Open Targets Genetics: systematic identification of trait-associated genes using large-scale genetics and functional genomics

Abstract

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.

eQTL Catalogue: a compendium of uniformly processed human gene expression and splicing QTLs

“…Database accessions for the raw gene expression and genotype datasets are listed on the eQTL Catalogue website (https://www.ebi.ac.uk/eqtl/Studies/). Our summary statistics have also been integrated into third party services such as the Open Targets Genetics Portal (102) and FUMA (13). The gene expression matrices will be made available via the EMBL-EBI Expression Atlas (103).…”

Open Targets Platform: supporting systematic drug–target identification and prioritisation

“…For example, drugs that have targets with underlying evidence for a genetic association with the relevant disease are twice as likely to succeed in clinical trials and be approved ( 5 , 6 ). To this end, a major new feature in the Platform is the incorporation of evidence from the Open Targets Genetics Portal ( https://genetics.opentargets.org/ ), which integrates publicly available human genome-wide association (GWAS) data with functional genomics to associate disease loci with target genes ( 7 ). The evidence from the genetics portal is integrated into our scoring system and informs target prioritisation for a given disease.…”

“…Nevertheless, it remains a long-standing challenge to link these loci to targetable causal genes. The Open Targets Genetics Portal addresses this problem by interpreting manually curated associations from the GWAS catalog, as well as independent signals from GWAS with publicly available summary statistics, most importantly the UK Biobank GWAS data ( 7 , 24 , 25 ). The Genetics Portal performs fine-mapping to narrow down the likely set of causal variants at a given trait-associated locus and to identify the potential causal gene for a particular association.…”

The Implications of ncRNAs in the Development of Human Diseases

“…These sequence changes are associated with diseases by performing genome-wide association studies (GWAS). The majority of GWAS-associated variants fall in ncRNAs loci, suggesting that they affect complex traits and diseases by altering expression of nearby genes, through regulatory mechanisms [70]. Among the examples that will be mentioned, we will see how the presence of SNPs in the sequence of a ncRNA can inhibit its maturation and therefore its cellular function.…”