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ELF5 is a potential respiratory epithelial cell-specific risk gene for severe COVID-19.

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Chua, Robert Lorenz 
Jechow, Katharina 
Willett, Julian DS 


Despite two years of intense global research activity, host genetic factors that predispose to a poorer prognosis of COVID-19 infection remain poorly understood. Here, we prioritise eight robust (e.g., ELF5) or suggestive but unreported (e.g., RAB2A) candidate protein mediators of COVID-19 outcomes by integrating results from the COVID-19 Host Genetics Initiative with population-based plasma proteomics using statistical colocalisation. The transcription factor ELF5 (ELF5) shows robust and directionally consistent associations across different outcome definitions, including a >4-fold higher risk (odds ratio: 4.88; 95%-CI: 2.47-9.63; p-value < 5.0 × 10-6) for severe COVID-19 per 1 s.d. higher genetically predicted plasma ELF5. We show that ELF5 is specifically expressed in epithelial cells of the respiratory system, such as secretory and alveolar type 2 cells, using single-cell RNA sequencing and immunohistochemistry. These cells are also likely targets of SARS-CoV-2 by colocalisation with key host factors, including ACE2 and TMPRSS2. In summary, large-scale human genetic studies together with gene expression at single-cell resolution highlight ELF5 as a risk gene for severe COVID-19, supporting a role of epithelial cells of the respiratory system in the adverse host response to SARS-CoV-2.


Funder: Wellcome Trust

Funder: National Institute for Health Research (NIHR)


Angiotensin-Converting Enzyme 2, COVID-19, DNA-Binding Proteins, Epithelial Cells, Humans, Peptidyl-Dipeptidase A, Respiratory System, SARS-CoV-2, Transcription Factors

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Nat Commun

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Springer Science and Business Media LLC
Medical Research Council (MC_UU_12015/1)
MRC (MC_UU_00006/1)