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. Key demographic factors, such as age, gender and race, are known to affect how susceptible an individual is to infection. However, molecular factors, such as unique gene mutations and gene expression levels can also have a major impact on patient responses by affecting the levels of proteins in the body. Proteins that are too abundant or too scarce may mean the difference between dying from or surviving COVID-19.

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. Hence, insights would likely apply across all virus strains, including current strains, such as alpha and delta, and any new strains that may emerge in the future.

Using such a ‘natural experiment’ approach, Karim et al. compared the genetic profiles of over 30,000 COVID-19 patients and a million healthy individuals. Nine proteins were found to have an impact on COVID-19 infection and disease severity. Four proteins were ranked as top priorities for potential treatment targets. One protein, called CD209 (also known as DC-SIGN), is involved in how the virus enters the host cells, and had one of the strongest associations with COVID-19. Two proteins, called IL-6R and FAS, were involved in the immune response and could be responsible for the immune over-activation often seen in severe COVID-19. Finally, one protein, called OAS1, formed part of the body’s innate antiviral defence system and appeared to reduce susceptibility to COVID-19.

Knowing more about the proteins that influence the severity of COVID-19 opens up new ways to predict, protect and treat patients who may have severe or fatal reactions to infection. Indeed, one of the identified proteins (IL-6R) had already been targeted in recent clinical trials with some encouraging results. Considering CD209 as a potential receptor for the virus could provide another avenue for therapeutics, similar to previously successful approaches to block the virus’ known interaction with a receptor protein. Ultimately, this research could supply an entirely new set of treatment options to help combat the COVID-19 pandemic.

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 susceptible 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 the ABO signal with a number of clinically actionable 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 concentrations, 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 significant 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 concentrations and several COVID-19 GWAS phenotypes from the ICDA COVID-19 Host Genetics Initiative (October 2020 release) (Huang et al., 2020). First, we showed that genetically predicted circulating ABO protein was associated with COVID-19 susceptibility and severity and the lead ABO signal was associated strongly with plasma concentrations of soluble CD209. Second, we collected evidence for a direct mechanism of interaction between the SARS-CoV-2 spike protein and human CD209 protein. Third, we performed proteome-wide genetic colocalisation tests, followed by single-instrument cis-MR analysis, and we report additional novel targets of therapeutic relevance. Finally, 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.

Our systematic proteome-wide MR and genetic colocalisation analysis supported several previously proposed proteins and suggested additional clinically actionable targets for COVID-19 (Table 1). Of particular note, we provided pan- and cis-MR evidence with strong genetic colocalisation support for the ABO signal for most COVID-19 phenotypes. Although the ABO protein itself is not clinically actionable, the ABO signal was linked to plasma concentrations of several clinically tractable targets. We demonstrated that the CD209 protein we had found to have the strongest association with this ABO signal has a direct interaction with the SARS-CoV-2 spike protein, providing further evidence for a plausible mechanism. Our analyses also supported the role of soluble IL-6R in hospitalised COVID-19, with evidence from pan- and cis-MR analyses but limited evidence of genetic colocalisation with hospitalised COVID-19 but supported by the recent COVID-19 clinical trials of tocilizumab (which is partially mimicked by the IL-6R instrument used in the present study). Using a proteome-wide ‘colocalisation-first’ approach, we recapitulated previously reported targets (e.g. OAS1) and uncovered additional novel proteins that may play causal roles in COVID-19 susceptibility (THBS3), or severity (FAS).

