Genetic mechanisms of critical illness in COVID-19

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Pairo-Castineira, E ORCID: 0000-0002-2423-3090, Clohisey, S, Klaric, L ORCID: 0000-0003-3105-8929, Bretherick, AD ORCID: 0000-0001-9258-3140, Rawlik, K ORCID: 0000-0002-0010-370X, Pasko, D, Walker, S ORCID: 0000-0002-5016-6426, Parkinson, N, Fourman, MH ORCID: 0000-0001-7381-2278, Russell, CD ORCID: 0000-0002-9873-8243 et al (show 88 more authors) , Furniss, J, Richmond, A, Gountouna, E ORCID: 0000-0001-7870-2780, Wrobel, N, Harrison, D, Wang, B ORCID: 0000-0002-1580-797X, Wu, Y ORCID: 0000-0002-0128-7280, Meynert, A, Griffiths, F, Oosthuyzen, W, Kousathanas, A ORCID: 0000-0001-6265-6521, Moutsianas, L ORCID: 0000-0001-5453-345X, Yang, Z, Zhai, R ORCID: 0000-0002-5834-9120, Zheng, C, Grimes, G, Beale, R ORCID: 0000-0002-6705-8560, Millar, J, Shih, B, Keating, S ORCID: 0000-0001-8552-5604, Zechner, M, Haley, C ORCID: 0000-0002-9811-0210, Porteous, DJ ORCID: 0000-0003-1249-6106, Hayward, C ORCID: 0000-0002-9405-9550, Yang, J ORCID: 0000-0003-2001-2474, Knight, J ORCID: 0000-0002-0377-5536, Summers, C ORCID: 0000-0002-7269-2873, Shankar-Hari, M ORCID: 0000-0002-5338-2538, Klenerman, P, Turtle, L ORCID: 0000-0002-0778-1693, Ho, A, Moore, SC ORCID: 0000-0001-8610-2806, Hinds, C ORCID: 0000-0001-5094-8324, Horby, P, Nichol, A, Maslove, D, Ling, L, McAuley, D ORCID: 0000-0002-3283-1947, Montgomery, H ORCID: 0000-0001-8797-5019, Walsh, T, Pereira, AC, Renieri, A ORCID: 0000-0002-0846-9220, Millar, J, Meikle, J, Finernan, P, Mcmaster, E, Law, A, Baillie, JK, Paterson, T, Wackett, T, Armstrong, R, Clark, R, Coutts, A, Donnelly, L, Gilchrist, T, Hafezi, K, Macgillivray, L, Maclean, A, McCafferty, S, Morrice, K, Weaver, J, Boz, C, Golightly, A, Ward, M, Mal, H, Szoor-McElhinney, H, Brown, A, Hendry, R, Stenhouse, A, Cullum, L, Law, D, Law, S, Law, R, Swets, M, Day, N, Taneski, F, Duncan, E, Collier, D, Wood, S, Zak, A, Borra, C, Matharu, M, May, P, Alldis, Z, Mitchelmore, O, Bowles, R, Easthope, A and Bibi, F (2021) Genetic mechanisms of critical illness in COVID-19 Nature, 591 (7848). pp. 92-98. ISSN 0028-0836, 1476-4687

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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.

Item Type:	Article
Uncontrolled Keywords:	GenOMICC Investigators, ISARIC4C Investigators, COVID-19 Human Genetics Initiative, 23andMe Investigators, BRACOVID Investigators, Gen-COVID Investigators, Lung, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 19, Chromosomes, Human, Pair 21, Humans, Critical Illness, Inflammation, 2',5'-Oligoadenylate Synthetase, Critical Care, Multigene Family, Female, Male, TYK2 Kinase, Receptor, Interferon alpha-beta, Receptors, CCR2, Genome-Wide Association Study, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Drug Repositioning, United Kingdom, COVID-19
Depositing User:	Symplectic Admin
Date Deposited:	08 Mar 2021 08:10
Last Modified:	01 Mar 2026 10:22
DOI:	10.1038/s41586-020-03065-y
Related Websites:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3112058
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