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The DOI matches its Crossref record; 24 of the 24 references it cites were found in a registry or an index.

Genetic mechanisms of critical illness in COVID-19

Open access
The GenOMICC Investigators, Pairo-Castineira, Erola, The ISARIC4C Investigators, The COVID-19 Human Genetics Initiative, 23andMe Investigators, BRACOVID Investigators, Gen-COVID Investigators, 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, Alexandre C., 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·2021·Nature
DOI 10.1038/s41586-020-03065-y
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Abstract

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10−8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10−8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 × 10−12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10−8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and 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. However, large-scale randomized clinical trials will be essential before any change to clinical practice. A genome-wide association study of critically ill patients with COVID-19 identifies genetic signals that relate to important host antiviral defence mechanisms and mediators of inflammatory organ damage that may be targeted by repurposing drug treatments.

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Authors
The GenOMICC Investigators, Pairo-Castineira, E., The ISARIC4C Investigators, Initiative, T. C.-1. H. G., 23andMe Investigators, BRACOVID Investigators, Gen-COVID Investigators, Clohisey, S., Klaric, L., Bretherick, A. D., Rawlik, K., Pasko, D., Walker, S., Parkinson, N., Fourman, M. H., Russell, C. D., 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. J., Hayward, C., Yang, J., Knight, J., Summers, C., Shankar-Hari, M., Klenerman, P., Turtle, L., Ho, A., Moore, S. C., Hinds, C., Horby, P., Nichol, A., Maslove, D., Ling, L., McAuley, D., Montgomery, H., Walsh, T., Pereira, A. C., Renieri, A., Shen, X., Ponting, C. P., Fawkes, A., Tenesa, A., Caulfield, M., Scott, R., Rowan, K., Murphy, L., Openshaw, P. J. M., Semple, M. G., Law, A., Vitart, V., Wilson, J. F., & Baillie, J. K.
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2020-12-11
Volume
591
Issue
7848
Pages
92-98
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-020-03065-y
OpenAlex
W3112105690
Cited by
1,365
References
24
FWCI
136.45
Type
journal article
Language
en
Open access
hybrid

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