Repurposing dipeptidyl peptidase-4 inhibitor for Parkinson's disease prevention: A drug-target Mendelian...

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 (IV_eQTL) and protein QTL (IV_pQTL) 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 IV_eQTL and 1.21 (1.02-1.45) for IV_pQTL. This beneficial effect was more pronounced in men-IV_eQTL: 2.25 (1.55-3.28); IV_pQTL 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.