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Cited by 25Genomics and Rare DiseasesGenetic Associations and EpidemiologyComputational Drug Discovery Methods

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Identifying therapeutic drug targets using bidirectional effect genes

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Estrada, Karol, Froelich, Steven, Wuster, Arthur, Bauer, Christopher R., Sterling, Teague, Clark, Wyatt T., Ru, Yuanbin, Trinidad, Marena, Nguyen, Hong Phuc, Luu, Amanda R., Wendt, Daniel J., Yogalingam, Gouri, Yu, Guoying Karen, LeBowitz, Jonathan H., Cardon, Lon R.·2021·Nature Communications
DOI 10.1038/s41467-021-21843-8PMC PMC8044152
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Abstract

Prioritizing genes for translation to therapeutics for common diseases has been challenging. Here, we propose an approach to identify drug targets with high probability of success by focusing on genes with both gain of function (GoF) and loss of function (LoF) mutations associated with opposing effects on phenotype (Bidirectional Effect Selected Targets, BEST). We find 98 BEST genes for a variety of indications. Drugs targeting those genes are 3.8-fold more likely to be approved than non-BEST genes. We focus on five genes (IGF1R, NPPC, NPR2, FGFR3, and SHOX) with evidence for bidirectional effects on stature. Rare protein-altering variants in those genes result in significantly increased risk for idiopathic short stature (ISS) (OR = 2.75, p = 3.99 × 10−8). Finally, using functional experiments, we demonstrate that adding an exogenous CNP analog (encoded by NPPC) rescues the phenotype, thus validating its potential as a therapeutic treatment for ISS. Our results show the value of looking for bidirectional effects to identify and validate drug targets.

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  • Drugs targeting genes with bidirectional effects have a higher probability of being approved in the clinic.

    “It has been demonstrated that drugs targeting genes with bidirectional effects have a higher probability of being approved in the clinic44.”

    From Effects of SPI1-mediated transcriptome remodeling on Alzheimer's disease-related phenotypes in mouse models of Aβ amyloidosis (2024) · cites this paper as [44]

  • The targets of transcription factors are not randomly selected.

    “One critical concept to keep in mind here is that the targets of transcription factors are not randomly selected.”

    From Effects of SPI1-mediated transcriptome remodeling on Alzheimer's disease-related phenotypes in mouse models of Aβ amyloidosis (2024) · cites this paper as [44]

    The Introduction discusses selecting genes as therapeutic drug targets, and the Results discuss genes associated with human traits; neither addresses how transcription factors select their targets. Searches for “transcription factors” and nonrandom target selection found no passage in our copy that speaks to the claim. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • Target genes of transcription factors are almost always within the same or similar pathways that need to be co-regulated in a coordinated manner.

    “These target genes are almost always within the same or similar pathways that need to be co-regulated in a coordinated manner43,44.”

    From Effects of SPI1-mediated transcriptome remodeling on Alzheimer's disease-related phenotypes in mouse models of Aβ amyloidosis (2024) · cites this paper as [44]

    The Introduction describes bidirectional-effect genes as potential drug targets, and the Discussion identifies pathways involved in growth. Neither section addresses whether transcription-factor target genes are almost always in the same or similar pathways or require coordinated co-regulation. Searches for transcription factors and coordinated pathway regulation found no passage establishing that claim. (LLM, conf=0.77)

    Experimental — accuracy not yet measured

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Metadata

Authors
Estrada, K., Froelich, S., Wuster, A., Bauer, C. R., Sterling, T., Clark, W. T., Ru, Y., Trinidad, M., Nguyen, H. P., Luu, A. R., Wendt, D. J., Yogalingam, G., Yu, G. K., LeBowitz, J. H., & Cardon, L. R.
Affiliations
BioMarin (United States) (US)
Corresponding author
Estrada, Karol
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-04-13
Volume
12
Issue
1
Pages
2224-2224
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-021-21843-8
PMC
PMC8044152
OpenAlex
W3155106196
Cited by
25
References
9
Citations by year
2026: 2 · 2025: 9 · 2024: 5 · 2023: 5 · 2022: 1 · 2021: 3
FWCI
1.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
Masarykova Univerzita
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
Keywords
drug target identification, gain-of-function mutations, loss-of-function mutations, drug approval, idiopathic short stature, IGF-1 receptor, NPPC, NPR2, FGFR3, SHOX, height, therapeutic validation
MeSH terms
Short Stature Homeobox Protein, Atrial Natriuretic Factor Receptor B, Pharmaceutical Preparations, Dwarfism, Genes, Humans, Phenotype, Receptors, Atrial Natriuretic Factor, Receptor, IGF Type 1, Natriuretic Peptide, C-Type, Receptor, Fibroblast Growth Factor, Type 3, Drug Discovery, Genetic Association Studies

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