GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19

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Pairo-Castineira, Erola, Rawlik, Konrad, Bretherick, Andrew D, Qi, Ting, Wu, Yang, Nassiri, Isar, McConkey, Glenn A, Zechner, Marie, Klaric, Lucija, Griffiths, Fiona et al (show 45 more authors) , Oosthuyzen, Wilna, Kousathanas, Athanasios, Richmond, Anne, Millar, Jonathan, Russell, Clark D, Malinauskas, Tomas, Thwaites, Ryan, Morrice, Kirstie, Keating, Sean, Maslove, David, Nichol, Alistair, Semple, Malcolm G ORCID: 0000-0001-9700-0418, Knight, Julian, Shankar-Hari, Manu, Summers, Charlotte, Hinds, Charles, Horby, Peter, Ling, Lowell, McAuley, Danny, Montgomery, Hugh, Openshaw, Peter JM, Begg, Colin, Walsh, Timothy, Tenesa, Albert, Flores, Carlos, Riancho, Jose A, Rojas-Martinez, Augusto, Lapunzina, Pablo, Yang, Jian, Ponting, Chris P, Wilson, James F, Vitart, Veronique, Abedalthagafi, Malak, Luchessi, Andre D, Parra, Esteban J, Cruz, Raquel, Carracedo, Angel, Fawkes, Angie, Murphy, Lee, Rowan, Kathy, Pereira, Alexandre C, Law, Andy, Fairfax, Benjamin, Hendry, Sara Clohisey and Baillie, J Kenneth (2023) GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19. NATURE, 617 (7962). 764-+.

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Abstract

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown¹ to be highly efficient for discovery of genetic associations². Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group³. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte-macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Item Type:	Article
Uncontrolled Keywords:	GenOMICC Investigators, SCOURGE Consortium, ISARICC Investigators, 23andMe COVID-19 Team, Monocytes, Humans, Critical Illness, Genetic Predisposition to Disease, rab GTP-Binding Proteins, Genotype, Phenotype, Genetic Variation, Genome-Wide Association Study, Transcriptome, Genotyping Techniques, Whole Genome Sequencing, COVID-19
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences
Depositing User:	Symplectic Admin
Date Deposited:	31 Aug 2023 07:39
Last Modified:	31 Aug 2023 08:32
DOI:	10.1038/s41586-023-06034-3
Open Access URL:	https://doi.org/10.1038/s41586-023-06034-3
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3172445