Our proteome-wide genetic colocalisation analysis prioritised soluble Fas (sFas, also known as soluble CD95) receptor protein in the very severe COVID-19 phenotype. This finding was not reported in previous proteomic MR studies of COVID-19 most likely because they only assessed evidence of shared signals for targets prioritised by an MR-first approach. The soluble Fas receptor is reported to act as a decoy receptor competing with the trans-membrane Fas receptor for Fas ligand (FasL) (Cheng, 1994). Genetically predicted higher circulating sFas is, therefore, likely to represent effects of lower Fas-FasL signalling and, in our study, was associated with a higher risk of very severe COVID-19. Fas-FasL signalling typically initiates a cascade of intracellular programmes that result in cell death or apoptosis. Fas-mediated apoptosis plays a central role in T- and B-cell homeostasis (Hao, 2008), preventing the emergence of autoreactive or overactive immune cells (Hao, 2008; Butt, 2015). Excessive inflammation by hyperactive T-cells and autoantibodies was reported to underlie several cases of severe COVID-19 (Khamsi, 2021). To what extent sFas contributes to the excessive pro-inflammatory response in severe COVID-19 remains to be determined. Furthermore, Fas-mediated apoptosis of virus-infected cells is a major mechanism of resolution of viral infections (Thomson, 2001). Delayed apoptosis is reported to be one of the strategies exploited by SARS-CoV-2 in the early stages of infection to facilitate viral replication (Thomson, 2001; Ivanisenko et al., 2020). Additional insights for the role of sFas in COVID-19 can be gleaned from the results of recent drug trials. For example, Fas is one of the major targets of lopinavir-ritonavir – a combination HIV protease inhibitor (Sorbera et al., 2020); clinical trials of lopinavir-ritonavir failed to provide any therapeutic benefits beyond standard care in hospitalised COVID-19 patients (Cao et al., 2020). On the other hand, clinical trials testing dexamethasone demonstrated beneficial effects on survival for COVID-19 patients who were on respiratory support (RECOVERY Collaborative Group et al., 2021). In addition to its anti-inflammatory effects, dexamethasone downregulates molecules associated with decelerating apoptosis (Achuthan, 2018), including sFas (Joashi et al., 2002). An in-depth assessment of the specific role of soluble Fas in COVID-19, including whether or not it contributes to the beneficial effects of dexamethasone, is warranted in future studies.

Observational studies were the first to report differences in risk of severe COVID-19 based on ABO blood groups, although with some conflicting reports (Zhao, 2020; Zietz et al., 2020; Bhattacharjee et al., 2020). GWAS of COVID-19 susceptibility have, however, consistently reported a signal in the ABO locus (Bhattacharjee et al., 2020; Shelton, 2020), despite prior observations that controls used in the first published GWAS of COVID-19 (Ellinghaus et al., 2020) may be over-represented for blood group O (the most common blood group) and can result in associations due to selection bias. However, in a meta-analysis of GWAS of COVID-19, the ABO signal remained even when Ellinghaus et al. was excluded.

Furthermore, using these GWAS data, we and Katz et al. (in a preprint) (Katz et al., 2020; Karim et al., 2020) had previously linked the ABO signal with CD209/DC-SIGN protein, clotting factors, coagulation disorders, and concentrations of IL-6, all potential risk factors for COVID-19. In the present study, we build on previous work and show consistent cis- and pan-MR associations of genetically predicted circulating ABO protein with an expanded list of COVID phenotypes which colocalise with the ABO signal, supporting a shared genetic signal of ABO protein and the COVID-19 phenotypes.

We show that, next to the ABO protein, the ABO signal had the strongest association with the CD209 protein relative to other proteins and present experimental evidence of binding of CD209 with the full-length spike protein of SARS-CoV-2, independently but consistent with a concurrent preprint (Amraie, 2020). CD209 is a receptor on monocyte-derived dendritic cells (moDCs) that was shown, before this binding interaction was known, to facilitate entry of replication-competent SARS-CoV-2 and demonstrated to switch off the type I interferon signalling pathways necessary for transcription of several antiviral genes (Yang, 2020). The soluble isoforms of CD209 measured in our proteome datasets are known to correlate in expression levels to the membrane isoforms (Mummidi et al., 2001; Plazolles, 2011), making it plausible that the signal we observed is associated with greater abundance of CD209 as a cell-surface viral receptor. Alternatively, in the context of other viruses known to directly bind CD209 as we show here for SARS-CoV-2, soluble CD209 has been demonstrated to modulate infection, such as by promoting endocytosis if the soluble CD209 coating the virus acts as opsonins (Plazolles, 2011). Further research would be beneficial to reveal which of these mechanisms explain the association we observed. These findings may also help interpret the clinical significance of the higher CD209 gene expression in immune cells (extracted from bronchoalveolar lavage fluid) in severe COVID patients than healthy controls (Gao, 2020). It should be noted that the present study developed a therapeutic hypothesis for CD209 based solely on the strong evidence of association of the ABO signal with plasma concentrations of CD209 and evidence from the pan-MR association of CD209 with COVID-19 phenotypes (the pan-MR associations being driven mainly by trans-acting ABO SNPs) with no corresponding support of cis-MR or colocalisation. This suggests that while cis-MR and colocalisation analyses can support pan-MR associations of a target with disease, the lack of cis-MR or colocalisation for a target is not necessarily evidence against its therapeutic relevance.

