Genetic mechanisms of critical illness in Covid-19.

Pairo-Castineira, Erola; Clohisey, Sara; Klaric, Lucija; Bretherick, Andrew D; Rawlik, Konrad; Pasko, Dorota; Walker, Susan; Parkinson, Nick; Fourman, Max Head; Russell, Clark D; Furniss, James; Richmond, Anne; Gountouna, Elvina; Wrobel, Nicola; Harrison, David; Wang, Bo; Wu, Yang; Meynert, Alison; Griffiths, Fiona; Oosthuyzen, Wilna; Kousathanas, Athanasios; Moutsianas, Loukas; Yang, Zhijian; Zhai, Ranran; Zheng, Chenqing; Grimes, Graeme; Beale, Rupert; Millar, Jonathan; Shih, Barbara; Keating, Sean; Zechner, Marie; Haley, Chris; Porteous, David J; Hayward, Caroline; Yang, Jian; Knight, Julian; Summers, Charlotte; Shankar-Hari, Manu; Klenerman, Paul; Turtle, Lance; Ho, Antonia; Moore, Shona C; Hinds, Charles; Horby, Peter; Nichol, Alistair; Maslove, David; Ling, Lowell; McAuley, Danny; Montgomery, Hugh; Walsh, Timothy; Pereira, Alex; Renieri, Alessandra; Shen, Xia; Ponting, Chris P; Fawkes, Angie; Tenesa, Albert; Caulfield, Mark; Scott, Richard; Rowan, Kathy; Murphy, Lee; Openshaw, Peter J M; Semple, Malcolm G; Law, Andrew; Vitart, Veronique; Wilson, James F; Baillie, J Kenneth

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.