IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v591y2021i7848d10.1038_s41586-020-03065-y.html
   My bibliography  Save this article

Genetic mechanisms of critical illness in COVID-19

Author

Listed:
  • Erola Pairo-Castineira

    (University of Edinburgh
    University of Edinburgh, Western General Hospital)

  • Sara Clohisey

    (University of Edinburgh)

  • Lucija Klaric

    (University of Edinburgh, Western General Hospital)

  • Andrew D. Bretherick

    (University of Edinburgh, Western General Hospital)

  • Konrad Rawlik

    (University of Edinburgh)

  • Dorota Pasko

    (Genomics England)

  • Susan Walker

    (Genomics England)

  • Nick Parkinson

    (University of Edinburgh)

  • Max Head Fourman

    (University of Edinburgh)

  • Clark D. Russell

    (University of Edinburgh
    University of Edinburgh)

  • James Furniss

    (University of Edinburgh)

  • Anne Richmond

    (University of Edinburgh, Western General Hospital)

  • Elvina Gountouna

    (University of Edinburgh, Western General Hospital)

  • Nicola Wrobel

    (University of Edinburgh)

  • David Harrison

    (Intensive Care National Audit & Research Centre)

  • Bo Wang

    (University of Edinburgh)

  • Yang Wu

    (The University of Queensland)

  • Alison Meynert

    (University of Edinburgh, Western General Hospital)

  • Fiona Griffiths

    (University of Edinburgh)

  • Wilna Oosthuyzen

    (University of Edinburgh)

  • Athanasios Kousathanas

    (Genomics England)

  • Loukas Moutsianas

    (Genomics England)

  • Zhijian Yang

    (Sun Yat-sen University)

  • Ranran Zhai

    (Sun Yat-sen University)

  • Chenqing Zheng

    (Sun Yat-sen University)

  • Graeme Grimes

    (University of Edinburgh, Western General Hospital)

  • Rupert Beale

    (The Crick Institute)

  • Jonathan Millar

    (University of Edinburgh)

  • Barbara Shih

    (University of Edinburgh)

  • Sean Keating

    (Intensive Care Unit, Royal Infirmary of Edinburgh)

  • Marie Zechner

    (University of Edinburgh)

  • Chris Haley

    (University of Edinburgh)

  • David J. Porteous

    (University of Edinburgh, Western General Hospital)

  • Caroline Hayward

    (University of Edinburgh, Western General Hospital
    University of Edinburgh, Western General Hospital)

  • Jian Yang

    (Westlake University
    Westlake Laboratory of Life Sciences and Biomedicine)

  • Julian Knight

    (University of Oxford)

  • Charlotte Summers

    (University of Cambridge)

  • Manu Shankar-Hari

    (Guy’s and St Thomas’ NHS Foundation Trust
    School of Immunology and Microbial Sciences, King’s College London)

  • Paul Klenerman

    (University of Oxford)

  • Lance Turtle

    (University of Liverpool)

  • Antonia Ho

    (University of Glasgow)

  • Shona C. Moore

    (University of Liverpool)

  • Charles Hinds

    (Queen Mary University of London)

  • Peter Horby

    (University of Oxford)

  • Alistair Nichol

    (Clinical Research Centre at St Vincent’s University Hospital, University College Dublin
    Monash University
    Intensive Care Unit, Alfred Hospital)

  • David Maslove

    (Queen’s University and Kingston Health Sciences Centre, Kingston)

  • Lowell Ling

    (The Chinese University of Hong Kong, Prince of Wales Hospital)

  • Danny McAuley

    (Queen’s University Belfast
    Royal Victoria Hospital)

  • Hugh Montgomery

    (University College London)

  • Timothy Walsh

    (Intensive Care Unit, Royal Infirmary of Edinburgh)

  • Alexandre C. Pereira

    (University of São Paulo
    University of São Paulo)

  • Alessandra Renieri

    (University of Siena
    Genetica Medica, Azienda Ospedaliero-Universitaria Senese)

  • Xia Shen

    (Sun Yat-sen University
    Usher Institute of Population Health Sciences and Informatics
    Karolinska Institutet)

  • Chris P. Ponting

    (University of Edinburgh, Western General Hospital)

  • Angie Fawkes

    (University of Edinburgh)

  • Albert Tenesa

    (University of Edinburgh
    University of Edinburgh, Western General Hospital
    Usher Institute of Population Health Sciences and Informatics)

  • Mark Caulfield

    (Genomics England
    Queen Mary University of London)

  • Richard Scott

    (Genomics England
    Great Ormond Street Hospital for Children NHS Foundation Trust)

  • Kathy Rowan

    (Intensive Care National Audit & Research Centre)

  • Lee Murphy

    (University of Edinburgh)

  • Peter J. M. Openshaw

    (National Heart and Lung Institute, Imperial College London
    Imperial College Healthcare NHS Trust London)

  • Malcolm G. Semple

    (University of Liverpool
    University of Liverpool)

  • Andrew Law

    (University of Edinburgh)

  • Veronique Vitart

    (University of Edinburgh, Western General Hospital)

  • James F. Wilson

    (University of Edinburgh, Western General Hospital
    Usher Institute of Population Health Sciences and Informatics)

  • J. Kenneth Baillie

    (University of Edinburgh
    University of Edinburgh, Western General Hospital
    Intensive Care Unit, Royal Infirmary of Edinburgh)

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.