In the present study, we also found that genetically predicted higher OAS1 – an interferon-induced broad-spectrum antiviral enzyme – was associated with lower risk of both susceptibility and severity of COVID-19, consistent with findings of a recent published report (Zhou et al., 2021). A large clinical trial of systemically administered interferons failed to show any substantial therapeutic benefits for severe COVID-19 (WHO Solidarity Trial Consortium et al., 2021). However, the strong evidence from human genetics supports reconsidering the role of interferon-based therapies in a new light, especially with respect to timing of administration (which current genetic studies are unable to provide any insights on) and route (systemic vs. nebulised) (Monk, 2020).

Non-O blood group individuals generally have higher risk of DVT and other coagulation disorders than O blood group individuals (Groot, 2020). The ABO signal, which largely determines the non-O blood groups, was also associated with DVT, PE, and higher levels of vWF and F8; vWF binds to and protects F8 from biological degradation (Federici, 2003). F8 is a key protein in the intrinsic coagulation pathway that activates Factor X and induces the formation of fibrin – the central component of blood clots (Bhopale and Nanda, 2003). Both DVT and PE are reported to affect almost a third of ICU-admitted COVID-19 patients (Malas, 2020). While several clinical trials evaluating the efficacy of anticoagulants for severe COVID-19 are underway, the National Institute of Clinical Excellence in the UK has suggested screening all hospitalised COVID-19 patients for any contraindications to anticoagulant use and offering prophylactic anticoagulation to eligible patients (National Institute for Health and Care Excellence, 2020).

We found moderate evidence for the role of IL-6 signalling in COVID-19 in agreement with a previous report (Bovijn et al., 2021). However, there was ambiguous evidence of genetic colocalisation (PP.H4: 0.46). Nevertheless, there was more support for a shared genetic signal between sIL-6R and hospitalised COVID-19 than for them to be driven by independent signals (H4/ H3 = 3.6). As noted by Bovign and colleagues (Bovijn et al., 2021), with some caveats, the phenotypic consistency of associations between the IL-6R genetic instrument and pharmacological effect of tocilizumab enable potential use of the IL-6R instrument to investigate therapeutic or adverse effects of tocilizumab. Although a previous report showed largely neutral effects of tocilizumab compared to placebo in hospitalised COVID-19 patients (Stone et al., 2020), two recent trials (REMAP-CAP Anthony C and Paul R, 2021 and RECOVERY RECOVERY Collaborative Group, 2021) with a longer follow-up period showed beneficial effects on survival at 90 days, consistent with the prediction of a protective effect using the tocilizumab-mimicking IL-6R genetic instrument in the present study and the previous report.

The major strengths of our study include the use of both genome-wide and local genetic instruments for MR analysis, the proteome-wide genetic colocalisation tests to nominate additional proteins of therapeutic relevance, and the expanded list of COVID-19 phenotypes analysed. We showed consistency of the association of ABO with the different COVID-19 phenotypes for both instrument selection strategies. Proteome-wide colocalisation tests implicated additional proteins that likely lacked sufficient genetic instruments to be detected by the multi-instrument GSMR method. For our top-ranked association with the CD209 protein, we provide experimental evidence for a mechanism that implicates CD209 as having a potentially causal role in disease pathology. Our experiments provide both direct evidence of biochemical binding between the purified spike protein of SARS-CoV-2 and CD209, and verification that this interaction occurs in live human cells. Host-directed therapies involving pathogen binding receptors have previously been developed against other infectious diseases where pathogen mutations or variants stymied more traditional approaches (Zenonos et al., 2015).

