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.
- Pietzner, M.
- Chua, R. L.
- Wheeler, E.
- Jechow, K.
- Willett, J. D. S.
- Radbruch, H.
- Trump, S.
- Heidecker, B.
- Zeberg, H.
- Heppner, F. L.
- Eils, R.
- Mall, M. A.
- Richards, J. B.
- Sander, L. E.
- Lehmann, I.
- Lukassen, S.
- Wareham, N. J.
- Conrad, C.
- Langenberg, C.
Keywords
- Angiotensin-Converting Enzyme 2/genetics
- *COVID-19/genetics
- DNA-Binding Proteins/genetics
- Epithelial Cells/metabolism
- Humans
- Peptidyl-Dipeptidase A/metabolism
- Respiratory System
- SARS-CoV-2
- Transcription Factors/genetics