Whole-genome sequencing reveals host factors underlying critical COVID-19

Kousathanas, A, Pairo-Castineira, E, Rawlik, K, Stuckey, A, Odhams, CA, Walker, S, Russell, CD, Malinauskas, T, Wu, Y, Millar, J, Shen, X, Elliott, KS, Griffiths, F, Oosthuyzen, W, Morrice, K, Keating, S, Wang, B, Rhodes, D, Klaric, L, Zechner, M, Parkinson, N, Siddiq, A, Goddard, P, Donovan, S, Maslove, D, Nichol, A, Semple, MG, Zainy, T, Maleady-Crowe, F, Todd, L, Salehi, S, Knight, J, Elgar, G, Chan, G, Arumugam, P, Patch, C, Rendon, A, Bentley, D, Kingsley, C, Kosmicki, JA, Horowitz, JE, Baras, A, Abecasis, GR, Ferreira, MAR, Justice, A, Mirshahi, T, Oetjens, M, Rader, DJ, Ritchie, MD, Verma, A, Fowler, TA, Shankar-Hari, M, Summers, C, Hinds, C, Horby, P, Ling, L, McAuley, D, Montgomery, H, Openshaw, PJM, Elliott, P, Walsh, T, Tenesa, A, GenOMICC investigators, 23andMe investigators, COVID-19 Human Genetics Initiative (El-Sherbiny, YM) ORCID: https://orcid.org/0000-0003-4791-3475, COVID-19 Human Genetics Initiative (El-Jawhari, JJ) ORCID: https://orcid.org/0000-0002-0580-4492, Fawkes, A, Murphy, L, Rowan, K, Ponting, CP, Vitart, V, Wilson, JF, Yang, J, Bretherick, AD, Scott, RH, Hendry, SC, Moutsianas, L, Law, A, Caulfield, MJ and Baillie, JK, 2022. Whole-genome sequencing reveals host factors underlying critical COVID-19. Nature, 607 (7917), pp. 97-103. ISSN 0028-0836

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Abstract

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.

Item Type:	Journal article
Publication Title:	Nature
Creators:	Kousathanas, A., Pairo-Castineira, E., Rawlik, K., Stuckey, A., Odhams, C.A., Walker, S., Russell, C.D., Malinauskas, T., Wu, Y., Millar, J., Shen, X., Elliott, K.S., Griffiths, F., Oosthuyzen, W., Morrice, K., Keating, S., Wang, B., Rhodes, D., Klaric, L., Zechner, M., Parkinson, N., Siddiq, A., Goddard, P., Donovan, S., Maslove, D., Nichol, A., Semple, M.G., Zainy, T., Maleady-Crowe, F., Todd, L., Salehi, S., Knight, J., Elgar, G., Chan, G., Arumugam, P., Patch, C., Rendon, A., Bentley, D., Kingsley, C., Kosmicki, J.A., Horowitz, J.E., Baras, A., Abecasis, G.R., Ferreira, M.A.R., Justice, A., Mirshahi, T., Oetjens, M., Rader, D.J., Ritchie, M.D., Verma, A., Fowler, T.A., Shankar-Hari, M., Summers, C., Hinds, C., Horby, P., Ling, L., McAuley, D., Montgomery, H., Openshaw, P.J.M., Elliott, P., Walsh, T., Tenesa, A., GenOMICC investigators, 23andMe investigators, COVID-19 Human Genetics Initiative (El-Sherbiny, YM), COVID-19 Human Genetics Initiative (El-Jawhari, JJ), Fawkes, A., Murphy, L., Rowan, K., Ponting, C.P., Vitart, V., Wilson, J.F., Yang, J., Bretherick, A.D., Scott, R.H., Hendry, S.C., Moutsianas, L., Law, A., Caulfield, M.J. and Baillie, J.K.
Publisher:	Springer Science and Business Media LLC
Date:	7 July 2022
Volume:	607
Number:	7917
ISSN:	0028-0836
Identifiers:	Number Type 10.1038/s41586-022-04576-6 DOI 1584825 Other
Rights:	This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Divisions:	Schools > School of Science and Technology
Record created by:	Laura Ward
Date Added:	11 Aug 2022 15:17
Last Modified:	11 Aug 2022 15:17
URI:	https://irep.ntu.ac.uk/id/eprint/46862

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