TY - JOUR TI - Genetic mechanisms of critical illness in Covid-19 AU - Pairo-Castineira, Erola AU - Clohisey, Sara AU - Klaric, Lucija AU - Bretherick, Andrew D. AU - Rawlik, Konrad AU - Pasko, Dorota AU - Walker, Susan AU - Parkinson, Nick AU - Fourman, Max Head AU - Russell, Clark D. AU - Furniss, James AU - Richmond, Anne AU - Gountouna, Elvina AU - Wrobel, Nicola AU - Harrison, David AU - Wang, Bo AU - Wu, Yang AU - Meynert, Alison AU - Griffiths, Fiona AU - Oosthuyzen, Wilna AU - Kousathanas, Athanasios AU - Moutsianas, Loukas AU - Yang, Zhijian AU - Zhai, Ranran AU - Zheng, Chenqing AU - Grimes, Graeme AU - Beale, Rupert AU - Millar, Jonathan AU - Shih, Barbara AU - Keating, Sean AU - Zechner, Marie AU - Haley, Chris AU - Porteous, David J. AU - Hayward, Caroline AU - Yang, Jian AU - Knight, Julian AU - Summers, Charlotte AU - Shankar-Hari, Manu AU - Klenerman, Paul AU - Turtle, Lance AU - Ho, Antonia AU - Moore, Shona C. AU - Hinds, Charles AU - Horby, Peter AU - Nichol, Alistair AU - Maslove, David AU - Ling, Lowell AU - McAuley, Danny AU - Montgomery, Hugh AU - Walsh, Timothy AU - Pereira, Alex AU - Renieri, Alessandra AU - Shen, Xia AU - Ponting, Chris P. AU - Fawkes, Angie AU - Tenesa, Albert AU - Caulfield, Mark AU - Scott, Richard AU - Rowan, Kathy AU - Murphy, Lee AU - Openshaw, Peter J. M. AU - Malcolm G. Semple AU - Law, Andrew AU - Vitart, Veronique AU - Wilson, James F. AU - Baillie, J. Kenneth T2 - Nature AB - 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. DA - 2020/12/11/ PY - 2020 DO - 10.1038/s41586-020-03065-y DP - www.nature.com SP - 1 EP - 1 LA - en SN - 1476-4687 UR - https://www.nature.com/articles/s41586-020-03065-y Y2 - 2020/12/12/06:23:47 ER -