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Repositioning drugs by targeting network modules: a Parkinson’s disease case study

Overview of attention for article published in BMC Bioinformatics, December 2017
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43 Mendeley
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Repositioning drugs by targeting network modules: a Parkinson’s disease case study
Published in
BMC Bioinformatics, December 2017
DOI 10.1186/s12859-017-1889-0
Pubmed ID

Zongliang Yue, Itika Arora, Eric Y. Zhang, Vincent Laufer, S. Louis Bridges, Jake Y. Chen


Much effort has been devoted to the discovery of specific mechanisms between drugs and single targets to date. However, as biological systems maintain homeostasis at the level of functional networks robustly controlling the internal environment, such networks commonly contain multiple redundant mechanisms designed to counteract loss or perturbation of a single member of the network. As such, investigation of therapeutics that target dysregulated pathways or processes, rather than single targets, may identify agents that function at a level of the biological organization more relevant to the pathology of complex diseases such as Parkinson's Disease (PD). Genome-wide association studies (GWAS) in PD have identified common variants underlying disease susceptibility, while gene expression microarray data provide genome-wide transcriptional profiles. These genomic studies can illustrate upstream perturbations causing the dysfunction in signaling pathways and downstream biochemical mechanisms leading to the PD phenotype. We hypothesize that drugs acting at the level of a gene expression module specific to PD can overcome the lack of efficacy associated with targeting a single gene in polygenic diseases. Thus, this approach represents a promising new direction for module-based drug discovery in human diseases such as PD. We built a framework that integrates GWAS data with gene co-expression modules from tissues representing three brain regions-the frontal gyrus, the lateral substantia, and the medial substantia in PD patients. Using weighted gene correlation network analysis (WGCNA) software package in R, we conducted enrichment analysis of data from a GWAS of PD. This led to the identification of two over-represented PD-specific gene co-expression network modules: the Brown Module (Br) containing 449 genes and the Turquoise module (T) containing 905 genes. Further enrichment analysis identified four functional pathways within the Br module (cellular respiration, intracellular transport, energy coupled proton transport against the electrochemical gradient, and microtubule-based movement), and one functional pathway within the T module (M-phase). Next, we utilized drug-protein regulatory relationship databases (DMAP) and developed a Drug Effect Sum Score (DESS) to evaluate all candidate drugs that might restore gene expression to normal level across the Br and T modules. Among the drugs with the 12 highest DESS scores, 5 had been reported as potential treatments for PD and 6 hold potential repositioning applications. In this study, we present a systems pharmacology framework which draws on genetic data from GWAS and gene expression microarray data to reposition drugs for PD. Our innovative approach integrates gene co-expression modules with biomolecular interaction network analysis to identify network modules critical to the PD pathway and disease mechanism. We quantify the positive effects of drugs in a DESS score that is based on known drug-target activity profiles. Our results illustrate that this modular approach is promising for repositioning drugs for use in polygenic diseases such as PD, and is capable of addressing challenges of the hindered gene target in drug repositioning approaches to date.

Twitter Demographics

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Mendeley readers

The data shown below were compiled from readership statistics for 43 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 43 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 12 28%
Researcher 5 12%
Student > Bachelor 5 12%
Student > Postgraduate 4 9%
Professor 4 9%
Other 4 9%
Unknown 9 21%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 9 21%
Agricultural and Biological Sciences 5 12%
Medicine and Dentistry 5 12%
Pharmacology, Toxicology and Pharmaceutical Science 4 9%
Computer Science 3 7%
Other 6 14%
Unknown 11 26%

Attention Score in Context

This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 31 May 2018.
All research outputs
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Outputs from BMC Bioinformatics
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Outputs of similar age
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Outputs of similar age from BMC Bioinformatics
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Altmetric has tracked 13,017,042 research outputs across all sources so far. This one is in the 42nd percentile – i.e., 42% of other outputs scored the same or lower than it.
So far Altmetric has tracked 4,861 research outputs from this source. They receive a mean Attention Score of 4.8. This one is in the 40th percentile – i.e., 40% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 381,404 tracked outputs that were published within six weeks on either side of this one in any source. This one has gotten more attention than average, scoring higher than 52% of its contemporaries.
We're also able to compare this research output to 444 others from the same source and published within six weeks on either side of this one. This one is in the 46th percentile – i.e., 46% of its contemporaries scored the same or lower than it.