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GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19

Author

Listed:
  • Erola Pairo-Castineira

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

  • Konrad Rawlik

    (University of Edinburgh)

  • Andrew D. Bretherick

    (University of Edinburgh
    University of Edinburgh, Western General Hospital
    Ninewells Hospital and Medical School)

  • Ting Qi

    (Westlake University
    Westlake Laboratory of Life Sciences and Biomedicine)

  • Yang Wu

    (The University of Queensland)

  • Isar Nassiri

    (University of Oxford)

  • Glenn A. McConkey

    (University of Leeds)

  • Marie Zechner

    (University of Edinburgh
    University of Edinburgh)

  • Lucija Klaric

    (University of Edinburgh, Western General Hospital)

  • Fiona Griffiths

    (University of Edinburgh
    University of Edinburgh)

  • Wilna Oosthuyzen

    (University of Edinburgh
    University of Edinburgh)

  • Athanasios Kousathanas

    (Genomics England)

  • Anne Richmond

    (University of Edinburgh, Western General Hospital)

  • Jonathan Millar

    (University of Edinburgh
    University of Edinburgh
    Royal Infirmary of Edinburgh)

  • Clark D. Russell

    (University of Edinburgh)

  • Tomas Malinauskas

    (University of Oxford)

  • Ryan Thwaites

    (Imperial College London)

  • Kirstie Morrice

    (University of Edinburgh)

  • Sean Keating

    (Royal Infirmary of Edinburgh)

  • David Maslove

    (Queen’s University and Kingston Health Sciences Centre)

  • Alistair Nichol

    (University College Dublin)

  • Malcolm G. Semple

    (Institute of Infection, Veterinary and Ecological Sciences University of Liverpool
    University of Liverpool, Alder Hey Children’s Hospital)

  • Julian Knight

    (University of Oxford)

  • Manu Shankar-Hari

    (Royal Infirmary of Edinburgh
    University of Edinburgh)

  • Charlotte Summers

    (University of Cambridge)

  • Charles Hinds

    (William Harvey Research Institute Barts and the London School of Medicine and Dentistry, Queen Mary University of London)

  • Peter Horby

    (University of Oxford)

  • Lowell Ling

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

  • Danny McAuley

    (Queen’s University Belfast
    Royal Victoria Hospital)

  • Hugh Montgomery

    (UCL Centre for Human Health and Performance)

  • Peter J. M. Openshaw

    (Imperial College London
    Imperial College Healthcare NHS Trust)

  • Colin Begg

    (Royal Hospital for Children)

  • Timothy Walsh

    (Royal Infirmary of Edinburgh)

  • Albert Tenesa

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

  • Carlos Flores

    (Instituto Tecnológico y de Energías Renovables
    Research Unit, Hospital Universitario N.S. de Candelaria
    Instituto de Salud Carlos III
    University Fernando Pessoa Canarias)

  • José A. Riancho

    (IDIVAL
    Universidad de Cantabria
    Hospital U M Valdecilla)

  • Augusto Rojas-Martinez

    (Escuela de Medicina y Ciencias de la Salud and Hospital San Jose TecSalud)

  • Pablo Lapunzina

    (Instituto de Salud Carlos III
    Hospital Universitario La Paz-IDIPAZ
    ERN-ITHACA-European Reference Network)

  • Jian Yang

    (Westlake University
    Westlake Laboratory of Life Sciences and Biomedicine)

  • Chris P. Ponting

    (University of Edinburgh, Western General Hospital)

  • James F. Wilson

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

  • Veronique Vitart

    (University of Edinburgh, Western General Hospital)

  • Malak Abedalthagafi

    (King Fahad Medical City
    Emory University Hospital)

  • Andre D. Luchessi

    (Federal University of Rio Grande do Norte
    University of Toronto at Mississauga)

  • Esteban J. Parra

    (University of Toronto at Mississauga)

  • Raquel Cruz

    (Instituto de Salud Carlos III
    Universidade de Santiago de Compostela)

  • Angel Carracedo

    (Instituto de Salud Carlos III
    Universidade de Santiago de Compostela
    Instituto de Investigación Sanitaria de Santiago (IDIS)
    Sistema Galego de Saúde (SERGAS) Santiago de Compostela)

  • Angie Fawkes

    (University of Edinburgh)

  • Lee Murphy

    (University of Edinburgh)

  • Kathy Rowan

    (Intensive Care National Audit & Research Centre)

  • Alexandre C. Pereira

    (Heart Institute, University of Sao Paulo)

  • Andy Law

    (University of Edinburgh)

  • Benjamin Fairfax

    (University of Oxford)

  • Sara Clohisey Hendry

    (University of Edinburgh
    University of Edinburgh)

  • J. Kenneth Baillie

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

Abstract

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Suggested Citation

  • Erola Pairo-Castineira & Konrad Rawlik & Andrew D. Bretherick & Ting Qi & Yang Wu & Isar Nassiri & Glenn A. McConkey & Marie Zechner & Lucija Klaric & Fiona Griffiths & Wilna Oosthuyzen & Athanasios K, 2023. "GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19," Nature, Nature, vol. 617(7962), pages 764-768, May.
  • Handle: RePEc:nat:nature:v:617:y:2023:i:7962:d:10.1038_s41586-023-06034-3
    DOI: 10.1038/s41586-023-06034-3
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    Cited by:

    1. Junqing Xie & Beatriz Mothe & Marta Alcalde Herraiz & Chunxiao Li & Yu Xu & Annika M. Jödicke & Yaqing Gao & Yunhe Wang & Shuo Feng & Jia Wei & Zhuoyao Chen & Shenda Hong & Yeda Wu & Binbin Su & Xiaoy, 2024. "Relationship between HLA genetic variations, COVID-19 vaccine antibody response, and risk of breakthrough outcomes," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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