Investigating the genetic association between synaptic genes and Parkinson's disease risk

Recent research indicates a strong link between synaptic dysfunction and Parkinson's disease (PD). This study utilizes summary data-based Mendelian randomization (SMR) to explore genetic associations and causal relationships between synaptic genes and the risk of developing PD. This study utilized the GeneCards database to gather synaptic genes. Subsequently, we integrated QTL data related to these genes, encompassing DNA methylation (mQTLs), gene expression (eQTLs), and protein expression (pQTLs). GWAS data on PD were acquired from the GWAS Catalog, with validation datasets from the FinnGen dataset. The SMR method was used to assess potential causal relationships, and colocalization analysis was performed to verify that the signals were due to shared genetic variants, thereby enhancing the robustness of the findings. Furthermore, 5 tissue eQTL datasets were used for tissue-specific validation. Through SMR and colocalization analyses, we identified 67 methylation sites corresponding to 33 genes in mQTLs, 10 genes in eQTLs, and 4 proteins in pQTLs associated with PD. Integration of multi-omics evidence highlighted Adhesion Molecule With Ig Like Domain 1 (AMIGO1) as a potentially key gene in the association between synapses and PD, with positive SMR results in both mQTL-eQTL analysis and eQTL-pQTL analysis. The tissue-specific validation results further underscore the critical role of AMIGO1 in the disease. Our study emphasizes the importance of synaptic genes, particularly AMIGO1, in the pathogenesis of PD. Future research should build on these findings by elucidating the specific mechanisms of these genes through functional experiments, with the ultimate goal of developing effective prevention and treatment strategies.