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dc.contributor.authorKousathanas, Athanasios
dc.contributor.authorPairo-Castineira, Erola
dc.contributor.authorRawlik, Konrad
dc.contributor.authorStuckey, Alex
dc.contributor.authorOdhams, Christopher A
dc.contributor.authorWalker, Susan
dc.contributor.authorRussell, Clark D
dc.contributor.authorMalinauskas, Tomas
dc.contributor.authorWu, Yang
dc.contributor.authorMillar, Jonathan
dc.contributor.authorShen, Xia
dc.contributor.authorElliott, Katherine S
dc.contributor.authorGriffiths, Fiona
dc.contributor.authorOosthuyzen, Wilna
dc.contributor.authorMorrice, Kirstie
dc.contributor.authorKeating, Sean
dc.contributor.authorWang, Bo
dc.contributor.authorRhodes, Daniel
dc.contributor.authorKlaric, Lucija
dc.contributor.authorZechner, Marie
dc.contributor.authorParkinson, Nick
dc.contributor.authorSiddiq, Afshan
dc.contributor.authorGoddard, Peter
dc.contributor.authorDonovan, Sally
dc.contributor.authorMaslove, David
dc.contributor.authorNichol, Alistair
dc.contributor.authorSemple, Malcolm G
dc.contributor.authorZainy, Tala
dc.contributor.authorMaleady-Crowe, Fiona
dc.contributor.authorTodd, Linda
dc.contributor.authorSalehi, Shahla
dc.contributor.authorKnight, Julian
dc.contributor.authorElgar, Greg
dc.contributor.authorChan, Georgia
dc.contributor.authorArumugam, Prabhu
dc.contributor.authorPatch, Christine
dc.contributor.authorRendon, Augusto
dc.contributor.authorBentley, David
dc.contributor.authorKingsley, Clare
dc.contributor.authorKosmicki, Jack A
dc.contributor.authorHorowitz, Julie E
dc.contributor.authorBaras, Aris
dc.contributor.authorAbecasis, Goncalo R
dc.contributor.authorFerreira, Manuel AR
dc.contributor.authorJustice, Anne
dc.contributor.authorMirshahi, Tooraj
dc.contributor.authorOetjens, Matthew
dc.contributor.authorRader, Daniel J
dc.contributor.authorRitchie, Marylyn D
dc.contributor.authorVerma, Anurag
dc.contributor.authorFowler, Tom A
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 JM
dc.contributor.authorElliott, Paul
dc.contributor.authorWalsh, Timothy
dc.contributor.authorTenesa, Albert
dc.contributor.authorGenOMICC investigators
dc.contributor.author23andMe investigators
dc.contributor.authorCOVID-19 Human Genetics Initiative
dc.contributor.authorFawkes, Angie
dc.contributor.authorMurphy, Lee
dc.contributor.authorRowan, Kathy
dc.contributor.authorPonting, Chris P
dc.contributor.authorVitart, Veronique
dc.contributor.authorWilson, James F
dc.contributor.authorYang, Jian
dc.contributor.authorBretherick, Andrew D
dc.contributor.authorScott, Richard H
dc.contributor.authorHendry, Sara Clohisey
dc.contributor.authorMoutsianas, Loukas
dc.contributor.authorLaw, Andy
dc.contributor.authorCaulfield, Mark J
dc.contributor.authorBaillie, J Kenneth
dc.date.accessioned2022-02-24T00:30:46Z
dc.date.available2022-02-24T00:30:46Z
dc.date.issued2022-03-07
dc.identifier.issn0028-0836
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/334396
dc.description.abstractCritical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2-4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.
dc.publisherSpringer Science and Business Media LLC
dc.rightsAll Rights Reserved
dc.rights.urihttp://www.rioxx.net/licenses/all-rights-reserved
dc.titleWhole-genome sequencing reveals host factors underlying critical COVID-19.
