- 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
Original language | English |
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Publisher | medRxiv |
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DOIs | |
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Publication status | Published - 25 Sep 2020 |
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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