RESEARCH ARTICLE A proteome- wide genetic investigation identifies several SARS- CoV-2- exploited host targets of clinical relevance Mohd Anisul1,2*, Jarrod Shilts1, Jeremy Schwartzentruber1,2, James Hayhurst2,3, Annalisa Buniello2,3, Elmutaz Shaikho Elhaj Mohammed4, Jie Zheng5, Michael Holmes6,7, David Ochoa2,3, Miguel Carmona2,3, Joseph Maranville4, Tom R Gaunt5, Valur Emilsson8,9, Vilmundur Gudnason8,9, Ellen M McDonagh2,3, Gavin J Wright1,10, Maya Ghoussaini1,2*†, Ian Dunham1,2,3*† 1Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, United Kingdom; 2Open Targets, Wellcome Genome Campus, Hinxton, United Kingdom; 3European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL- EBI), Wellcome Genome Campus, Cambridge, United Kingdom; 4Bristol- Myers Squibb, Cambridge, United States; 5Medical Research Council (MRC) Integrative Epidemiology Unit, Department of Population Health Sciences, University of Bristol, Bristol, United Kingdom; 6Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom; 7Medical Research Council Population Health Research Unit (MRC PHRU), Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom; 8Icelandic Heart Association, Kopavogur, Iceland; 9Faculty of Medicine, University of Iceland, Reykjavik, Iceland; 10Department of Biology, York *For correspondence: Biomedical Research Institute, Hull York Medical School, University of York, York, mk31@ sanger. ac. uk (MA); United Kingdom mg29@ sanger. ac. uk (MG); dunham@ ebi. ac. uk (ID) †These authors are Joint Senior Authors to this work Abstract Competing interest: See page Background: The virus SARS- CoV-2 can exploit biological vulnerabilities (e.g. host proteins) in 17 susceptible hosts that predispose to the development of severe COVID-19. Funding: See page 17 Methods: To identify host proteins that may contribute to the risk of severe COVID-19, we under- took proteome- wide genetic colocalisation tests, and polygenic (pan) and cis- Mendelian randomisa- Preprinted: 17 March 2021 tion analyses leveraging publicly available protein and COVID-19 datasets. Received: 23 April 2021 Accepted: 07 August 2021 Results: Our analytic approach identified several known targets (e.g. ABO, OAS1), but also nomi- -4 Published: 17 August 2021 nated new proteins such as soluble Fas (colocalisation probability >0.9, p=1 10 ), implicating Fas- mediated apoptosis as a potential target for COVID-19 risk. The polygenic (pan) and cis- Mendelian Reviewing Editor: John W randomisation analyses showed consistent associations of genetically predicted ABO protein with Schoggins, University of Texas several COVID-19 phenotypes. The ABO signal is highly pleiotropic, and a look- up of proteins asso- Southwestern Medical Center, United States ciated 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, Copyright Anisul . This et al suggesting a mechanism that could explain the ABO association with COVID-19. article is distributed under the Conclusions: Our work provides a prioritised list of host targets potentially exploited by SARS- CoV-2 terms of the Creative Commons Attribution License, which and is a precursor for further research on CD209 and FAS as therapeutically tractable targets for permits unrestricted use and COVID-19. redistribution provided that the Funding: MAK, JSc, JH, AB, DO, MC, EMM, MG, ID were funded by Open Targets. J.Z. and T.R.G original author and source are were funded by the UK Medical Research Council Integrative Epidemiology Unit (MC_UU_00011/4). credited. JSh and GJW were funded by the Wellcome Trust Grant 206194. This research was funded in part by Anisul et al. eLife 2021;10:e69719. DOI: https:// doi. org/ 10. 7554/ eLife. 69719 1 of 22 Research article Epidemiology and Global Health | Genetics and Genomics 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. Introduction 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). Although effective vaccines have been developed to substantially reduce mortality and morbidity due to severe COVID-19, the emergence of mutated strains of the SARS- CoV-2 virus has challenged the effectiveness of existing vaccines and raised the urgency of identifying alternate therapeutic pathways to target the virus (Tegally, 2020; Erik et al., 2020 ; Collier et al., 2021). Nevertheless, it is likely that the mutated strains of SARS- CoV-2 will continue to exploit the same vulnerable host biology to bind onto and infect cells and, in suscep- tible individuals, evade immune defences and promote the excessive host inflammatory response that is characteristic