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oai:repisalud.isciii.es:20.500.12105/161172025-04-01T07:09:38Zcom_20.500.12105_2052com_20.500.12105_2051com_20.500.12105_15322col_20.500.12105_19609col_20.500.12105_16938col_20.500.12105_16958col_20.500.12105_16959col_20.500.12105_16960col_20.500.12105_16962col_20.500.12105_16963col_20.500.12105_16964col_20.500.12105_16966col_20.500.12105_16967col_20.500.12105_16970col_20.500.12105_16971col_20.500.12105_16973col_20.500.12105_16976col_20.500.12105_16975col_20.500.12105_16977col_20.500.12105_16978col_20.500.12105_16979col_20.500.12105_16981col_20.500.12105_16983col_20.500.12105_16972col_20.500.12105_16988
Repisalud author 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 GenOMICC Investigators author SCOURGE Consortium author ISARICC Investigators author The 23andMe COVID-19 Team author Brochado-Kith, Oscar author Ceballos, Francisco C author Fernandez-Rodriguez, Amanda author Jimenez-Sousa, Maria Angeles author Martin-Vicente, Maria author Resino, Salvador author Virseda-Berdices, Ana author Meijome, Xose M funder Instituto de Salud Carlos III funder Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) funder Banco Santander funder Gobierno de Canarias (España) funder Fundación Canaria de Investigación Sanitaria funder National Council for Scientific and Technological Development (Brasil) funder Wellcome Trust funder British Heart Foundation funder Biotechnology and Biological Sciences Research Council (Reino Unido) funder UK Research and Innovation funder Medical Research Council (Reino Unido) funder Fundación Amancio Ortega funder Centro de Supercomputación de Galicia funder Sepsis Trust NZ funder Illumina (Reino Unido) funder Westlake Educational Foundation funder LifeArc funder Department of Health and Social Care (Reino Unido) 2023-05-24T09:50:39Z 2023-05-24T09:50:39Z 2023-05-17 Nature. 2023 May;617(7962):764-768. 10.1038/s41586-023-06034-3 1476-4687 Nature 37198478 http://hdl.handle.net/20.500.12105/16117 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). eng GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19 research article 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 URL https://repisalud.isciii.es/bitstreams/02cb056e-ce64-4f3c-b026-e7f8b026ffd6/download File MD5 37cc1a759502a28f9122837b3be6ebc1 8550978 application/pdf GWASMeta-analysisIdentifies_2023.pdf URL https://repisalud.isciii.es/bitstreams/a5c68162-c836-46e8-a1cb-62d5e185ca27/download File MD5 ff12b1f6e03e42fa837433e6e9931bbc 12457504 application/pdf Supplementary_GWASMeta-analysisIdentifies_2023.pdf URL https://repisalud.isciii.es/bitstreams/2e85b753-ad7c-459e-8979-fd936f48bd30/download File MD5 98596c69b7a6794b5eaeaa3704a63819 171329 text/plain GWASMeta-analysisIdentifies_2023.pdf.txt URL https://repisalud.isciii.es/bitstreams/902cc49c-cdf3-4e71-9bf6-63c928c6e7bb/download File MD5 26c7e4fb5f6436909114115bfa342c18 249142 text/plain Supplementary_GWASMeta-analysisIdentifies_2023.pdf.txt