Abstract

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 × 10-8) in a gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, OAS3), on chr19p13.2 (rs2109069, p=2.3 × 10-12) near the gene encoding tyrosine kinase 2 (TYK2), on chr19p13.3 (rs2109069, p=3.98 × 10-12) within the gene encoding dipeptidyl peptidase 9 (DPP9), and on chr21q22.1 (rs2236757, p=4.99 × 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.

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Cite as

Pairo-Castineira, E., Clohisey, S., Klaric, L., Bretherick, A., Rawlik, K., Pasko, D., Walker, S., Parkinson, N., Head Fourman, M., Russell, C., 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, D., Hayward, C., Yang, J., Knight, J., Summers, C., Shankar-Hari, M., Klenerman, P., Turtle, L., Ho, A., Moore, S., Hinds, C., Horby, P., Maslove, D., Ling, L., McAuley, D., Montgomery, H., Walsh, T., Pereira, A., Renieri, A., The GenOMICC Investigators, ISARIC4C Investigators, The Covid-19 Human Genetics Initiative, 23andMe Investigators, BRACOVID Investigators, Gen-COVID Investigators, Shen, X., Ponting, C., Fawkes, A., Tenesa, A., Caulfield, M., Scott, R., Rowan, K., Openshaw, P., Semple, M., Law, A., Vitart, V., Wilson, J. & Baillie, J. 2020, 'Genetic mechanisms of critical illness in Covid-19', Nature, 591, pp. 92-98. http://dx.doi.org/10.1038/s41586-020-03065-y

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Last updated: 02 July 2022
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