Genetic mechanisms of critical illness in COVID-19
Authors: Dorota Pasko
Angie Fawkes
Lance Turtle
Malcolm G Semple
Rupert Beale
ISARIC4C Investigators
Zhijian Yang
David Harrison
Sean Keating
Sara Clohisey
Andrew Law
Bo Wang
Marie Zechner
Lowell Ling
Nicola Wrobel
Erola Pairo-Castineira
Kathy Rowan
Julian Knight
Veronique Vitart
Anne Richmond
Peter Horby
Loukas Moutsianas
Timothy Walsh
Chris Haley
Alison Meynert
Manu Shankar-Hari
Ranran Zhai
Peter J M Openshaw
Yang Wu
James Furniss
Graeme Grimes
Lee Murphy
Mark Caulfield
Antonia Ho
Chris P Ponting
Jian Yang
Wilna Oosthuyzen
Fiona Griffiths
Andrew D Bretherick
Athanasios Kousathanas
Charles Hinds
Jonathan Millar
Susan Walker
BRACOVID Investigators
Alessandra Renieri
David J Porteous
Danny McAuley
David Maslove
James F Wilson
Nick Parkinson
Chenqing Zheng
Paul Klenerman
Lucija Klaric
GenOMICC Investigators
Xia Shen
Alexandre C Pereira
Gen-COVID Investigators
Richard Scott
Charlotte Summers
Albert Tenesa
Clark D Russell
Konrad Rawlik
Hugh Montgomery
Max Head Fourman
Alistair Nichol
J Kenneth Baillie
Caroline Hayward
Elvina Gountouna
23andMe Investigators
Barbara Shih
COVID-19 Human Genetics Initiative
Shona C Moore
Journal: Nature (2021)
Discipline: Multidisciplinary
Keywords: Host-mediated lung inflammation; mortality; coronavirus disease 2019; critical illness; host genetic variants
Affiliations: Roslin Institute, University of Edinburgh, Edinburgh, UK., MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK., Genomics England, London, UK., Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK., Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK., Edinburgh Clinical Research Facility, Western General Hospital, University of Edinburgh, Edinburgh, UK., Intensive Care National Audit & Research Centre, London, UK., Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia., Biostatistics Group, School of Life Sciences, Sun Yat-sen University, Guangzhou, China., The Crick Institute, London, UK., Intensive Care Unit, Royal Infirmary of Edinburgh, Edinburgh, UK., School of Life Sciences, Westlake University, Hangzhou, China., Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China., Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK., Department of Medicine, University of Cambridge, Cambridge, UK., Department of Intensive Care Medicine, Guy's and St Thomas' NHS Foundation Trust, London, UK., School of Immunology and Microbial Sciences, King's College London, London, UK., NIHR Health Protection Research Unit for Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK., MRC-University of Glasgow Centre for Virus Research, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK., William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK., Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK., Clinical Research Centre at St Vincent's University Hospital, University College Dublin, Dublin, Ireland., Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Victoria, Australia., Intensive Care Unit, Alfred Hospital, Melbourne, Victoria, Australia., Department of Critical Care Medicine, Queen's University and Kingston Health Sciences Centre, Kingston, Ontario, Canada., Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China., Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK., Department of Intensive Care Medicine, Royal Victoria Hospital, Belfast, UK., UCL Centre for Human Health and Performance, University College London, London, UK., Faculty of Medicine, University of São Paulo, São Paulo, Brazil., Heart Institute, University of São Paulo, São Paulo, Brazil., Medical Genetics, University of Siena, Siena, Italy., Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Siena, Italy., Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, Edinburgh, UK., Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden., Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK., National Heart and Lung Institute, Imperial College London, London, UK., Imperial College Healthcare NHS Trust London, London, UK., Respiratory Medicine, Alder Hey Children's Hospital, Institute in The Park, University of Liverpool, Liverpool, UK., Roslin Institute, University of Edinburgh, Edinburgh, UK. ., MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK. ., Intensive Care Unit, Royal Infirmary of Edinburgh, Edinburgh, UK. .

Abstract:  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. 

Retracted: No

PubPeer comments:
 **Genetic associations with severe COVID-19** Nicholas M. Murphy, PhD [1] Gillian S. Dite, PhD [1] Richard Allman, PhD [1] [1] Genetic Technologies Ltd., Fitzroy, Victoria, Australia Identification of host genetic factors that predispose individuals to severe COVID-19 is important, not only for understanding the disease and guiding the development of treatments, but also for risk prediction when combined to form a polygenic risk score (PRS). Using population controls, Pairo-Castineira et al. identified 12 SNPs (a panel of 8 SNPs and a panel of 6 SNPs, with two SNPs in both panels) associated with severe COVID-19. Using controls with asymptomatic or mild COVID-19, we were able to replicate the association with severe COVID-19 for only three of their SNPs and found marginal evidence for an association for one other. When combined as an 8-SNP PRS and a 6-SNP PRS, we found no evidence of association with severe COVID-19. The difference in our results and the results of Pairo-Castineira et al. might be the choice of controls: population controls vs controls with asymptomatic or mild COVID-19. The full text of our investigation is available at: [medRxiv] ,