Karim, Mohd A.Shilts, JarrodSchwartzentruber, JeremyHayhurst, JamesBuniello, AnnalisaMohammed, Elmutaz Shaikho ElhajZheng, JieHolmes, Michael V.Ochoa, DavidCarmona, MiguelMaranville, JosephGaunt, Tom R.Emilsson, ValurGuðnason, Vilmundur G.McDonagh, Ellen M.Wright, Gavin J.Ghoussaini, MayaDunham, Ian2025-11-202025-11-202021-08-17Karim, M A, Shilts, J, Schwartzentruber, J, Hayhurst, J, Buniello, A, Mohammed, E S E, Zheng, J, Holmes, M V, Ochoa, D, Carmona, M, Maranville, J, Gaunt, T R, Emilsson, V, Guðnason, V G, McDonagh, E M, Wright, G J, Ghoussaini, M & Dunham, I 2021, 'A proteome-wide genetic investigation identifies several sars-cov-2-exploited host targets of clinical relevance', eLife, vol. 10, e69719. https://doi.org/10.7554/eLife.697192050-084X39164932c9b5a94e-b94e-4ab1-bd8b-ed3998b5fe2e8511409877334402426https://hdl.handle.net/20.500.11815/6396MAK, JSc, JH, AB, DO, MC, EMM, MG, ID were funded by Open Targets. J.Z. and T.R.G were funded by the UK Medical Research Council Integrative Epidemiology Unit (MC_UU_00011/4). JSh and GJW were funded by the Wellcome Trust Grant 206194. This research was funded in part by the Wellcome Trust [Grant 206194]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Publisher Copyright: © 2021, eLife Sciences Publications Ltd. All rights reserved.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 Fas-mediated 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. Funding: MAK, JSc, JH, AB, DO, MC, EMM, MG, ID were funded by Open Targets. J.Z. and T.R.G were funded by the UK Medical Research Council Integrative Epidemiology Unit (MC_UU_00011/4). JSh and GJW were funded by the Wellcome Trust Grant 206194. This research was funded in part by the Wellcome Trust [Grant 206194]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.1671634eninfo:eu-repo/semantics/openAccessCovid-19Genome associationSARS-CoV-2Severity of Illness IndexGenome-Wide Association StudyScavenger Receptors, Class A/geneticsCell Adhesion MoleculesHumansLectins, C-Typefas Receptor/geneticsProteomeReceptors, Cell Surface2',5'-Oligoadenylate Synthetase/geneticsSARS-CoV-2/physiologyCOVID-19/geneticsGeneral Biochemistry,Genetics and Molecular BiologyGeneral Immunology and MicrobiologyGeneral NeuroscienceSDG 3 - Good Health and Well-being/dk/atira/pure/researchoutput/researchoutputtypes/contributiontojournal/article10.7554/eLife.69719