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dc.contributor.authorPairo-Castineira, Erola
dc.contributor.authorRawlik, Konrad
dc.contributor.authorBretherick, Andrew D
dc.contributor.authorQi, Ting
dc.contributor.authorWu, Yang
dc.contributor.authorNassiri, Isar
dc.contributor.authorMcConkey, Glenn A
dc.contributor.authorZechner, Marie
dc.contributor.authorKlaric, Lucija
dc.contributor.authorGriffiths, Fiona
dc.contributor.authorOosthuyzen, Wilna
dc.contributor.authorKousathanas, Athanasios
dc.contributor.authorRichmond, Anne
dc.contributor.authorMillar, Jonathan
dc.contributor.authorRussell, Clark D
dc.contributor.authorMalinauskas, Tomas
dc.contributor.authorThwaites, Ryan
dc.contributor.authorMorrice, Kirstie
dc.contributor.authorKeating, Sean
dc.contributor.authorMaslove, David
dc.contributor.authorNichol, Alistair
dc.contributor.authorSemple, Malcolm G
dc.contributor.authorKnight, Julian
dc.contributor.authorShankar-Hari, Manu
dc.contributor.authorSummers, Charlotte
dc.contributor.authorHinds, Charles
dc.contributor.authorHorby, Peter
dc.contributor.authorLing, Lowell
dc.contributor.authorMcAuley, Danny
dc.contributor.authorMontgomery, Hugh
dc.contributor.authorOpenshaw, Peter J M
dc.contributor.authorBegg, Colin
dc.contributor.authorWalsh, Timothy
dc.contributor.authorTenesa, Albert
dc.contributor.authorFlores, Carlos
dc.contributor.authorRiancho, José A
dc.contributor.authorRojas-Martinez, Augusto
dc.contributor.authorLapunzina, Pablo
dc.contributor.authorYang, Jian
dc.contributor.authorPonting, Chris P
dc.contributor.authorWilson, James F
dc.contributor.authorVitart, Veronique
dc.contributor.authorAbedalthagafi, Malak
dc.contributor.authorLuchessi, Andre D
dc.contributor.authorParra, Esteban J
dc.contributor.authorCruz, Raquel
dc.contributor.authorCarracedo, Angel
dc.contributor.authorFawkes, Angie
dc.contributor.authorMurphy, Lee
dc.contributor.authorRowan, Kathy
dc.contributor.authorPereira, Alexandre C
dc.contributor.authorLaw, Andy
dc.contributor.authorFairfax, Benjamin
dc.contributor.authorHendry, Sara Clohisey
dc.contributor.authorBaillie, J Kenneth
dc.contributor.authorGenOMICC Investigators
dc.contributor.authorSCOURGE Consortium
dc.contributor.authorISARICC Investigators
dc.contributor.authorThe 23andMe COVID-19 Team
dc.contributor.authorBrochado-Kith, Oscar 
dc.contributor.authorCeballos, Francisco C 
dc.contributor.authorFernandez-Rodriguez, Amanda 
dc.contributor.authorJimenez-Sousa, Maria Angeles 
dc.contributor.authorMartin-Vicente, Maria 
dc.contributor.authorResino, Salvador 
dc.contributor.authorVirseda-Berdices, Ana 
dc.contributor.authorMeijome, Xose M
dc.date.accessioned2023-05-24T09:50:39Z
dc.date.available2023-05-24T09:50:39Z
dc.date.issued2023-05-17
dc.identifier.citationNature. 2023 May;617(7962):764-768.es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/16117
dc.description.abstractCritical 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).es_ES
dc.description.sponsorshipGenOMICC was funded by Sepsis Research (the Fiona Elizabeth Agnew Trust), the Intensive Care Society, a Wellcome Trust Senior Research Fellowship (to J.K.B., 223164/Z/21/Z), the Department of Health and Social Care (DHSC), Illumina, LifeArc, the Medical Research Council, UKRI, a BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070 and BBS/E/D/30002275) and UKRI grants MC_PC_20004, MC_PC_19025, MC_PC_1905 and MRNO2995X/1. A.D.B. acknowledges funding from the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z), the Edinburgh Clinical Academic Track (ECAT) programme. This research is supported in part by the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant MC_PC_20029). Laboratory work was funded by a Wellcome Intermediate Clinical Fellowship to B.F. (201488/Z/16/Z). We acknowledge the staff at NHS Digital, Public Health England and the Intensive Care National Audit and Research Centre who provided clinical data on the participants; and the National Institute for Healthcare Research Clinical Research Network (NIHR CRN) and the Chief Scientist’s Office (Scotland), who facilitate recruitment into research studies in NHS hospitals, and to the global ISARIC and InFACT consortia. GenOMICC genotype controls were obtained using UK Biobank Resource under