Identifying therapeutic drug targets for rare and common forms of short stature

摘要: Abstract While GWAS of common diseases has delivered thousands novel genetic findings, prioritizing genes for translation to therapeutics been challenging. Here, we propose an approach resolve that issue by identifying have both gain function (GoF) and loss (LoF) mutations associated with opposing effects on phenotype (Bidirectional Effect Selected Targets, BEST). Bidirectionality is a desirable feature the best targets because it implies causal role in one direction modulating target activity might be safe therapeutically beneficial other. We used height, highly heritable trait model complex diseases, test our approach. Using 34,231 individuals exome sequence data identified five (IGF1R, NPPC, NPR2, FGFR3, SHOX) evidence bidirectional stature. Rare protein-altering variants significantly increased risk idiopathic short stature (ISS) (OR=2.75, p= 3.99×10−8). These are key members only two pathways successfully targeted stature: Growth Hormone/Insulin-like growth factor 1 axis C-type Natriuretic peptide (CNP) Achondroplasia, monogenic form dwarfism. assayed subset NPR2 those elevated diminished found polygenic score height modulates penetrance pathogenic variants. also demonstrated adding exogenous CNP (encoded NPPC) rescues haploinsufficiency molecular CRISPR-engineered cell line, thus validating its potential therapeutic treatment inherited forms Finally, these BEST increase probability success clinical trials above beyond other evidence. Our results show value looking identify validate drug targets.