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oai:repisalud.isciii.es:20.500.12105/231262025-04-01T07:10:21Zcom_20.500.12105_2173com_20.500.12105_2051com_20.500.12105_15322col_20.500.12105_19597col_20.500.12105_16963col_20.500.12105_16966col_20.500.12105_16970

00925njm 22002777a 4500 dc Pairo-Castineira, Erola author Rawlik, Konrad author Bretherick, Andrew D author Qi, Ting author Wu, Yang author Nassiri, Isar author McConkey, Glenn A author Zechner, Marie author Klaric, Lucija author Griffiths, Fiona author Oosthuyzen, Wilna author Kousathanas, Athanasios author Richmond, Anne author Millar, Jonathan author Russell, Clark D author Malinauskas, Tomas author Thwaites, Ryan author Morrice, Kirstie author Keating, Sean author Maslove, David author Nichol, Alistair author Semple, Malcolm G author Knight, Julian author Shankar-Hari, Manu author Summers, Charlotte author Hinds, Charles author Horby, Peter author Ling, Lowell author McAuley, Danny author Montgomery, Hugh author Openshaw, Peter J M author Begg, Colin author Walsh, Timothy author Tenesa, Albert author Flores, Carlos author Riancho, José A author Rojas-Martinez, Augusto author Lapunzina, Pablo author Yang, Jian author Ponting, Chris P author Wilson, James F author Vitart, Veronique author Abedalthagafi, Malak author Luchessi, Andre D author Parra, Esteban J author Cruz, Raquel author Carracedo, Ángel author Fawkes, Angie author Murphy, Lee author Rowan, Kathy author Pereira, Alexandre C author Law, Andy author Fairfax, Benjamin author Hendry, Sara Clohisey author Baillie, J Kenneth author 2023-05 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). Nature . 2023 ;617(7962):764-768. 10.1038/s41586-023-06034-3 1476-4687 Nature 37198478 https://hdl.handle.net/20.500.12105/23126 GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19