dc.contributor.author | Karim, Mohd A. |
dc.contributor.author | Shilts, Jarrod |
dc.contributor.author | Schwartzentruber, Jeremy |
dc.contributor.author | Hayhurst, James |
dc.contributor.author | Buniello, Annalisa |
dc.contributor.author | Mohammed, Elmutaz Shaikho Elhaj |
dc.contributor.author | Zheng, Jie |
dc.contributor.author | Holmes, Michael V. |
dc.contributor.author | Ochoa, David |
dc.contributor.author | Carmona, Miguel |
dc.contributor.author | Maranville, Joseph |
dc.contributor.author | Gaunt, Tom R. |
dc.contributor.author | Emilsson, Valur |
dc.contributor.author | Guðnason, Vilmundur G. |
dc.contributor.author | McDonagh, Ellen M. |
dc.contributor.author | Wright, Gavin J. |
dc.contributor.author | Ghoussaini, Maya |
dc.contributor.author | Dunham, Ian |
dc.date.accessioned | 2022-03-10T01:02:26Z |
dc.date.available | 2022-03-10T01:02:26Z |
dc.date.issued | 2021-08-17 |
dc.identifier.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 |
dc.identifier.issn | 2050-084X |
dc.identifier.other | 39164932 |
dc.identifier.other | c9b5a94e-b94e-4ab1-bd8b-ed3998b5fe2e |
dc.identifier.other | 85114098773 |
dc.identifier.other | 34402426 |
dc.identifier.uri | https://hdl.handle.net/20.500.11815/2938 |
dc.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. |
dc.description.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. |
dc.format.extent | 1671634 |
dc.format.extent | |
dc.language.iso | en |
dc.relation.ispartofseries | eLife; 10() |
dc.rights | info:eu-repo/semantics/openAccess |
dc.subject | COVID-19 |
dc.subject | Veirufræði |
dc.subject | Genamengi |
dc.subject | Covid-19 |
dc.subject | Genome association |
dc.subject | SARS-CoV-2 |
dc.subject | Severity of Illness Index |
dc.subject | Genome-Wide Association Study |
dc.subject | Scavenger Receptors, Class A/genetics |
dc.subject | Cell Adhesion Molecules |
dc.subject | Humans |
dc.subject | Lectins, C-Type |
dc.subject | fas Receptor/genetics |
dc.subject | Proteome |
dc.subject | Receptors, Cell Surface |
dc.subject | 2',5'-Oligoadenylate Synthetase/genetics |
dc.subject | SARS-CoV-2/physiology |
dc.subject | COVID-19/genetics |
dc.subject | General Biochemistry,Genetics and Molecular Biology |
dc.subject | General Immunology and Microbiology |
dc.subject | General Neuroscience |
dc.title | A proteome-wide genetic investigation identifies several sars-cov-2-exploited host targets of clinical relevance |
dc.type | /dk/atira/pure/researchoutput/researchoutputtypes/contributiontojournal/article |
dc.description.version | Peer reviewed |
dc.identifier.doi | 10.7554/eLife.69719 |
dc.relation.url | http://www.scopus.com/inward/record.url?scp=85114098773&partnerID=8YFLogxK |
dc.contributor.department | Faculty of Medicine |