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A proteome-wide genetic investigation identifies several sars-cov-2-exploited host targets of clinical relevance

A proteome-wide genetic investigation identifies several sars-cov-2-exploited host targets of clinical relevance


Title: A proteome-wide genetic investigation identifies several sars-cov-2-exploited host targets of clinical relevance
Author: Karim, Mohd A.
Shilts, Jarrod
Schwartzentruber, Jeremy
Hayhurst, James
Buniello, Annalisa
Mohammed, Elmutaz Shaikho Elhaj
Zheng, Jie
Holmes, Michael V.
Ochoa, David
Carmona, Miguel
... 8 more authors Show all authors
Date: 2021-08-17
Language: English
Scope:
Department: Faculty of Medicine
Series: eLife; 10()
ISSN: 2050-084X
DOI: https://doi.org/10.7554/eLife.69719
Subject: COVID-19; Veirufræði; Genamengi; Covid-19; Genome association; SARS-CoV-2; Severity of Illness Index; Genome-Wide Association Study; Scavenger Receptors, Class A/genetics; Cell Adhesion Molecules; Humans; Lectins, C-Type; fas Receptor/genetics; Proteome; Receptors, Cell Surface; 2',5'-Oligoadenylate Synthetase/genetics; SARS-CoV-2/physiology; COVID-19/genetics; Biochemistry, Genetics and Molecular Biology (all); Immunology and Microbiology (all); Neuroscience (all)
URI: https://hdl.handle.net/20.500.11815/2938

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Citation:

Karim , 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.69719

Abstract:

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.

Description:

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. Publisher Copyright: © 2021, eLife Sciences Publications Ltd. All rights reserved.

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