Whole genome sequencing identifies multiple loci for critical illness caused by COVID-19
Christopher A Odhams,
Clark D Russell,
Katherine S Elliott,
Andrew D Bretherick,
David M Maslove,
Malcolm G Semple,
Tom A Fowler,
Charles J Hinds,
Peter W Horby,
Peter JM Openshaw,
Covid-19 Human Genetics Initiative,
Chris P Ponting,
James F Wilson,
Richard H Scott,
Sara Mary Rose Clohisey,
Mark J Caulfield,
J Kenneth Baillie
Posted 02 Sep 2021
medRxiv DOI: 10.1101/2021.09.02.21262965
Posted 02 Sep 2021
Critical illness in COVID-19 is caused by inflammatory lung injury, mediated by the host immune system. We and others have shown that host genetic variation influences the development of illness requiring critical care1 or hospitalisation2;3;4 following SARS-Co-V2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study is designed to compare genetic variants in critically-ill cases with population controls in order to find underlying disease mechanisms. Here, we use whole genome sequencing and statistical fine mapping in 7,491 critically-ill cases compared with 48,400 population controls to discover and replicate 22 independent variants that significantly predispose to life-threatening COVID-19. We identify 15 new independent associations with critical COVID-19, 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 expression of multiple genes, including reduced expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1), in critical disease. We show that comparison between critically-ill cases and population controls is highly efficient for genetic association analysis and enables detection of therapeutically-relevant mechanisms of disease. Therapeutic predictions arising from these findings require testing in clinical trials.
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