of severe COVID-19 (Gordon et al., 2020a). Therefore, the identification of host proteins that play roles in COVID-19 susceptibility and severity remains crucial to the development of therapeutics as host protein mechanisms are independent of genomic mutations in the virus. An improved understanding of these therapeutically relevant virus- host pathways may also be important in combating viruses beyond SARS- CoV-2 (Perrin- Cocon et al., 2020). Several large- scale systematic experimental efforts have identified key host proteins that interact with viral proteins in the pathogenesis of severe COVID-19 (Gordon et al., 2020a; Gordon et al., 2020b; Bouhaddou et al., 2020). These notably include efforts to identify direct interactions with the spike protein of SARS-CoV-2, which mediates virus attachment onto receptors to infect host cells and is also the basis of most vaccines (Shang et al., 2020; Harvey et al., 2021). To complement in vitro host protein characterisation efforts, several groups have leveraged genetic datasets of human proteins and COVID-19 disease to identify therapeutically actionable candidate host proteins that are likely to play roles in enhancing COVID-19 susceptibility or to be involved in the pathogenesis of severe COVID-19 (Pairo- Castineira et al., 2021; Zhou et al., 2021). One of the approaches used was Mendelian randomisation (MR). MR simulates the design of randomised trials, with the underlying principle that randomisation of alleles at conception offers the opportunity to examine approximate differences in average risk of disease between comparable groups in a population that differ only in the distribution of the risk factor of interest (Davies et al., 2018), for example, protein abundance (Zheng et al., 2020). This allows the use of alleles as genetic instruments representing genetically predicted protein levels to proxy effects of pharmacological modulation of the protein. Some of the clinically actionable proteins identified by the MR approach are part of type I interferon signalling (encoded by genes: IFNAR2, TYK2, OAS1) and interleukin-6 (IL-6) signalling pathways (IL6R). Only one of these proteins (encoded by OAS1) had any evidence of genetic colocalisation, that is, evidence that genetic associations of the protein and COVID outcomes shared the same causal genetic signal (Zhou et al., 2021). An additional protein that was supported by both MR and genetic colocalisation tests was ABO (Zhou et al., 2021), reported in several published genome- wide association studies (GWAS) of COVID-19 (Pairo- Castineira et al., 2021; Ellinghaus et al., 2020). In response to the first published GWAS of COVID-19, we reported findings that link theABO signal with a number of clinically action- able targets including coagulation factors (von Willebrand factor [vWF], and Factor VIII [F8]), IL-6, and CD209/DC- SIGN (Karim et al., 2020). However, in most of the previous MR studies (Pairo- Castineira et al., 2021; Zhou et al., 2021), investigators only used curated cis- acting variants (genetic variants near or in the gene encoding the relevant protein) as genetic instruments to represent effects of genetically predicted protein concen- trations, rather than genome-wide instruments. While the use of cis-acting variants can minimise the risk of horizontal pleiotropic effects (i.e. associations driven by other proteins not on the causal pathway for the disease), it can suffer from lower power than a genome- wide analysis due to fewer available instruments (Zheng et al., 2020). Furthermore, in previous protein-COVID-19 MR studies, genetic colocalisation tests were carried out only for protein- phenotype associations that were signifi- cant in the MR analysis, potentially excluding many protein- phenotype associations that may share the same causal genetic signal but are underpowered in a proteome- wide MR approach. In the present study, we expanded on these previous reports by undertaking a proteome- wide two- sample pan- and cis-MR analysis using the Sun et al. GWAS (Sun et al., 2018) of plasma protein Anisul et al. eLife 2021;10:e69719. DOI: https:// doi. org/ 10. 7554/ eLife. 69719 2 of 22 Research article Epidemiology and Global Health | Genetics and Genomics eLife digest Individuals who become infected with the virus that causes COVID-19 can experi- ence a wide variety of symptoms. These can range from no symptoms or minor symptoms to severe illness and death. Key demographic factors, such as age, gender and race, are known to affect how susceptible