Open Targets Genetics (https://genetics.opentargets.org) is an open-access integrative resource that aggregates human GWAS and functional genomics data including gene expression, protein abundance, chromatin interaction and conformation data from a wide range of cell types and tissues to make robust connections between GWAS-associated loci, variants and likely causal genes. This enables systematic identification and prioritisation of likely causal variants and genes across all published trait-associated loci. In this paper, we describe the public resources we aggregate, the technology and analyses we use, and the functionality that the portal offers. Open Targets Genetics can be searched by variant, gene or study/phenotype. It offers tools that enable users to prioritise causal variants and genes at disease-associated loci and access systematic cross-disease and disease-molecular trait colocalization analysis across 92 cell types and tissues including the eQTL Catalogue. Data visualizations such as Manhattan-like plots, regional plots, credible sets overlap between studies and PheWAS plots enable users to explore GWAS signals in depth. The integrated data is made available through the web portal, for bulk download and via a GraphQL API, and the software is open source. Applications of this integrated data include identification of novel targets for drug discovery and drug repurposing.
The Open Targets Platform integrates evidence from genetics, genomics, transcriptomics, drugs, animal models and scientific literature to score and rank target-disease associations for drug target identification. The associations are displayed in an intuitive user interface ( https://www.targetvalidation.org ), and are available through a REST-API ( https://api.opentargets.io/v3/platform/docs/swagger-ui ) and a bulk download ( https://www.targetvalidation.org/downloads/data ). In addition to target-disease associations, we also aggregate and display data at the target and disease levels to aid target prioritisation. Since our first publication two years ago, we have made eight releases, added new data sources for target-disease associations, started including causal genetic variants from non genome-wide targeted arrays, added new target and disease annotations, launched new visualisations and improved existing ones and released a new web tool for batch search of up to 200 targets. We have a new URL for the Open Targets Platform REST-API, new REST endpoints and also removed the need for authorisation for API fair use. Here, we present the latest developments of the Open Targets Platform, expanding the evidence and target-disease associations with new and improved data sources, refining data quality, enhancing website usability, and increasing our user base with our training workshops, user support, social media and bioinformatics forum engagement.
The Open Targets Platform (https://www.targetvalidation.org/) provides users with a queryable knowledgebase and user interface to aid systematic target identification and prioritisation for drug discovery based upon underlying evidence. It is publicly available and the underlying code is open source. Since our last update two years ago, we have had 10 releases to maintain and continuously improve evidence for target–disease relationships from 20 different data sources. In addition, we have integrated new evidence from key datasets, including prioritised targets identified from genome-wide CRISPR knockout screens in 300 cancer models (Project Score), and GWAS/UK BioBank statistical genetic analysis evidence from the Open Targets Genetics Portal. We have evolved our evidence scoring framework to improve target identification. To aid the prioritisation of targets and inform on the potential impact of modulating a given target, we have added evaluation of post-marketing adverse drug reactions and new curated information on target tractability and safety. We have also developed the user interface and backend technologies to improve performance and usability. In this article, we describe the latest enhancements to the Platform, to address the fundamental challenge that developing effective and safe drugs is difficult and expensive.
Genome-wide association studies (GWAS) have identified many variants associated with complex traits, but identifying the causal gene(s) is a major challenge. Here we present an open resource that provides systematic fine-mapping and gene prioritization across 133,441 published human GWAS loci. We integrate genetics (GWAS Catalog and UK Biobank) with transcriptomic, proteomic and epigenomic data, including systematic disease-disease and disease-molecular trait colocalization results across 92 cell types and tissues. We identify 729 loci fine-mapped to a single coding causal variant and colocalized with a single gene. We trained a machine learning model using the fine-mapped genetics and functional genomics data using 445 gold-standard curated GWAS loci to distinguish causal genes from neighboring, outperforming a naive distance-based model. Our prioritized genes were enriched for known approved drug targets (OR = 8.1, 95% CI: (5.7, 11.5)). These results are publicly available through a web portal ( http://genetics.opentargets.org ), enabling users to easily prioritize genes at disease-associated loci and assess their potential as drug targets.
