Views provided by UsageCountsGenetic mechanisms of critical illness in COVID-19
Copyright policy )UKRI| Understanding disease through environment-wide association studies ,
UKRI| Quantitative Traits in Health and Disease ,
WT| Stratifying Resilience and Depression Longitudinally (STRADL) ,
UKRI| Computational and Disease Genomics ,
UKRI| ISARIC - Coronavirus Clinical Characterisation Consortium (ISARIC-4C) ,
WT| Generation Scotland:NextGenScot ,
EC| PREPARE ,
WT| Establishing causal relationships from phenotypic, genotypic, and proteomic data. ,
WT| ISARIC ,
UKRI| Determining the causal links and clinical significance of rare genetic variants ,
HRB| unidentified ,
WT| Identification and characterisation of host factors underlying susceptibility to influenza.
Pairo-Castineira, Erola; Clohisey, Sara; Klaric, Lucija; Bretherick, Andrew D; Rawlik, Konrad; Pasko, Dorota; Walker, Susan; +193 Authors
Pairo-Castineira, Erola; Clohisey, Sara; Klaric, Lucija; Bretherick, Andrew D; Rawlik, Konrad; Pasko, Dorota; Walker, Susan; Parkinson, Nick; Fourman, Max Head; Russell, Clark D; Furniss, James; Richmond, Anne; Gountouna, Elvina; Wrobel, Nicola; Harrison, David; Wang, Bo; Wu, Yang; Meynert, Alison; Griffiths, Fiona; Oosthuyzen, Wilna; Kousathanas, Athanasios; Moutsianas, Loukas; Yang, Zhijian; Zhai, Ranran; Zheng, Chenqing; Grimes, Graeme; Beale, Rupert; Millar, Jonathan; Shih, Barbara; Keating, Sean; Zechner, Marie; Haley, Chris; Porteous, David J; Hayward, Caroline; Yang, Jian; Knight, Julian; Summers, Charlotte; Shankar-Hari, Manu; Klenerman, Paul; Turtle, Lance; Ho, Antonia; Moore, Shona C; Hinds, Charles; Horby, Peter; Nichol, Alistair; Maslove, David; Ling, Lowell; McAuley, Danny; Montgomery, Hugh; Walsh, Timothy; Pereira, Alexandre C; Renieri; Johnny Millar; Alistair Nichol; Tim Walsh; Manu Shankar-Hari; Chris Ponting; Jen Meikle; Paul Finernan; Ellie Mcmaster; Andy Law; J Kenneth Baillie; Trevor Paterson; Tony Wackett; Ruth Armstrong; Richard Clark; Audrey Coutts; Lorna Donnelly; Tammy Gilchrist; Katarzyna Hafezi; Louise Macgillivray; Alan Maclean; Sarah McCafferty; Kirstie Morrice; Jane Weaver; Ceilia Boz; Ailsa Golightly; Mari Ward; Hanning Mal; Helen Szoor-McElhinney; Adam Brown; Ross Hendry; Andrew Stenhouse; Louise Cullum; Dawn Law; Sarah Law; Rachel Law; Maaike Swets; Nicky Day; Filip Taneski; Esther Duncan; Nicholas Parkinson; D Collier; S Wood; A Zak; C Borra; M Matharu; P May; Z Alldis; O Mitchelmore; R Bowles; A Easthope; F Bibi; I Lancoma-Malcolm; J Gurasashvili; J Pheby; J Shiel; M Bolton; M Patel; M Taylor; O Zongo; P Ebano; P Harding; R Astin-Chamberlain; Y Choudhury; A Cox; D Kallon; M Burton; R Hall; S Blowes; Z Prime; J Biddle; O Prysyazhna; T Newman; C Tierney; J Kassam; M Shankar-Hari; M Ostermann; S Campos; A Bociek; R Lim; N Grau; T O Jones; C Whitton; M Marotti; G Arbane; S Bonner; K Hugill; J Reid; I Welters; V Waugh; K Williams; D Shaw; J Fernandez Roman; M Lopez Martinez; E Johnson; A Waite; B Johnston; D Hamilton; S Mulla; M McPhail; J Smith; J K Baillie; L Barclay; D Hope; C McCulloch; L McQuillan; S Clark; J Singleton; K Priestley; N Rea; M Callaghan; R Campbell; G Andrew; L Marshall; S McKechnie; P Hutton; A Bashyal; N Davidson; C Summers; P Polgarova; K Stroud; N Pathan; K Elston; S Agrawal; C Battle; L Newey; T Rees; R Harford; E Brinkworth; M Williams; C Murphy; I White; M Croft; N Bandla; M Gellamucho; J Tomlinson; H Turner; M Davies; A Quinn; I Hussain; C Thompson; H Parker; R Bradley; R Griffiths; J Scriven; A Nilsson; M Bates; J Dasgin; J Gill;
Genetic mechanisms of critical illness in COVID-19
Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 × 10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice.
