@article{Kousathanas_A-2022_79563,
title = {Whole genome sequencing reveals host factors underlying critical Covid-19},
author = {Kousathanas, A. and Pairo-Castineira, E. and Rawlik, K. and Stuckey, A. and Odhams, C. and Walker, S. and Russell, C. and Malinauskas, T. and Wu, Y. and Millar, J. and Shen, X. and Elliott, K. and Griffiths, F. and Oosthuyzen, W. and Morrice, K. and Keating, S. and Wang, B. and Rhodes, D. and Klaric, L. and Zechner, M. and Parkinson, N. and Siddiq, A. and Goddard, P. and Donovan, S. and Maslove, D. and Nichol, A. and Semple, M. and Zainy, T. and Maleady-Crowe, F. and Todd, L. and Salehi, S. and Knight, J. and Elgar, G. and Chan, G. and Arumugam, P. and Patch, C. and Rendon, A. and Bentley, D. and Kingsley, C. and Kosmicki, J. and Horowitz, J. and Baras, A. and Abecasis, G. and Ferreira, M. and Justice, A. and Mirshahi, T. and Oetjens, M. and Rader, D. and Ritchie, M. and Verma, A. and Fowler, T. and Shankar-Hari, M. and Summers, C. and Hinds, C. and Horby, P. and Ling, L. and McAuley, D. and Montgomery, H. and Openshaw, P. and Elliott, P. and Walsh, T. and Tenesa, A. and The GenOMICC Investigators and 23andMe and The Covid-19 Human Genetics Initiative and Fawkes, A. and Murphy, L. and Rowan, K. and Ponting, C. and Vitart, V. and Wilson, J. and Yang, J. and Bretherick, A. and Scott, R. and Hendry, S. and Moutsianas, L. and Law, A. and Caulfield, M. and Baillie, J.},
month = {mar},
year = {2022},
abstract = {Critical Covid-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalisation2-4 following SARS-CoV-2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from critically-ill cases with population controls in order to find underlying disease mechanisms. Here, we use whole genome sequencing in 7,491 critically-ill cases 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 involved in interferon signalling (IL10RB, PLSCR1), leucocyte differentiation (BCL11A), and blood type antigen secretor status (FUT2). Using transcriptome-wide association and colocalisation to infer the effect of gene expression on disease severity, we find evidence implicating multiple genes, including reduced expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1), in critical disease. Mendelian randomisation provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5, CD209) and 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 critically-ill cases and population controls is highly efficient for detection of therapeutically-relevant mechanisms of disease.},
journal = {Nature},
publisher = {Springer Nature},
url = {https://doi.org/10.1038/s41586-022-04576-6},
}