The Open Targets Platform (https://platform.opentargets.org/) is an open source resource to systematically assist drug target identification and prioritisation using publicly available data. Since our last update, we have reimagined, redesigned, and rebuilt the Platform in order to streamline data integration and harmonisation, expand the ways in which users can explore the data, and improve the user experience. The gene–disease causal evidence has been enhanced and expanded to better capture disease causality across rare, common, and somatic diseases. For target and drug annotations, we have incorporated new features that help assess target safety and tractability, including genetic constraint, PROTACtability assessments, and AlphaFold structure predictions. We have also introduced new machine learning applications for knowledge extraction from the published literature, clinical trial information, and drug labels. The new technologies and frameworks introduced since the last update will ease the introduction of new features and the creation of separate instances of the Platform adapted to user requirements. Our new Community forum, expanded training materials, and outreach programme support our users in a range of use cases.
Genome-wide association studies (GWAS) have identified many variants robustly associated with complex traits but identifying the gene(s) mediating such associations is a major challenge. Here we present an open resource that provides systematic fine-mapping and protein-coding gene prioritization across 133,441 published human GWAS loci. We integrate diverse data sources, including genetics (from GWAS Catalog and UK Biobank) as well as transcriptomic, proteomic and epigenomic data across many tissues and cell types. We also provide systematic disease-disease and disease-molecular trait colocalization results across 92 cell types and tissues and identify 729 loci fine-mapped to a single coding causal variant and colocalized with a single gene. We trained a machine learning model using the fine mapped genetics and functional genomics data using 445 gold standard curated GWAS loci to distinguish causal genes from background genes at the same loci, outperforming a naive distance based model. Genes prioritized by our model are enriched for known approved drug targets (OR = 8.1, 95% CI: [5.7, 11.5]). These results will be regularly updated and are publicly available through a web portal, Open Targets Genetics (OTG, http://genetics.opentargets.org), enabling users to easily prioritize genes at disease-associated loci and assess their potential as drug targets.
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 x 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.
Proteome-wide Mendelian randomization (MR) has emerged as a promising approach in uncovering novel therapeutic targets. However, genetic colocalization analysis has revealed that a third of MR associations lacked a shared causal signal between the protein and disease outcome, raising questions about the effectiveness of this approach. The impact of proteome-wide MR, stratified by cis-trans status, in the presence or absence of genetic colocalization, on therapeutic target identification remains largely unknown. In this study, we conducted genome-wide MR and cis/trans-genetic colocalization analyses using proteomic and complex trait genome-wide association studies. Using two different gold-standard datasets, we found that the enrichment of target-disease pairs supported by MR increased with more p-value stringent thresholds MR p-value, with the evidence of enrichment limited to colocalizing cis-MR associations. Using a phenome-wide proteogenetic colocalization approach, we identified 235 unique targets associated with 168 binary traits at high confidence (at colocalization posterior probability of shared signal > 0.8 and 5% FDR-corrected MR p-value). The majority of the target-trait pairs did not overlap with existing drug targets, highlighting opportunities to investigate novel therapeutic hypotheses. 42% of these non-overlapping target-trait pairs were supported by GWAS, interacting protein partners, animal models, and Mendelian disease evidence. Additionally, as previously reported, these high confidence target-trait pairs assisted with causal gene identification and helped uncover translationally informative novel biology, especially from trans-colocalizing signals, such as the association of lower intestinal alkaline phosphatase with a higher risk of inflammatory bowel disease in FUT2 non-secretors. Beyond target identification, we used MR of colocalizing signals to infer therapeutic directions and flag potential safety concerns. For example, we found that most genetically predicted therapeutic targets for inflammatory bowel disease could potentially worsen allergic disease phenotypes, except for TNFRSF6B where we observed directionally consistent associations for both phenotypes. Our results are publicly available (https://mk31.shinyapps.io/mr_app2/), enabling others to use proteogenomic evidence to appraise therapeutic targets.
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