ArticleBioinformatics (Oxford, England)2019
Large-scale analysis of human gene expression variability associates highly variable drug targets with lower drug effectiveness and safety.
Article in Bioinformatics (Oxford, England), 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed.
- Donor-specific, but not sex-specific, signatures dominate cell-type classification in lung scRNA-seq data.Biochemistry and biophysics reports · 2026Article
- Inter-individual gene expression variability implies stable regulation of brain-biased genes across organs in three ray-finned fishes.bioRxiv : the preprint server for biology · 2026Article
- Genetic Variation in Drug Targets: Are We Ready for the Era of Precision Medicinal Chemistry?ACS medicinal chemistry letters · 2025Article
- Deciphering single-cell gene expression variability and its role in drug response.Human molecular genetics · 2024Article
- Tissue-aware interpretation of genetic variants advances the etiology of rare diseases.Molecular systems biology · 2024Article
- A robust model for cell type-specific interindividual variation in single-cell RNA sequencing data.Nature communications · 2024Article
- Quantifying transcriptome diversity: a review.Briefings in functional genomics · 2024Review
- Monitoring Immune Modulation in Season Population: Identifying Effects and Markers Related toBiomolecules · 2023Article
- Measuring cell-to-cell expression variability in single-cell RNA-sequencing data: a comparative analysis and applications to B cell aging.Genome biology · 2023Article
- Rapid and biased evolution of canalization during adaptive divergence revealed by dominance in gene expression variability during Arctic charr early development.Communications biology · 2023Article
- Predicting molecular mechanisms of hereditary diseases by using their tissue-selective manifestation.Molecular systems biology · 2023Article
- Gene expression variability in long-term survivors of childhood cancer and cancer-free controls in response to ionizing irradiation.Molecular medicine (Cambridge, Mass.) · 2023Article
- A robust model for cell type-specific interindividual variation in single-cell RNA sequencing data.bioRxiv : the preprint server for biology · 2023Article
- Sex differences in interindividual gene expression variability across human tissues.PNAS nexus · 2022Article
- Article
- Identification of human long noncoding RNAs associated with nonalcoholic fatty liver disease and metabolic homeostasis.The Journal of clinical investigation · 2021Article
- Article
- Gene expression variability in human and chimpanzee populations share common determinants.eLife · 2020Article
- Variability in Gene Expression is Associated with Incomplete Penetrance in Inherited Eye Disorders.Genes · 2020Article
- ResponseNet v.3: revealing signaling and regulatory pathways connecting your proteins and genes across human tissues.Nucleic acids research · 2019Article
Corrections and comments
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Authors and funding
3 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
motivationThe effectiveness of drugs tends to vary between patients. One of the well-known reasons for this phenomenon is genetic polymorphisms in drug target genes among patients. Here, we propose that differences in expression levels of drug target genes across individuals can also contribute to this phenomenon.
resultsTo explore this hypothesis, we analyzed the expression variability of protein-coding genes, and particularly drug target genes, across individuals. For this, we developed a novel variability measure, termed local coefficient of variation (LCV), which ranks the expression variability of each gene relative to genes with similar expression levels. Unlike commonly used methods, LCV neutralizes expression levels biases without imposing any distribution over the variation and is robust to data incompleteness. Application of LCV to RNA-sequencing profiles of 19 human tissues and to target genes of 1076 approved drugs revealed that drug target genes were significantly more variable than protein-coding genes. Analysis of 113 drugs with available effectiveness scores showed that drugs targeting highly variable genes tended to be less effective in the population. Furthermore, comparison of approved drugs to drugs that were withdrawn from the market showed that withdrawn drugs targeted significantly more variable genes than approved drugs. Last, upon analyzing gender differences we found that the variability of drug target genes was similar between men and women. Altogether, our results suggest that expression variability of drug target genes could contribute to the variable responsiveness and effectiveness of drugs, and is worth considering during drug treatment and development. AVAILABILITY AND IMPLEMENTATION: LCV is available as a python script in GitHub (https://github.com/eyalsim/LCV). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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