Identifying therapeutic drug targets using bidirectional effect genes.
Drug Discovery
Dwarfism
/ genetics
Genes
Genetic Association Studies
Humans
Natriuretic Peptide, C-Type
/ genetics
Pharmaceutical Preparations
Phenotype
Receptor, Fibroblast Growth Factor, Type 3
/ genetics
Receptor, IGF Type 1
/ genetics
Receptors, Atrial Natriuretic Factor
/ genetics
Short Stature Homeobox Protein
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
13 04 2021
13 04 2021
Historique:
received:
11
06
2020
accepted:
12
02
2021
entrez:
14
4
2021
pubmed:
15
4
2021
medline:
29
4
2021
Statut:
epublish
Résumé
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
Identifiants
pubmed: 33850126
doi: 10.1038/s41467-021-21843-8
pii: 10.1038/s41467-021-21843-8
pmc: PMC8044152
doi:
Substances chimiques
IGF1R protein, human
0
NPPC protein, human
0
Pharmaceutical Preparations
0
SHOX protein, human
0
Short Stature Homeobox Protein
0
Natriuretic Peptide, C-Type
127869-51-6
FGFR3 protein, human
EC 2.7.10.1
Receptor, Fibroblast Growth Factor, Type 3
EC 2.7.10.1
Receptor, IGF Type 1
EC 2.7.10.1
Receptors, Atrial Natriuretic Factor
EC 4.6.1.2
atrial natriuretic factor receptor B
EC 4.6.1.2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
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