dc.typeArticle
dc.publisher.departmentDepartment of Medicine
dc.date.updated2022-02-23T13:41:55Z
prism.publicationNameNature
dc.identifier.doi10.17863/CAM.81812
dcterms.dateAccepted2022-02-23
rioxxterms.versionofrecord10.1038/s41586-022-04576-6
rioxxterms.versionAM
dc.contributor.orcidKousathanas, Athanasios [0000-0001-6265-6521]
dc.contributor.orcidPairo-Castineira, Erola [0000-0002-2423-3090]
dc.contributor.orcidRawlik, Konrad [0000-0002-0010-370X]
dc.contributor.orcidWalker, Susan [0000-0002-5016-6426]
dc.contributor.orcidMalinauskas, Tomas [0000-0002-4847-5529]
dc.contributor.orcidWu, Yang [0000-0002-0128-7280]
dc.contributor.orcidShen, Xia [0000-0003-4390-1979]
dc.contributor.orcidElliott, Katherine S [0000-0002-8125-797X]
dc.contributor.orcidKeating, Sean [0000-0001-8552-5604]
dc.contributor.orcidWang, Bo [0000-0002-1580-797X]
dc.contributor.orcidKlaric, Lucija [0000-0003-3105-8929]
dc.contributor.orcidParkinson, Nick [0000-0001-6336-5654]
dc.contributor.orcidNichol, Alistair [0000-0002-4689-1238]
dc.contributor.orcidSemple, Malcolm G [0000-0001-9700-0418]
dc.contributor.orcidSalehi, Shahla [0000-0002-5058-7706]
dc.contributor.orcidKnight, Julian [0000-0002-0377-5536]
dc.contributor.orcidElgar, Greg [0000-0001-7323-1596]
dc.contributor.orcidPatch, Christine [0000-0002-4191-0663]
dc.contributor.orcidBaras, Aris [0000-0002-6830-3396]
dc.contributor.orcidAbecasis, Goncalo R [0000-0003-1509-1825]
dc.contributor.orcidFerreira, Manuel AR [0000-0001-9059-1825]
dc.contributor.orcidRader, Daniel J [0000-0002-9245-9876]
dc.contributor.orcidRitchie, Marylyn D [0000-0002-1208-1720]
dc.contributor.orcidShankar-Hari, Manu [0000-0002-5338-2538]
dc.contributor.orcidSummers, Charlotte [0000-0002-7269-2873]
dc.contributor.orcidHinds, Charles [0000-0001-5094-8324]
dc.contributor.orcidMcAuley, Danny [0000-0002-3283-1947]
dc.contributor.orcidMontgomery, Hugh [0000-0001-8797-5019]
dc.contributor.orcidElliott, Paul [0000-0002-7511-5684]
dc.contributor.orcidTenesa, Albert [0000-0003-4884-4475]
dc.contributor.orcidMurphy, Lee [0000-0001-6467-7449]
dc.contributor.orcidRowan, Kathy [0000-0001-8217-5602]
dc.contributor.orcidPonting, Chris P [0000-0003-0202-7816]
dc.contributor.orcidVitart, Veronique [0000-0002-4991-3797]
dc.contributor.orcidWilson, James F [0000-0001-5751-9178]
dc.contributor.orcidYang, Jian [0000-0003-2001-2474]
dc.contributor.orcidBretherick, Andrew D [0000-0001-9258-3140]
dc.contributor.orcidHendry, Sara Clohisey [0000-0001-7489-9846]
dc.contributor.orcidMoutsianas, Loukas [0000-0001-5453-345X]
dc.contributor.orcidLaw, Andy [0000-0003-1868-2364]
dc.contributor.orcidCaulfield, Mark J [0000-0001-9295-3594]
dc.contributor.orcidBaillie, J Kenneth [0000-0001-5258-793X]
dc.identifier.eissn1476-4687
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (MC_PC_14089)
cam.issuedOnline2022-03-07
cam.orpheus.successWed Mar 23 10:26:36 GMT 2022 - Embargo updated
cam.orpheus.counter1
cam.depositDate2022-02-23
pubs.licence-identifierapollo-deposit-licence-2-1
pubs.licence-display-nameApollo Repository Deposit Licence Agreement
rioxxterms.freetoread.startdate2022-09-07


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