A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance

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 colocalis...

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Autores principales:	Mohd Anisul, Jarrod Shilts, Jeremy Schwartzentruber, James Hayhurst, Annalisa Buniello, Elmutaz Shaikho Elhaj Mohammed, Jie Zheng, Michael Holmes, David Ochoa, Miguel Carmona, Joseph Maranville, Tom R Gaunt, Valur Emilsson, Vilmundur Gudnason, Ellen M McDonagh, Gavin J Wright, Maya Ghoussaini, Ian Dunham
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	COVID-19 proteins mendelian randomization genetic colocalization apoptosis Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/683976ef43454b7b95974612097b3624
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spelling	oai:doaj.org-article:683976ef43454b7b95974612097b36242021-11-30T10:03:42ZA proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance10.7554/eLife.697192050-084Xe69719https://doaj.org/article/683976ef43454b7b95974612097b36242021-08-01T00:00:00Zhttps://elifesciences.org/articles/69719https://doaj.org/toc/2050-084XBackground: 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.Mohd AnisulJarrod ShiltsJeremy SchwartzentruberJames HayhurstAnnalisa BunielloElmutaz Shaikho Elhaj MohammedJie ZhengMichael HolmesDavid OchoaMiguel CarmonaJoseph MaranvilleTom R GauntValur EmilssonVilmundur GudnasonEllen M McDonaghGavin J WrightMaya GhoussainiIan DunhameLife Sciences Publications LtdarticleCOVID-19proteinsmendelian randomizationgenetic colocalizationapoptosisMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	COVID-19 proteins mendelian randomization genetic colocalization apoptosis Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	COVID-19 proteins mendelian randomization genetic colocalization apoptosis Medicine R Science Q Biology (General) QH301-705.5 Mohd Anisul Jarrod Shilts Jeremy Schwartzentruber James Hayhurst Annalisa Buniello Elmutaz Shaikho Elhaj Mohammed Jie Zheng Michael Holmes David Ochoa Miguel Carmona Joseph Maranville Tom R Gaunt Valur Emilsson Vilmundur Gudnason Ellen M McDonagh Gavin J Wright Maya Ghoussaini Ian Dunham A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance
description	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.
format	article
author	Mohd Anisul Jarrod Shilts Jeremy Schwartzentruber James Hayhurst Annalisa Buniello Elmutaz Shaikho Elhaj Mohammed Jie Zheng Michael Holmes David Ochoa Miguel Carmona Joseph Maranville Tom R Gaunt Valur Emilsson Vilmundur Gudnason Ellen M McDonagh Gavin J Wright Maya Ghoussaini Ian Dunham
author_facet	Mohd Anisul Jarrod Shilts Jeremy Schwartzentruber James Hayhurst Annalisa Buniello Elmutaz Shaikho Elhaj Mohammed Jie Zheng Michael Holmes David Ochoa Miguel Carmona Joseph Maranville Tom R Gaunt Valur Emilsson Vilmundur Gudnason Ellen M McDonagh Gavin J Wright Maya Ghoussaini Ian Dunham
author_sort	Mohd Anisul
title	A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance
title_short	A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance
title_full	A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance
title_fullStr	A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance
title_full_unstemmed	A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance
title_sort	proteome-wide genetic investigation identifies several sars-cov-2-exploited host targets of clinical relevance
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/683976ef43454b7b95974612097b3624
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A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance

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