Multi-omics integration prioritizes NPC2, PCDH12 and IL10RB as candidate targets associated with spina bifida
Italian Journal of Pediatrics, 2026
Sun C., Liu G., Zhong Z., Lei X., Deng H., Huang F., Zeng J.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Developmental Biology | Pathophysiology | Plasma |  Olink Explore 3072/384 |
Abstract
Background
Neural tube defects may cause major congenital malformations, including spina bifida (SB). Despite advances in the prevention, prenatal diagnosis and surgical intervention, reliable biomarkers and therapeutic targets remain limited.
Methods
This study integrated Mendelian randomization (MR) and GEO transcriptomic data from placental and fetal tissues to prioritize candidate SB-associated biomarkers and potential therapeutic targets requiring further validation. Three large-scale pQTL datasets (Decode, UKB_PPP, and Prot_a) and two tissue gene expression datasets (GSE33111 and GSE252552) were included. MR analyses were performed using both cis- and trans-pQTLs, followed by exploratory transcriptomic analysis, GO/KEGG enrichment, GSMR, and single-gene GSEA to prioritize genes. Finally, PheWAS, drug prediction, molecular docking and molecular dynamics (MD) simulations were employed to explore the preliminary druggability and computational ligand-binding properties of the prioritized candidates.
Results
By integrating MR and transcriptomic results, three candidate SB-associated genes were prioritized: NPC2 (OR = 0.753, 95% CI: 0.646–0.879), PCDH12 (OR = 0.636, 95% CI: 0.507–0.798), and IL10RB (OR = 0.665, 95% CI: 0.549–0.805). These genes are involved in cholesterol metabolism, cell adhesion, and immune regulation, respectively. Enrichment analysis implicated the JAK-STAT, CCRI, and CAMs pathways. Docking and MD simulations supported NPC2-cholesterol binding as an endogenous reference complex, while docking supported tamibarotene as a preliminary IL10RB-targeting computational candidate, although its binding stability and biological activity require further validation.
Conclusion
Through a multi-omics integrative strategy, this study prioritized NPC2, PCDH12, and IL10RB as candidate SB-associated biomarkers and potential therapeutic targets requiring functional validation. Cholesterol served as an endogenous reference ligand for NPC2, while tamibarotene emerged as a preliminary computational hit that requires further experimental validation.