Integration of the Drug-Gene Interaction Database (DGIdb) with open crowdsource efforts

Freshour, Sharon; Kiwala, Susanna; Cotto, Kelsy C.; Coffman, Adam C.; McMichael, Joshua F.; Song, Jonathan J; Griffith, Malachi; Griffith, Obi L.; Wagner, Alex H.

doi:10.1101/2020.09.18.301721

Cited by 17 publications

(13 citation statements)

References 29 publications

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“…We searched genes prioritised from the TWAS/PWAS or MR analyses in the Drug-gene interaction database (DGIdb v4.2.0 – accessed April 2021) to identify approved compounds that could reverse the odds increasing direction of expression for SZ or BIP [33]. DGIdb combines data from databases such as DrugBank, as well as curated literature sources.…”

Section: Methodsmentioning

confidence: 99%

Directional anchor genes refine polygenic informed treatment selection in schizophrenia and bipolar disorder

Geaghan

Atkins

Carr

et al. 2022

Preprint

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Genetically informed drug development and repurposing is an attractive prospect for improving outcomes in patients with psychiatric illness; however, the effectiveness of these endeavours can be confounded by heterogeneity. In this study, we propose a novel approach that links interventions implicated by disorder-associated genetic risk, at the population level, to a framework that can target these compounds to individuals. Specifically, results from genome-wide association studies are integrated with expression data to prioritise individual 'directional anchor' genes for which the predicted risk-increasing direction of expression could be counteracted by an existing drug. While these compounds represent plausible therapeutic candidates, they are not likely to be equally efficacious for all individuals. To account for this heterogeneity, we constructed polygenic scores restricted to variants annotated to the network of genes that interact with each directional anchor gene. These metrics, we call pharmagenic enrichment scores (PES), identify individuals with a higher burden of genetic risk, localised in biological processes related to the candidate drug target, to inform precision drug repurposing. We used this approach to investigate schizophrenia and bipolar disorder and reveal several compounds targeting specific directional anchor genes that could be plausibly repurposed, including antioxidants, vitamins, antiarrhythmics, and lipid modifying agents. These genetic risk scores, mapped to the networks associated with target genes, revealed biological insights that cannot be observed in undifferentiated genome-wide polygenic risk score (PRS). For example, an enrichment of these partitioned scores in schizophrenia cases with otherwise low PRS and distinct correlations with measured biochemical traits. In summary, genetic risk could be used more specifically to direct drug repurposing candidates that target particular genes implicated in psychiatric and other complex disorders.

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Section: Methodsmentioning

confidence: 99%

Directional anchor genes refine polygenic informed treatment selection in schizophrenia and bipolar disorder

Geaghan

Atkins

Carr

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…DGIdb (drug-gene interaction database, www.dgidb.org) is a webserver with drug-gene interaction and druggable genes information, collected from more than thirty high-quality web sources [16]. If biomarkers or therapeutic targets are identified, then researchers could search which drugs could target the biomarker or therapeutic target using DGIdb, achieving a quick translational opportunity.…”

Section: Databases Of Genes Pathways and Drugs For Drug Repositioningmentioning

confidence: 99%

Gene Signature-Based Drug Repositioning

Jia¹,

Song²,

Shi³

et al. 2022

Drug Repurposing - Molecular Aspects and Therapeutic Applications

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With the advent of dynamical omics technology, especially the transcriptome and proteome, a huge amount of data related to various diseases and approved drugs are available under multi global projects or researches with their interests. These omics data and new machine learning technology largely promote the translation of drug research into clinical trials. We will cover the following topics in this chapter. 1) An introduction to the basic discipline of gene signature-based drug repurposing; 2) databases of genes, drugs and diseases; 3) gene signature databases of the approved drugs; 4) gene signature databases of various diseases; 5) gene signature-based methods and tools for drug repositioning; 6) new omics technology for drug repositioning; 7) drug repositioning examples with reproducible code. And finally, discuss the future trends and conclude.

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“…Differentially expressed genes were queried in Drug Gene Interaction Database (DGIdb) to identify existing drugs with experimentally determined associations with our DEGs 11 . Any genes with known drug interactions were annotated using DGIdb.…”

Section: Identifying Drug-gene Interactionsmentioning

confidence: 99%

Large Scale Profiling of SARS-CoV-2-Infected Patients Identified Potential Therapeutic Host Targets and Drug Candidates for COVID-19

Jain¹,

Rego²,

Dakshanamurthy

2021

Preprint

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Given the rapid spread of SARS-CoV-2 and rising death toll of COVID-19 in the current absence of effective treatments, it is imperative that therapeutics are developed and made available to patients as quickly as possible. Publicly available COVID-19 patient data can be used to identify host therapeutic targets, tailoring treatments to the disease signatures observed in patients. In this study, we identify potential host therapeutic targets based on gene expression alterations observed in COVID-19 patients. We analyzed RNAseq data from airway samples of COVID-19 patients and healthy controls to detect significantly differentially expressed genes and pathways that present potential therapeutic targets. Our analysis revealed expression changes in key genes involved in activation of immune pathways, as well as genes targeted by SARS-CoV2 to interfere with normal host cell functioning. Critical changes were observed in a number of genes, including EIF2AK2, which was shown to play important roles in activating the interferon response and interfering with host cell translational machinery in SARS-CoV-2 infection, presenting a prospective therapeutic target. We also identified drugs with potential to modulate multiple therapeutic targets within the most significant pathways. Our results both validate key genes, pathways, and drug candidates that have been reported by other studies and suggest others that have not been well-characterized and warrant further investigation by future studies. Further investigation of these therapeutic targets and their drug interactions may lead to effective therapeutic strategies to combat the current COVID-19 pandemic and protect against future outbreaks.<br>

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Integration of the Drug-Gene Interaction Database (DGIdb) with open crowdsource efforts

Cited by 17 publications

References 29 publications

Directional anchor genes refine polygenic informed treatment selection in schizophrenia and bipolar disorder

Directional anchor genes refine polygenic informed treatment selection in schizophrenia and bipolar disorder

Gene Signature-Based Drug Repositioning

Large Scale Profiling of SARS-CoV-2-Infected Patients Identified Potential Therapeutic Host Targets and Drug Candidates for COVID-19

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