- St Mary's Hospital United Kingdom
- Norfolk and Norwich University Hospitals NHS Foundation Trust United Kingdom
- University of Glasgow United Kingdom
- Salford Royal NHS Foundation Trust United Kingdom
- Airedale NHS Foundation Trust United Kingdom
Male, 2',5'-Oligoadenylate Synthetase/genetics, Chromosomes, Human, Pair 21, Pair 19/genetics, Receptor, Interferon alpha-beta, Genome-wide association studies, 23andMe Investigators, Interferon alpha-beta, Inflammation/genetics, Receptors, 2',5'-Oligoadenylate Synthetase, Receptors, CCR2/genetics, Pair 12, Receptor, Interferon alpha-beta/genetics, genetics, CCR2/genetics, Lung, 2'; 5'-Oligoadenylate Synthetase; COVID-19; Chromosomes; Human; Pair 12; Chromosomes; Human; Pair 19; Chromosomes; Human; Pair 21; Critical Care; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Drug Repositioning; Female; Genome-Wide Association Study; Humans; Inflammation; Lung; Male; Multigene Family; Receptor; Interferon alpha-beta; Receptors; CCR2; TYK2 Kinase; United Kingdom; Critical Illness, BRACOVID Investigators, Pair 12/genetics, Multidisciplinary, Chromosomes, Human, Pair 21/genetics, Multigene Family/genetics, GenOMICC Investigators, COVID-19/genetics, covid-19, Multigene Family, Female, Dipeptidyl-Peptidases and Tripeptidyl-Peptidase, 5'-Oligoadenylate Synthetase, Human, Receptor, Critical Care, General Science & Technology, Receptors, CCR2, Critical Illness, Genome-wide association studiesm, Lung/pathology, 610, Chromosomes, Human, Pair 19/genetics, 5'-Oligoadenylate Synthetase/genetics, Chromosomes, 616, Immunogenetics, critical illness, Humans, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Gen-COVID Investigators, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics, TYK2 Kinase/genetics, Inflammation, TYK2 Kinase, Chromosomes, Human, Pair 12/genetics, Chromosomes, Human, Pair 12, Pair 19, Interferon alpha-beta/genetics, SARS-CoV-2, covid 19, Drug Repositioning, COVID-19, Pair 21/genetics, United Kingdom, COVID-19 Human Genetics Initiative, Viral infection, 2',5'-Oligoadenylate Synthetase; COVID-19; Chromosomes, Human, Pair 12; Chromosomes, Human, Pair 19; Chromosomes, Human, Pair 21; Critical Care; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Drug Repositioning; Female; Genome-Wide Association Study; Humans; Inflammation; Lung; Male; Multigene Family; Receptor, Interferon alpha-beta; Receptors, CCR2; TYK2 Kinase; United Kingdom; Critical Illness, ISARICC Investigators, CCR2, Pair 21, 2', Chromosomes, Human, Pair 19, Genome-Wide Association Study
Male, 2',5'-Oligoadenylate Synthetase/genetics, Chromosomes, Human, Pair 21, Pair 19/genetics, Receptor, Interferon alpha-beta, Genome-wide association studies, 23andMe Investigators, Interferon alpha-beta, Inflammation/genetics, Receptors, 2',5'-Oligoadenylate Synthetase, Receptors, CCR2/genetics, Pair 12, Receptor, Interferon alpha-beta/genetics, genetics, CCR2/genetics, Lung, 2'; 5'-Oligoadenylate Synthetase; COVID-19; Chromosomes; Human; Pair 12; Chromosomes; Human; Pair 19; Chromosomes; Human; Pair 21; Critical Care; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Drug Repositioning; Female; Genome-Wide Association Study; Humans; Inflammation; Lung; Male; Multigene Family; Receptor; Interferon alpha-beta; Receptors; CCR2; TYK2 Kinase; United Kingdom; Critical Illness, BRACOVID Investigators, Pair 12/genetics, Multidisciplinary, Chromosomes, Human, Pair 21/genetics, Multigene Family/genetics, GenOMICC Investigators, COVID-19/genetics, covid-19, Multigene Family, Female, Dipeptidyl-Peptidases and Tripeptidyl-Peptidase, 5'-Oligoadenylate Synthetase, Human, Receptor, Critical Care, General Science & Technology, Receptors, CCR2, Critical Illness, Genome-wide association studiesm, Lung/pathology, 610, Chromosomes, Human, Pair 19/genetics, 5'-Oligoadenylate Synthetase/genetics, Chromosomes, 616, Immunogenetics, critical illness, Humans, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Gen-COVID Investigators, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics, TYK2 Kinase/genetics, Inflammation, TYK2 Kinase, Chromosomes, Human, Pair 12/genetics, Chromosomes, Human, Pair 12, Pair 19, Interferon alpha-beta/genetics, SARS-CoV-2, covid 19, Drug Repositioning, COVID-19, Pair 21/genetics, United Kingdom, COVID-19 Human Genetics Initiative, Viral infection, 2',5'-Oligoadenylate Synthetase; COVID-19; Chromosomes, Human, Pair 12; Chromosomes, Human, Pair 19; Chromosomes, Human, Pair 21; Critical Care; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Drug Repositioning; Female; Genome-Wide Association Study; Humans; Inflammation; Lung; Male; Multigene Family; Receptor, Interferon alpha-beta; Receptors, CCR2; TYK2 Kinase; United Kingdom; Critical Illness, ISARICC Investigators, CCR2, Pair 21, 2', Chromosomes, Human, Pair 19, Genome-Wide Association Study
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This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
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This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
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This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
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This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
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