Abstract
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. 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. 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. 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. 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.
Highlights
At the current time, the coronavirus disease 2019 (COVID-19) pandemic is implicated in the deaths of more than 4 million people worldwide (Dong et al, 2020)
The pan-Mendelian randomisation (MR) analysis leveraged genetic data from both cis- and trans-a cting pQTLs, for some protein- COVID-1 9 pairs that were associated at 5 % FDR, the associations with COVID-19 outcomes were exclusively driven by trans-a cting pQTLs or cis-a cting genetic instruments
We provided pan- and cis-M R evidence with strong genetic colocalisation support for the ABO signal for most COVID-1 9 phenotypes
Summary
The coronavirus disease 2019 (COVID-19) pandemic is implicated in the deaths of more than 4 million people worldwide (Dong et al, 2020). We expanded on these previous reports by undertaking a proteome-wide two-s ample pan- and cis-M R analysis using the Sun et al GWAS (Sun et al, 2018) of plasma protein eLife digest Individuals who become infected with the virus that causes COVID-19 can experience a wide variety of symptoms These can range from no symptoms or minor symptoms to severe illness and death. Identifying the molecular factors in a host that affect how viruses can infect individuals, evade immune defences or trigger severe illness, could provide new ways to treat patients with COVID- 19 Such factors are likely to remain constant, even when the virus mutates into new strains. We examined associated phenotypes using the colocalising signals from the Open Targets Genetics portal (http://genetics.opentargets.org) to shed light on the biological basis of association of the proteins with the COVID-19 phenotypes
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