The Causal Relationship Between Palmitoylation Genes and Parkinson's Disease: A Mendelian Randomization Study.

This work examined the causal link between palmitoylation-related genes and Parkinson's disease (PD) by Mendelian randomization (MR). We conducted two-sample Mendelian randomization utilizing genome-wide association study (GWAS) summary statistics. Expression quantitative trait loci (eQTL) data for palmitoylation genes were sourced from eQTLGen, whilst PD data were derived from the GWAS Catalogue (15,056 cases, 12,637 controls) and FinnGen (4,681 cases, 407,500 controls). Instrumental variables (p < 5 × 10⁻⁶, r2 < 0.1) were examined using inverse-variance weighted (IVW) regression, along with weighted median, MR-Egger, and Summary-data-based MR (SMR) methods. Sensitivity analyses evaluated pleiotropy and resilience. The IVW analysis revealed significant correlations with Parkinson's disease for ZDHHC14 (OR = 1.09, P = 0.037), ZDHHC17 (OR = 1.18, P = 0.002), ZDHHC2 (OR = 1.16, P = 0.039), ZDHHC20 (OR = 0.82, P = 0.019), and ZDHHC8 (OR = 1.24, P = 0.022). SMR validation corroborated solely ZDHHC8 (OR = 1.35, P = 0.040). Replication in FinnGen corroborated ZDHHC1, ZDHHC13, ZDHHC17, and ZDHHC8. No heterogeneity or pleiotropy was observed (P > 0.05). ZDHHC8 has a strong causative relationship with PD, suggesting that palmitoylation dysregulation plays a role in disease etiology. These findings underscore synaptic dysfunction as a viable therapeutic target.