TY - JOUR TI - A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance AU - Anisul, Mohd AU - Shilts, Jarrod AU - Schwartzentruber, Jeremy AU - Hayhurst, James AU - Buniello, Annalisa AU - Shaikho Elhaj Mohammed, Elmutaz AU - Zheng, Jie AU - Holmes, Michael AU - Ochoa, David AU - Carmona, Miguel AU - Maranville, Joseph AU - Gaunt, Tom R AU - Emilsson, Valur AU - Gudnason, Vilmundur AU - McDonagh, Ellen M AU - Wright, Gavin J AU - Ghoussaini, Maya AU - Dunham, Ian A2 - Schoggins, John W A2 - Van der Meer, Jos W VL - 10 PY - 2021 DA - 2021/08/17 SP - e69719 C1 - eLife 2021;10:e69719 DO - 10.7554/eLife.69719 UR - https://doi.org/10.7554/eLife.69719 AB - 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. KW - COVID-19 KW - proteins KW - mendelian randomization KW - genetic colocalization KW - apoptosis JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -