Genetic mechanisms of critical illness in Covid-19 - Repository

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: http://dx.doi.org/10.1038/s41586-020-03065-y

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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Pairo-Castineira, E., Clohisey, S., Klaric, L., Bretherick, A., Rawlik, K., Pasko, D., Walker, S., Parkinson, N., 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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DOI: http://dx.doi.org/10.1038/s41586-020-03065-y

Repository URI: http://eprints.gla.ac.uk/226569/