project 788 funded by Roslin Institute Strategic Programme Grants from the BBSRC (BBS/E/D/10002070 and BBS/E/D/30002275) and Health Data Research UK (HDR-9004 and HDR-9003). UK Biobank data were used in the GSMR analyses presented here under project 66982. The UK Biobank was established by the Wellcome Trust medical charity, Medical Research Council, Department of Health, Scottish Government and the Northwest Regional Development Agency. It has also had funding from the Welsh Assembly Government, British Heart Foundation and Diabetes UK. The work of L.K. was supported by an RCUK Innovation Fellowship from the National Productivity Investment Fund (MR/R026408/1). J.Y. is supported by the Westlake Education Foundation. SCOURGE is funded by the Instituto de Salud Carlos III (COV20_00622 to A.C., PI20/00876 to C.F.), European Union (ERDF) ‘A way of making Europe’, Fundación Amancio Ortega, Banco de Santander (to A.C.), Cabildo Insular de Tenerife (CGIEU0000219140 ‘Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19’ to C.F.) and Fundación Canaria Instituto de Investigación Sanitaria de Canarias (PIFIISC20/57 to C.F.). We also acknowledge the contribution of the Centro National de Genotipado (CEGEN) and Centro de Supercomputación de Galicia (CESGA) for funding this project by providing supercomputing infrastructures. A.D.L. is a recipient of fellowships from the National Council for Scientific and Technological Development (CNPq)-Brazil (309173/2019-1 and 201527/2020-0). We thank the members of the Banco Nacional de ADN and the GRA@CE cohort group; and the research participants and employees of 23andMe for making this work possible. A full list of contributors who have provided data that were collated in the HGI project, including previous iterations, is available online (https://www.covid19hg.org/acknowledgements).es_ES
dc.language.isoenges_ES
dc.publisherNature Publishing Group es_ES
dc.type.hasVersionVoRes_ES
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.titleGWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19es_ES
dc.typejournal articlees_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.identifier.pubmedID37198478es_ES
dc.format.volume617
dc.format.number7962
dc.format.page764-768
dc.identifier.doi10.1038/s41586-023-06034-3es_ES
dc.contributor.funderInstituto de Salud Carlos III es_ES
dc.contributor.funderUnión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) es_ES
dc.contributor.funderFundación Amancio Ortegaes_ES
dc.contributor.funderBanco Santander es_ES
dc.contributor.funderGobierno de Canarias (España) es_ES
dc.contributor.funderFundación Canaria de Investigación Sanitaria es_ES
dc.contributor.funderCentro de Supercomputación de Galiciaes_ES
dc.contributor.funderNational Council for Scientific and Technological Development (Brasil) es_ES
dc.contributor.funderSepsis Trust NZes_ES
dc.contributor.funderWellcome Trust es_ES
dc.contributor.funderIllumina (Reino Unido)es_ES
dc.contributor.funderWestlake Educational Foundationes_ES
dc.contributor.funderBritish Heart Foundation es_ES
dc.contributor.funderBiotechnology and Biological Sciences Research Council (Reino Unido) es_ES
dc.contributor.funderUK Research and Innovation es_ES
dc.contributor.funderMedical Research Council (Reino Unido) es_ES
dc.contributor.funderLifeArces_ES
dc.contributor.funderDepartment of Health and Social Care (Reino Unido)es_ES
dc.description.peerreviewedes_ES
dc.identifier.e-issn1476-4687es_ES
dc.relation.publisherversionhttps://doi.org/10.1038/s41586-023-06034-3es_ES
dc.identifier.journalNaturees_ES
dc.repisalud.centroISCIII::Centro Nacional de Microbiologíaes_ES
dc.repisalud.centroISCIII::Unidad de Investigación en Cuidados de Salud (Investén-isciii)es_ES
dc.repisalud.institucionISCIIIes_ES
dc.rights.accessRightsopen accesses_ES
dc.relation.projectFISinfo:eu-repo/grantAgreement/ES/COV20_00622es_ES
dc.relation.projectFISinfo:fis/Instituto de Salud Carlos III/Programa Estatal de Generación de Conocimiento y Fortalecimiento del Sistema Español de I+D+I/Subprograma Estatal de Generación de Conocimiento/PI20 - Proyectos de investigacion en salud (AES 2020). Modalidad proyectos de investigación en salud. (2020)/PI20/00876es_ES


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