965
Related URLs:	Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3141191