Background: The virus SARS- CoV-2 can exploit biological vulnerabilities (e.g. host proteins) in susceptible hosts that predispose to the development of severe COVID-19. Methods: To identify host proteins that may contribute to the risk of severe COVID-19, we undertook proteome- wide genetic colocalisation tests, and polygenic (pan) and cis- Mendelian randomisation analyses leveraging publicly available protein and COVID-19 datasets. Results: Our analytic approach identified several known targets (e.g. ABO, OAS1), but also nominated new proteins such as soluble Fas (colocalisation probability >0.9, p=1 10-4), implicating Fasmediated apoptosis as a potential target for COVID-19 risk. The polygenic (pan) and cis- Mendelian randomisation analyses showed consistent associations of genetically predicted ABO protein with several COVID-19 phenotypes. The ABO signal is highly pleiotropic, and a look- up of proteins associated with the ABO signal revealed that the strongest association was with soluble CD209. We demonstrated experimentally that CD209 directly interacts with the spike protein of SARS- CoV-2, suggesting a mechanism that could explain the ABO association with COVID-19. Conclusions: Our work provides a prioritised list of host targets potentially exploited by SARS- CoV-2 and is a precursor for further research on CD209 and FAS as therapeutically tractable targets for COVID-19. [ABSTRACT FROM AUTHOR]