Our study also has several limitations. The reliability of the MR approach depends on the selection of the appropriate genetic instruments for the exposure (Schmidt, 2020). Where proteins are the exposure, the use of genetic instruments from across the genome can result in more instruments and potentially higher power to detect associations. However, the inclusion of a broader set of genetic instruments for protein-MR analysis can lead to associations not mediated by the protein under investigation (i.e. horizontal pleiotropy). In these cases, the use of genetic variants near or in the locus encoding the protein (cis-acting SNPs) can provide more specific estimates of risk, albeit at a potential power cost, associated with genetically predicted concentrations of the protein under investigation (Schmidt, 2020). A key problem of the latter approach is the selection of correlated genetic instruments that can lead to numerical approximation errors (Gkatzionis et al., 2021). In the present study, we leveraged both pan- and cis-MR approaches and used an MR method (GSMR) that automates the selection of near-independent genetic instruments and performs MR adjusting for any residual correlation (Zhu et al., 2018). Nevertheless, horizontal pleiotropy can also affect cis-MR analyses when different variants from the same gene region represent different biological pathways, indicated by heterogeneous effect estimates, or driven by a single variant with a large effect (e.g. missense variants) (Gkatzionis et al., 2021). To prevent the selection of heterogeneous instruments and minimise the selection of variants with large effects, the multi-instrument GSMR method used in the present study implements the HEIDI test which excludes genetic variants with strong or heterogeneous effects. The exclusion of missense variants with potential aptamer binding effects is evidenced in our study, where SNPs in 96% of nominally significant protein probes associated with COVID-19 also had effects on corresponding gene expression in different tissues across gene expression datasets as curated by our portal (Open Targets Genetics, 2019). Even while using cis-acting genetic instruments, the MR associations can be confounded due to LD between cis-pQTLs and disease-associated SNPs, and this is at least partially mitigated by genetic colocalisation tests. However, the genetic colocalisation tests used in our study assumed a single causal variant in each locus and will, therefore, result in higher false-negative tests if there is more than one trait-associated causal variant. An additional issue is related to the selection of COVID-19 GWAS datasets used for analyses. Most protein-MR studies have used COVID-19 phenotypes with population-based controls, given their larger number of controls providing additional power to detect signals but at a cost of not being able to distinguish signals relevant to disease progression. While study designs with milder/asymptomatic cases as controls are useful to study disease progression, they are frequently underpowered and, because the selection of study participants are conditioned on the outcome, are susceptible to collider-stratification bias (Griffith, 2020). To enable a comprehensive assessment, we used all published COVID-19 phenotypes (October 2020 freeze), irrespective of controls used and, as expected, found most signals in COVID-19 phenotypes with population-based controls. For one of the targets (CD209), although we experimentally demonstrate binding of CD209 with spike protein of SARS-CoV-2, understanding the functional significance CD209 has on viral entry and any immunological relevance during infection requires further research. Finally, although we nominate several targets that may be therapeutically relevant for COVID-19, clinical trials are required for definitive assessments and to guide therapy. For example, the findings related to the ABO signal strongly implicated the adverse role of dysregulated coagulation in COVID-19 specifically in non-O blood group individuals; whether pre-emptive use of anticoagulants guided by blood groups can prevent severe COVID-19 is subject to findings of trials such as the ongoing ACTIV-4 trial (NCT04505774) (U.S. National Library of Medicine, 2020).

In conclusion, we integrated genetic investigation with functional assessments of CD209, a receptor in moDCs, and postulated that this target may convey the COVID-19 risk of the ABO signal. Based on proteome-wide genetic colocalisation and MR, we also prioritised sFas for more detailed investigations of its therapeutic relevance to severe COVID-19 risk.

Summary data used for genetic analyses are publicly available (Sun et al can be downloaded from GWAS catalog https://www.ebi.ac.uk/gwas/downloads/summary-statistics and COVID-19 HGI summary statistics can be downloaded from their website https://www.covid19hg.org/results/). Data generated from our study are provided in the supplementary files (pan-MR and cis-MR association results filtered at p < 0.05 and no filters applied to colocalisation results).

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Author details

1. Mohd Anisul

   1. Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, United Kingdom
   2. Open Targets, Wellcome Genome Campus, Hinxton, United Kingdom

   Contribution

   Conceptualization, Data curation, Formal analysis, Visualization, Writing – original draft, Investigation

   For correspondence

   mk31@sanger.ac.uk

   Competing interests

   Open Targets is a pre-competitive partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners.

   "This ORCID iD identifies the author of this article:" 0000-0003-2960-6017

2. Jarrod Shilts

   Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, United Kingdom

   Contribution

   Conceptualization, Project administration, Writing – original draft, Investigation

   Competing interests

   none

3. Jeremy Schwartzentruber

   1. Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, United Kingdom
   2. Open Targets, Wellcome Genome Campus, Hinxton, United Kingdom

   Contribution

   Conceptualization, Supervision, Investigation

   Competing interests

   Open Targets is a pre-competitive partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners.

4. James Hayhurst

   1. Open Targets, Wellcome Genome Campus, Hinxton, United Kingdom
   2. European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge, United Kingdom

   Contribution

   Data curation, Resources, Software, Investigation

   Competing interests

   Open Targets is a pre-competitive partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners.

5. Annalisa Buniello

   1. Open Targets, Wellcome Genome Campus, Hinxton, United Kingdom
   2. European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge, United Kingdom

   Contribution

   Data curation, Resources, Investigation

   Competing interests

   Open Targets is a pre-competitive partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners.

6. Elmutaz Shaikho Elhaj Mohammed

   Bristol-Myers Squibb, Cambridge, United States

   Contribution

   Conceptualization, Writing – review and editing, Supervision, Investigation

   Competing interests

   Open Targets is a pre-competitive partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners. ES is also a full-time employee of Bristol-Myers Squibb.

