Edinburgh Research Explorer

Genetic mechanisms of critical illness in Covid-19

Research output: Working paper

  • Dorota Pasko
  • Susan Walker
  • Anne Richmond
  • Max Head Fourman
  • Nicola Wrobel
  • Loukas Moutsianas
  • Bo Wang
  • Zhijun Yang
  • Ranran Zhai
  • Chenqing Zheng
  • Fiona Griffith
  • Wilna Oosthuyzen
  • Sean Keating
  • Marie Zechner
  • Christopher Haley
  • D J Porteus
  • Julian Knight
  • Charlotte Summers
  • Manu Shankar-Hari
  • Lance Turtle
  • Antonia Ho
  • Charles Hinds
  • Peter Horby
  • Alistair Nichol
  • David M Maslove
  • Lowell Ling
  • Paul Klenerman
  • Daniel F McAuley
  • Hugh Montgomery
  • The GenOMICC Investigators
  • The ISARIC4C Investigators,
  • The Covid-19 Human Genetics Initiative
  • Kathy Rowan
  • Mark Caulfield
  • Richard Scott
  • Peter J. M. Openshaw
  • Malcolm G Semple
  • James F Wilson
  • J Kenneth Baillie

Related Edinburgh Organisations

Original languageEnglish
Publication statusPublished - 25 Sep 2020


The subset of patients who develop critical illness in Covid-19 have extensive inflammation affecting the lungs[PMID: 32526193] and are strikingly different from other patients: immunosuppressive therapy benefits critically-ill patients, but may harm some non-critical cases.[PMID: 32678530] 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.[PMID: 24855243] GenOMICC (Genetics Of Mortality In Critical Care, <a href="https://genomicc.org">genomicc.org</a>) 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 and results were confirmed in GWAS comparisons with two other population control groups: the 100,000 genomes project and Generation Scotland. We identify and replicate three novel genome-wide significant associations, at chr19p13.3 (rs2109069, p = 3.98 x 10-12), within the gene encoding dipeptidyl peptidase 9 (DPP9), at chr12q24.13 (rs10735079, p = 1.65 x 10-8) in a gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, OAS3), and at chr21q22.1 (rs2236757, p = 4.99 x 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 = 4.77 x 10-30).

ID: 180307839