Genetic mechanisms of critical illness in Covid-19

Erola Pairo-Castineira, Sara Clohisey, Lucija Klaric, Andrew Bretherick, Konrad Rawlik, Nicholas Parkinson, Dorota Pasko, Susan Walker, Anne Richmond , Max Head Fourman, Andy Law, James Furniss, Elvina Gountouna, Nicola Wrobel, Clark D Russell, Loukas Moutsianas, Bo Wang, Alison M Meynert, Zhijian Yang, Ranran ZhaiChenqing Zheng, Fiona Griffith , Wilna Oosthuyzen, Barbara Shih, Sean Keating, Marie Zechner, Chris S Haley, David Porteous, Caroline Hayward, Julian Knight, Charlotte Summers, Manu Shankar-Hari, Lance Turtle, Antonia Ho, Charles Hinds , Peter Horby, Alistair Nichol, David M Maslove, Lowell Ling, Paul Klenerman, Danny F. McAuley, Hugh E Montgomery, Timothy S. Walsh, The GenOMICC Investigators, The ISARIC4C Investigators,, The Covid-19 Human Genetics Initiative, Xia Shen, Kathy Rowan, Angie Fawkes, Lee Murphy, Chris P Ponting, Albert Tenesa, M. Caulfield, Richard Scott , Peter Openshaw, Malcolm G Semple, Veronique Vitart, Jim Wilson, J Kenneth Baillie

Research output: Contribution to journalArticlepeer-review

Abstract

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).
Original languageEnglish
Article numbern/a
JournalNature
Volumen/a
Early online date11 Dec 2020
DOIs
Publication statusE-pub ahead of print - 11 Dec 2020

Keywords

  • Genome-wide association studies
  • Immunogenetics
  • SARS-CoV-2
  • Viral infection

Fingerprint Dive into the research topics of 'Genetic mechanisms of critical illness in Covid-19'. Together they form a unique fingerprint.

Cite this