Genetic mechanisms of critical illness in Covid-19
Genetic mechanisms of critical illness in Covid-19
Abstract The subset of patients who develop critical illness in Covid-19 have extensive inflammation affecting the lungs1 and are strikingly different from other patients: immunosuppressive therapy benefits critically-ill patients, but may harm some non-critical cases.2 Since susceptibility to life-threatening infections and immune-mediated diseases are both strongly heritable traits, we reasoned that host genetic variation may identify mechanistic targets for therapeutic development in Covid-19.3 GenOMICC (Genetics Of Mortality In Critical Care, genomicc.org) is a global collaborative study to understand the genetic basis of critical illness. Here we report the results of a genome-wide association study (GWAS) in 2244 critically-ill Covid-19 patients from 208 UK intensive care units (ICUs), representing >95% of all ICU beds. Ancestry-matched controls were drawn from the UK Biobank population study. We identify and replicate three novel genome-wide significant associations, at chr19p13.3 (rs2109069, p = 3.98 × 10?12), within the gene encoding dipeptidyl peptidase 9 (DPP9), at chr12q24.13 (rs10735079, p = 1.65 × 10?8) in a gene cluster encoding antiviral viral restriction enzymes (OAS1, OAS2, OAS3), and at chr21q22.1 (rs2236757, p = 4.99 × 10?8) in the interferon receptor gene IFNAR2. Consistent with our focus on extreme disease in younger patients with less comorbidity, we detect a stronger signal at the known 3p21.31 locus than previous studies (rs73064425, p = 1.2 × 10?27). We identify potential targets for repurposing of licensed medications. Using Mendelian randomisation we found evidence in support of a causal link from low expression of IFNAR2, and high expression of TYK2, to life-threatening disease. 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. Large-scale randomised clinical trials will be essential before any change to clinical practice.
Wilson James F.、Hayward Caroline、Horby Peter、Moutsianas Loukas、Fourman Max Head、The GenOMICC Investigators,The ISARIC-4C Investigators, The Covid-19 Human Genetics Initiative、Porteous David J.、Zheng Chenqing、Griffiths Fiona、Oosthuyzen Wilna、Keating Sean、Summers Charlotte、Turtle Lance、Ho Antonia、McAuley Danny、Montgomery Hugh、Walsh Timothy、Rowan Kathy、Fawkes Angie、Ponting Chris P.、Tenesa Albert、Vitart Veronique、Baillie J. Kenneth、Barrett Jeffery C、Knight Julian、Rawlik Konrad、Pasko Dorota、Richmond Anne、Law Andrew、Furniss James、Gountouna Elvina、Semple Malcolm G.、Zhai Ranran、Nichol Alistair、Russell Clark D、Wrobel Nicola、Caulfield Mark、Zechner Marie、Yang Zhijian、Parkinson Nick、Ling Lowell、Walker Susan、Klaric Lucija、Shen Xia、Meynert Alison、Wang Bo、Murphy Lee、Haley Chris、Hinds Charles、Scott Richard、Shih Barbara、Maslove David、Klenerman Paul、Bretherick Andrew、Openshaw Peter J.M.、Pairo-Castineira Erola、Shankar-Hari Manu、van Heel David、Grimes Graeme、Clohisey Sara
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital||Centre for Global Health Research, Usher Institute of Population Health Sciences and InformaticsCentre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General HospitalCentre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Old Road Campus, Roosevelt DriveGenomics EnglandRoslin Institute, University of EdinburghCentre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General HospitalBiostatistics Group, School of Life Sciences, Sun Yat-sen UniversityRoslin Institute, University of EdinburghRoslin Institute, University of EdinburghIntenstive Care Unit, Royal Infirmary of Edinburgh, 54 Little France DriveDepartment of Medicine, University of CambridgeNIHR Health Protection Research Unit for Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences University of LiverpoolMRC-University of Glasgow Centre for Virus Research, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of GlasgowWellcome-Wolfson Institute for Experimental Medicine, Queen?