Genetic mechanisms of critical illness in Covid-19

Type Journal Article Author Erola Pairo-Castineira Author Sara Clohisey Author Lucija Klaric Author Andrew D. Bretherick Author Konrad Rawlik Author Dorota Pasko Author Susan Walker Author Nick Parkinson Author Max Head Fourman Author Clark D. Russell Author James Furniss Author Anne Richmond Author Elvina Gountouna Author Nicola Wrobel Author David Harrison Author Bo Wang Author Yang Wu Author Alison Meynert Author Fiona Griffiths Author Wilna Oosthuyzen Author Athanasios Kousathanas Author Loukas Moutsianas Author Zhijian Yang Author Ranran Zhai Author Chenqing Zheng Author Graeme Grimes Author Rupert Beale Author Jonathan Millar Author Barbara Shih Author Sean Keating Author Marie Zechner Author Chris Haley Author David J. Porteous Author Caroline Hayward Author Jian Yang Author Julian Knight Author Charlotte Summers Author Manu Shankar-Hari Author Paul Klenerman Author Lance Turtle Author Antonia Ho Author Shona C. Moore Author Charles Hinds Author Peter Horby Author Alistair Nichol Author David Maslove Author Lowell Ling Author Danny McAuley Author Hugh Montgomery Author Timothy Walsh Author Alex Pereira Author Alessandra Renieri Author Xia Shen Author Chris P. Ponting Author Angie Fawkes Author Albert Tenesa Author Mark Caulfield Author Richard Scott Author Kathy Rowan Author Lee Murphy Author Peter J. M. Openshaw Author Malcolm G. Semple Author Andrew Law Author Veronique Vitart Author James F. Wilson Author J. Kenneth Baillie URL https://www.nature.com/articles/s41586-020-03065-y Rights 2020 The Author(s), under exclusive licence to Springer Nature Limited Pages 1-1 Publication Nature ISSN 1476-4687 Date 11/12/2020 Extra Publisher: Nature Publishing Group DOI 10.1038/s41586-020-03065-y Library Catalog www.nature.com Language en Abstract 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 $$\times $$×10-8) in a gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, OAS3), on chr19p13.2 (rs2109069, p=2.3 $$\times $$×10-12) near the gene encoding tyrosine kinase 2 (TYK2), on chr19p13.3 (rs2109069, p=3.98 $$\times $$×10-12) within the gene encoding dipeptidyl peptidase 9 (DPP9), and on chr21q22.1 (rs2236757, p=4.99 $$\times $$×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.