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

Despite two years of intense global research activity, host genetic factors that predispose to a poorer prognosis and severe course of COVID-19 infection remain poorly understood. Here, we identified eight candidate protein mediators of COVID-19 outcomes by establishing a shared genetic architecture at protein-coding loci using large-scale human genetic studies. The transcription factor ELF5 (ELF5) showed robust and directionally consistent associations across different outcome definitions, including a >4-fold higher risk (odds ratio: 4.85; 95%-CI: 2.65-8.89; p-value<3.1×10⁻⁷) 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. We also observed a 25% reduced risk of severe COVID-19 per 1 s.d. higher genetically predicted plasma G-CSF, a finding corroborated by a clinical trial of recombinant human G-CSF in COVID-19 patients with lymphopenia reporting a lower number of patients developing critical illness and death. In summary, large-scale human genetic studies together with gene expression at single-cell resolution highlight ELF5 as a novel risk gene for COVID-19 prognosis, supporting a role of epithelial cells of the respiratory system in the adverse host response to SARS-CoV-2.