Suggested Citation

  • Erola Pairo-Castineira & Sara Clohisey & Lucija Klaric & Andrew D. Bretherick & Konrad Rawlik & Dorota Pasko & Susan Walker & Nick Parkinson & Max Head Fourman & Clark D. Russell & James Furniss & Ann, 2021. "Genetic mechanisms of critical illness in COVID-19," Nature, Nature, vol. 591(7848), pages 92-98, March.
  • Handle: RePEc:nat:nature:v:591:y:2021:i:7848:d:10.1038_s41586-020-03065-y
    DOI: 10.1038/s41586-020-03065-y
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41586-020-03065-y
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.

    File URL: https://libkey.io/10.1038/s41586-020-03065-y?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Shelly J. Robertson & Olivia Bedard & Kristin L. McNally & Carl Shaia & Chad S. Clancy & Matthew Lewis & Rebecca M. Broeckel & Abhilash I. Chiramel & Jeffrey G. Shannon & Gail L. Sturdevant & Rebecca , 2023. "Genetically diverse mouse models of SARS-CoV-2 infection reproduce clinical variation in type I interferon and cytokine responses in COVID-19," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Elsa Brunet-Ratnasingham & Sacha Morin & Haley E. Randolph & Marjorie Labrecque & Justin Bélair & Raphaël Lima-Barbosa & Amélie Pagliuzza & Lorie Marchitto & Michael Hultström & Julia Niessl & Rose Cl, 2024. "Sustained IFN signaling is associated with delayed development of SARS-CoV-2-specific immunity," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    3. Maik Pietzner & Robert Lorenz Chua & Eleanor Wheeler & Katharina Jechow & Julian D. S. Willett & Helena Radbruch & Saskia Trump & Bettina Heidecker & Hugo Zeberg & Frank L. Heppner & Roland Eils & Mar, 2022. "ELF5 is a potential respiratory epithelial cell-specific risk gene for severe COVID-19," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. Thomas Liechti & Yaser Iftikhar & Massimo Mangino & Margaret Beddall & Charles W. Goss & Jane A. O’Halloran & Philip A. Mudd & Mario Roederer, 2022. "Immune phenotypes that are associated with subsequent COVID-19 severity inferred from post-recovery samples," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    5. Yvonne M. Mueller & Thijs J. Schrama & Rik Ruijten & Marco W. J. Schreurs & Dwin G. B. Grashof & Harmen J. G. van de Werken & Giovanna Jona Lasinio & Daniel Álvarez-Sierra & Caoimhe H. Kiernan & Melis, 2022. "Stratification of hospitalized COVID-19 patients into clinical severity progression groups by immuno-phenotyping and machine learning," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    6. Benjamin J. Schmiedel & Job Rocha & Cristian Gonzalez-Colin & Sourya Bhattacharyya & Ariel Madrigal & Christian H. Ottensmeier & Ferhat Ay & Vivek Chandra & Pandurangan Vijayanand, 2021. "COVID-19 genetic risk variants are associated with expression of multiple genes in diverse immune cell types," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    7. Guillermo Barturen & Elena Carnero-Montoro & Manuel Martínez-Bueno & Silvia Rojo-Rello & Beatriz Sobrino & Óscar Porras-Perales & Clara Alcántara-Domínguez & David Bernardo & Marta E. Alarcón-Riquelme, 2022. "Whole blood DNA methylation analysis reveals respiratory environmental traits involved in COVID-19 severity following SARS-CoV-2 infection," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    8. Katarzyna Orlewska & Justyna Klusek & Dorota Zarębska-Michaluk & Kamila Kocańda & Ruslan Oblap & Anna Cedro & Bartosz Witczak & Jolanta Klusek & Andrzej Śliwczyński & Ewa Orlewska, 2023. "Association between Glutathione S-Transferases Gene Variants and COVID-19 Severity in Previously Vaccinated and Unvaccinated Polish Patients with Confirmed SARS-CoV-2 Infection," IJERPH, MDPI, vol. 20(4), pages 1-11, February.
    9. Victoria N. Parikh & Alexander G. Ioannidis & David Jimenez-Morales & John E. Gorzynski & Hannah N. Jong & Xiran Liu & Jonasel Roque & Victoria P. Cepeda-Espinoza & Kazutoyo Osoegawa & Chris Hughes & , 2022. "Deconvoluting complex correlates of COVID-19 severity with a multi-omic pandemic tracking strategy," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    10. Tomoko Nakanishi & Julian Willett & Yossi Farjoun & Richard J. Allen & Beatriz Guillen-Guio & Darin Adra & Sirui Zhou & J. Brent Richards, 2023. "Alternative splicing in lung influences COVID-19 severity and respiratory diseases," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:591:y:2021:i:7848:d:10.1038_s41586-020-03065-y. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.