Genetic mechanisms of critical illness in Covid-19.
Pairo-Castineira E., Clohisey S., Klaric L., Bretherick AD., Rawlik K., Pasko D., Walker S., Parkinson N., Fourman MH., Russell CD., Furniss J., Richmond A., Gountouna E., Wrobel N., Harrison D., Wang B., Wu Y., Meynert A., Griffiths F., Oosthuyzen W., Kousathanas A., Moutsianas L., Yang Z., Zhai R., Zheng C., Grimes G., Beale R., Millar J., Shih B., Keating S., Zechner M., Haley C., Porteous DJ., Hayward C., Yang J., Knight J., Summers C., Shankar-Hari M., Klenerman P., Turtle L., Ho A., Moore SC., Hinds C., Horby P., Nichol A., Maslove D., Ling L., McAuley D., Montgomery H., Walsh T., Pereira A., Renieri A., GenOMICC Investigators None., ISARICC Investigators None., COVID-19 Human Genetics Initiative None., 23andMe Investigators None., BRACOVID Investigators None., Gen-COVID Investigators None., Shen X., Ponting CP., Fawkes A., Tenesa A., Caulfield M., Scott R., Rowan K., Murphy L., Openshaw PJM., Semple MG., Law A., Vitart V., Wilson JF., Baillie JK.
Host-mediated lung inflammation is present,<sup>1</sup> and drives mortality,<sup>2</sup> in critical illness caused by Covid-19. Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development.<sup>3</sup> 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<sup>-8</sup>) in a gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, OAS3), on chr19p13.2 (rs2109069, p=2.3 [Formula: see text] 10<sup>-12</sup>) near the gene encoding tyrosine kinase 2 (TYK2), on chr19p13.3 (rs2109069, p=3.98 [Formula: see text] 10<sup>-12</sup>) within the gene encoding dipeptidyl peptidase 9 (DPP9), and on chr21q22.1 (rs2236757, p=4.99 [Formula: see text] 10<sup>-8</sup>) 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.