7. Jie Zheng

   Medical Research Council (MRC) Integrative Epidemiology Unit, Department of Population Health Sciences, University of Bristol, Bristol, United Kingdom

   Contribution

   Supervision, Investigation

   Competing interests

   Open Targets is a pre-competitive partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners.

   "This ORCID iD identifies the author of this article:" 0000-0002-6623-6839

8. Michael Holmes

   1. Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
   2. Medical Research Council Population Health Research Unit (MRC PHRU), Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom

   Contribution

   Conceptualization, Supervision, Project administration, Writing – original draft, Investigation

   Competing interests

   Dr Holmes has consulted for Boehringer Ingelheim, and in adherence to the University of Oxford’s Clinical Trial Service Unit & Epidemiological Studies Unit (CSTU) staff policy, did not accept personal honoraria or other payments from pharmaceutical companies.

9. David Ochoa

   1. Open Targets, Wellcome Genome Campus, Hinxton, United Kingdom
   2. European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge, United Kingdom

   Contribution

   Data curation, Resources, Software, Investigation

   Competing interests

   Open Targets is a pre-competitive partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners.

10. Miguel Carmona

    1. Open Targets, Wellcome Genome Campus, Hinxton, United Kingdom
    2. European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge, United Kingdom

    Contribution

    Data curation, Validation, Resources

    Competing interests

    Open Targets is a pre-competitive partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners.

11. Joseph Maranville

    Bristol-Myers Squibb, Cambridge, United States

    Contribution

    Conceptualization, Supervision, Investigation

    Competing interests

    JM is a full-time employee of Bristol-Myers Squibb and retains stock or stock options in Bristol-Myers Squibb. The author has no other competing interests to declare.

12. Tom R Gaunt

    Medical Research Council (MRC) Integrative Epidemiology Unit, Department of Population Health Sciences, University of Bristol, Bristol, United Kingdom

    Contribution

    Supervision, Investigation

    Competing interests

    TG received grants from Biogen and GlaxoSmithKline. The author has no other competing interests to declare.

    "This ORCID iD identifies the author of this article:" 0000-0003-0924-3247

13. Valur Emilsson

    1. Icelandic Heart Association, Kopavogur, Iceland
    2. Faculty of Medicine, University of Iceland, Reykjavik, Iceland

    Contribution

    Validation, Resources, Investigation

    Competing interests

    Open Targets is a pre-competitive partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners.

14. Vilmundur Gudnason

    1. Icelandic Heart Association, Kopavogur, Iceland
    2. Faculty of Medicine, University of Iceland, Reykjavik, Iceland

    Contribution

    Resources, Supervision, Investigation

    Competing interests

    Open Targets is a pre-competitive partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners.

    "This ORCID iD identifies the author of this article:" 0000-0001-5696-0084

15. Ellen M McDonagh

    1. Open Targets, Wellcome Genome Campus, Hinxton, United Kingdom
    2. European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge, United Kingdom

    Contribution

    Resources, Supervision, Investigation

    Competing interests

    Open Targets is a pre-competitive partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners.

16. Gavin J Wright

    1. Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, United Kingdom
    2. Department of Biology, York Biomedical Research Institute, Hull York Medical School, University of York, York, United Kingdom

    Contribution

    Conceptualization, Writing – review and editing, Supervision, Investigation

    Competing interests

    Open Targets is a pre-competitive partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners.

    "This ORCID iD identifies the author of this article:" 0000-0003-0537-0863

17. Maya Ghoussaini

    1. Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, United Kingdom
    2. Open Targets, Wellcome Genome Campus, Hinxton, United Kingdom

    Contribution

    Conceptualization, Supervision, Investigation

    Contributed equally with

    Ian Dunham

    For correspondence

    mg29@sanger.ac.uk

    Competing interests

    Open Targets is a pre-competitive partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners.

18. Ian Dunham

    1. Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, United Kingdom
    2. Open Targets, Wellcome Genome Campus, Hinxton, United Kingdom
    3. European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge, United Kingdom

    Contribution

    Conceptualization, Validation, Supervision, Investigation

    Contributed equally with

    Maya Ghoussaini

    For correspondence

    dunham@ebi.ac.uk

    Competing interests

    Open Targets is a pre-competitive partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners. ID also received travel costs within the last 36 months from Takeda for speaking at their Reverse Translation Symposium. The author has no other competing interests to declare.

    "This ORCID iD identifies the author of this article:" 0000-0003-2525-5598

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