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

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 Kousathanas, Anne Richmond , Jonathan Millar, Clark D Russell, Tomas Malinauskas, Ryan Thwaites, Kirstie Morrice, Sean Keating, David M MasloveAlistair D Nichol, Malcolm Gracie Semple, Julian Knight, Manu Shankar-Hari, Charlotte Summers, Charles Hinds , Peter Horby, Lowell Ling, Danny F. McAuley, Hugh Montgomery, Peter J.M. Openshaw, Colin Begg, Timothy S. Walsh, Albert Tenesa, Carlos Flores, Jose A. Riancho, Augusto Rojas-Martinez, Pablo Lapunzina, Jian Yang, Chris P Ponting, James F Wilson, Veronique Vitart, Malak S Abedalthagafi, Andre Luchessi, Esteban J Parra, Raquel Cruz, Angel Carracedo, Angie Fawkes, Lee Murphy, Kathy Rowan, Alexandre C Pereira, Andy Law, Benjamin P Fairfax, Sara Clohisey Hendry, J Kenneth Baillie

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown 1 to be highly efficient for discovery of genetic associations 2. 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 group 3. 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).

Original languageEnglish
Pages (from-to)764-768
Number of pages30
JournalNature
Volume617
Issue number7962
Early online date17 May 2023
DOIs
Publication statusPublished - May 2023

Keywords / Materials (for Non-textual outputs)

  • COVID-19/genetics
  • Critical Illness
  • Genetic Predisposition to Disease/genetics
  • Genetic Variation/genetics
  • Genome-Wide Association Study
  • Genotype
  • Genotyping Techniques
  • Humans
  • Monocytes/metabolism
  • Phenotype
  • Transcriptome
  • Whole Genome Sequencing
  • rab GTP-Binding Proteins/genetics

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