ˉs University Belfast||Department of Intensive Care Medicine, Royal Victoria HospitalUCL Centre for Human Health and PerformanceIntenstive Care Unit, Royal Infirmary of Edinburgh, 54 Little France DriveIntensive Care National Audit & Research CentreEdinburgh Clinical Research Facility, Western General Hospital, University of EdinburghMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General HospitalRoslin Institute, University of EdinburghMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General HospitalRoslin Institute, University of Edinburgh||Intenstive Care Unit, Royal Infirmary of Edinburgh, 54 Little France DriveWellcome Sanger Institute, Wellcome Genome CampusWellcome Centre for Human Genetics, University of OxfordRoslin Institute, University of EdinburghGenomics EnglandMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General HospitalRoslin Institute, University of EdinburghRoslin Institute, University of EdinburghCentre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General HospitalUniversity of LiverpoolBiostatistics Group, School of Life Sciences, Sun Yat-sen UniversityClinical Research Centre at St Vincent?ˉs University Hospital, University College Dublin||Australian and New Zealand Intensive Care Research Centre, Monash University||Intensive Care Unit, Alfred HospitalRoslin Institute, University of Edinburgh||University of Edinburgh Centre for Inflammation Research, The Queen?ˉs Medical Research InstituteEdinburgh Clinical Research Facility, Western General Hospital, University of EdinburghGenomics England||William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of LondonRoslin Institute, University of EdinburghBiostatistics Group, School of Life Sciences, Sun Yat-sen UniversityRoslin Institute, University of EdinburghDepartment of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Prince of Wales HospitalGenomics EnglandMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General HospitalBiostatistics Group, School of Life Sciences, Sun Yat-sen University||Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics||Department of Medical Epidemiology and Biostatistics, Karolinska InstitutetMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General HospitalRoslin Institute, University of EdinburghEdinburgh Clinical Research Facility, Western General Hospital, University of EdinburghRoslin Institute, University of EdinburghWilliam Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of LondonGenomics England||Great Ormond Street Hospital for Children NHS Foundation TrustRoslin Institute, University of EdinburghDepartment of Critical Care Medicine, Queen?ˉs University and Kingston Health Sciences CentreWellcome Centre for Human Genetics, University of OxfordRoslin Institute, University of EdinburghNational Heart & Lung Institute, Imperial College London (St Mary?ˉs Campus)Roslin Institute, University of EdinburghDepartment of Intensive Care Medicine, Guy?ˉs and St. Thomas NHS Foundation Trust||School of Immunology and Microbial Sciences, King?ˉs College LondonBlizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of LondonMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General HospitalRoslin Institute, University of Edinburgh
基础医学遗传学医学研究方法
Wilson James F.,Hayward Caroline,Horby Peter,Moutsianas Loukas,Fourman Max Head,The GenOMICC Investigators,The ISARIC-4C Investigators, The Covid-19 Human Genetics Initiative,Porteous David J.,Zheng Chenqing,Griffiths Fiona,Oosthuyzen Wilna,Keating Sean,Summers Charlotte,Turtle Lance,Ho Antonia,McAuley Danny,Montgomery Hugh,Walsh Timothy,Rowan Kathy,Fawkes Angie,Ponting Chris P.,Tenesa Albert,Vitart Veronique,Baillie J. Kenneth,Barrett Jeffery C,Knight Julian,Rawlik Konrad,Pasko Dorota,Richmond Anne,Law Andrew,Furniss James,Gountouna Elvina,Semple Malcolm G.,Zhai Ranran,Nichol Alistair,Russell Clark D,Wrobel Nicola,Caulfield Mark,Zechner Marie,Yang Zhijian,Parkinson Nick,Ling Lowell,Walker Susan,Klaric Lucija,Shen Xia,Meynert Alison,Wang Bo,Murphy Lee,Haley Chris,Hinds Charles,Scott Richard,Shih Barbara,Maslove David,Klenerman Paul,Bretherick Andrew,Openshaw Peter J.M.,Pairo-Castineira Erola,Shankar-Hari Manu,van Heel David,Grimes Graeme,Clohisey Sara.Genetic mechanisms of critical illness in Covid-19[EB/OL].(2025-03-28)[2025-08-02].https://www.medrxiv.org/content/10.1101/2020.09.24.20200048.点此复制
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