GWAS and meta-analysis identifies multiple new genetic mechanisms underlying severe Covid-19
Author:
Pairo-Castineira ErolaORCID, Rawlik KonradORCID, Klaric LucijaORCID, Kousathanas Athanasios, Richmond Anne, Millar Jonathan, Russell Clark D, Malinauskas Tomas, Thwaites Ryan, Stuckey Alex, Odhams Christopher A, Walker Susan, Griffiths Fiona, Oosthuyzen Wilna, Morrice Kirstie, Keating Sean, Nichol Alistair, Semple Malcolm G, Knight Julian, Shankar-Hari Manu, Summers Charlotte, Hinds Charles, Horby Peter, Ling Lowell, McAuley Danny, Montgomery Hugh, Openshaw Peter J.M., Walsh Timothy, Tenesa Albert, Scott Richard H, Caulfield Mark J, Moutsianas Loukas, Ponting Chris P, Wilson James F, Vitart Veronique, Pereira Alexandre C, Luchessi Andre, Parra Esteban, Cruz-Guerrero Raquel, Carracedo Angel, Fawkes Angie, Murphy Lee, Rowan Kathy, Law AndyORCID, Hendry Sara ClohiseyORCID, Baillie J. KennethORCID, , , ,
Abstract
AbstractPulmonary inflammation drives critical illness in Covid-19, 1;2 creating a clinically homogeneous extreme phenotype, which we have previously shown to be highly efficient for discovery of genetic associations. 3;4 Despite the advanced stage of illness, we have found that immunomodulatory therapies have strong beneficial effects in this group. 1;5 Further genetic discoveries may identify additional therapeutic targets to modulate severe disease. 6 In this new data release from the GenOMICC (Genetics Of Mortality in Critical Care) study we include new microarray genotyping data from additional critically-ill cases in the UK and Brazil, together with cohorts of severe Covid-19 from the ISARIC4C 7 and SCOURGE 8 studies, and meta-analysis with previously-reported data. We find an additional 14 new genetic associations. Many are in potentially druggable targets, in inflammatory signalling (JAK1, PDE4A), monocyte-macrophage differentiation (CSF2), immunometabolism (SLC2A5, AK5), and host factors required for viral entry and replication (TMPRSS2, RAB2A). As with our previous work, these results provide tractable therapeutic targets for modulation of harmful host-mediated inflammation in Covid-19.
Publisher
Cold Spring Harbor Laboratory
Reference36 articles.
1. Horby, P. et al. Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report. New England Journal of Medicine (2020). 2. Dorward, D. A. et al. Tissue-specific Immunopathology in Fatal COVID-19. American Journal of Respiratory and Critical Care Medicine (2020). 3. Genetic mechanisms of critical illness in COVID-19 4. Kousathanas, A. et al. Whole genome sequencing reveals host factors underlying critical Covid-19. Nature 1–10 (2022). 5. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial
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