| Title: | Repurposing dipeptidyl peptidase-4 inhibitor for Parkinson's disease prevention: A drug-target Mendelian randomization study |
| Journal: | Neurotherapeutics |
| Published: | 29 Dec 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41469306/ |
| DOI: | https://doi.org/10.1016/j.neurot.2025.e00815 |
| URL: | https://www.neurotherapeuticsjournal.org/article/S1878-7479(25)00293-4/pdf |
Publication 16950
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
Abstract
Parkinson's disease (PD) remains without effective disease-modifying therapies, primarily due to limited understanding of its underlying mechanisms. Emerging evidence suggests that dipeptidyl peptidase-4 inhibitors (DPP-4Is), commonly used as anti-diabetics, may offer neuroprotective effects. We aimed to evaluate the potential of repurposing DPP-4Is for reducing the PD risk, using a drug-target Mendelian randomization (MR) approach, with specific attention to sex. We performed two-sample MR analyses using instrumental variables (IVs) for DPP-4Is derived from gene expression quantitative trait loci (IVeQTL) and protein QTL (IVpQTL) data sourced from the eQTLGen consortium and UK Biobank, respectively. Associations were tested using the largest PD genome-wide association studies (GWAS) dataset from the International Parkinson's Disease Genomics Consortium, including sex-stratified analyses. Primary analyses used inverse variance weighted MR, with additional sensitivity analyses (alternative MR methods, varying IV selection thresholds, and tissue-specific eQTL), mediation analysis through diabetes and colocalization analysis. Genetically proxied DPP-4 inhibition was associated with reduced PD risk: OR (95% CI) = 1.78 (1.21-2.61) for IVeQTL and 1.21 (1.02-1.45) for IVpQTL. This beneficial effect was more pronounced in men-IVeQTL: 2.25 (1.55-3.28); IVpQTL 1.35 (1.15-1.57)-but not significant in women, suggesting sex-specific effects. Findings were robust across sensitivity analyses and replicated in an independent PD GWAS. Diabetes did not mediate this relationship, and colocalization provided partial evidence for a shared causal variant only in men. This multi-omics drug-target MR study suggests that DPP-4Is may reduce PD risk, supporting their potential for repurposing, particularly in male patients.</p>
3 Authors
- Joo-Yeon Lee
- Don Gueu Park
- Joohon Sung
1 Application
| Application ID | Title |
|---|---|
| 87860 | Explorative analyses to investigate the genetic structure underlying complex traits |
Enabling scientific discoveries that improve human health