A well-powered meta-analysis of nine studies (1613 PD cases, 2126 controls) found no significant association between the PINK1 rs3738136 (Ala340Thr) polymorphism and Parkinson's disease risk across multiple genetic models, with results robust to sensitivity analyses though heterogeneity remained.

Provides useful negative evidence that this specific PINK1 variant is unlikely to be a PD risk biomarker or direct therapeutic target, helping researchers avoid pursuing a low-yield locus and focus on other PINK1 sites, mitochondrial mechanisms, or multi-locus/gene–environment interactions.

BACKGROUND: Parkinson's Disease (PD) is a progressive neurodegenerative disorder impacting motor and non-motor functions. The PTEN-induced putative kinase 1 (PINK1) gene, particularly the rs3738136 (Ala340Thr) polymorphism, is a potential genetic risk factor. PURPOSE: This meta-analysis investigated the association between rs3738136 (Ala340Thr) polymorphism and PD risk. STUDY TYPE: Meta-analysisPopulation:Nine studies (1613 PD cases, 2126 controls) were included following PRISMA guidelines.Assessment Techniques:Rigorous quality assessment using the Newcastle-Ottawa Scale (NOS) and Hardy-Weinberg Equilibrium (HWE) checks. Gene ontology and protein-protein interaction (PPI) network analyses were also performed. STATISTICAL TESTS: Meta-analyses employed fixed and random-effects models across various genetic models (allelic, dominant, recessive, overdominant). Sensitivity analyses addressed publication bias and HWE deviations. Power analysis was conducted to assess the study's ability to detect effects. RESULTS: No statistically significant association was found between the rs3738136 polymorphism and PD risk (p>0.05 for all models). Sensitivity analyses confirmed the robustness of these findings. The power analysis indicated statistical power (>0.8). However, meta-regression revealed high unexplained heterogeneity across studies. DATA CONCLUSION: This meta-analysis provides a high-powered and functionally integrated investigation into the rs3738136 polymorphism of the PINK1 gene. Although the findings do not support a direct association with PD susceptibility, our results contribute to clarifying prior conflicting evidence and suggest that this variant is likely functionally neutral. Future studies should explore multi-locus interactions and gene-environment models to better capture the genetic complexity of PD.