Genetic mechanisms of critical illness in Covid-19
Authors listErola Pairo-Castineira Sara Clohisey Lucija Klaric Andrew D Bretherick Konrad Rawlik Dorota Pasko Susan Walker Nick Parkinson Max Head Fourman Clark D Russell James Furniss Anne Richmond Elvina Gountouna Nicola Wrobel David Harrison Bo Wang Yang Wu Alison Meynert Fiona Griffiths Wilna Oosthuyzen Athanasios Kousathanas Loukas Moutsianas Zhijian Yang Ranran Zhai Chenqing Zheng Graeme Grimes Rupert Beale Jonathan Millar Barbara Shih Sean Keating Marie Zechner Chris Haley David J Porteous Caroline Hayward Jian Yang Julian Knight Charlotte Summers Manu Shankar-Hari Paul Klenerman Lance Turtle Antonia Ho Shona C Moore Charles Hinds Peter Horby Alistair Nichol David Maslove Lowell Ling Danny McAuley Hugh Montgomery Timothy Walsh Alex Pereira Alessandra Renieri GenOMICC Investigators ISARICC Investigators COVID-19 Human Genetics Initiative 23andMe Investigators BRACOVID Investigators Gen-COVID Investigators Xia Shen Chris P Ponting Angie Fawkes Albert Tenesa Mark Caulfield Richard Scott Kathy Rowan Lee Murphy Peter JM Openshaw Malcolm G Semple Andrew Law Veronique Vitart James F Wilson J Kenneth Baillie
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Host-mediated lung inflammation is present,1 and drives mortality,2 in critical illness caused by Covid-19. Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development.3 Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study(GWAS) in 2244 critically ill Covid-19 patients from 208 UK intensive care units (ICUs). We identify and replicate novel genome-wide significant associations, on chr12q24.13 (rs10735079, p=1.65 [Formula: see text] 10-8) in a gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, OAS3), on chr19p13.2 (rs2109069, p=2.3 [Formula: see text] 10-12) near the gene encoding tyrosine kinase 2 (TYK2), on chr19p13.3 (rs2109069, p=3.98 [Formula: see text] 10-12) within the gene encoding dipeptidyl peptidase 9 (DPP9), and on chr21q22.1 (rs2236757, p=4.99 [Formula: see text] 10-8) in the interferon receptor gene IFNAR2. We identify potential targets for repurposing of licensed medications: using Mendelian randomisation we found evidence in support of a causal link from low expression of IFNAR2, and high expression of TYK2, to life-threatening disease; transcriptome-wide association in lung tissue revealed that high expression of the monocyte/macrophage chemotactic receptor CCR2 is associated with severe Covid-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms, and mediators of inflammatory organ damage in Covid-19. Both mechanisms may be amenable to targeted treatment with existing drugs. Large-scale randomised clinical trials will be essential before any change to clinical practice.