Parkinson's disease (PD) is a debilitating neurodegenerative disorder affecting a growing population due to increasing life expectancy. Its etiology is complex, involving genetic and environmental factors, yet the precise molecular mechanisms remain poorly understood. Genetic modifications and epigenetic mechanisms, such as DNA methylation at CpG dinucleotides, are being investigated for their roles in PD pathogenesis. DNA methylation is crucial for gene expression regulation and can be influenced by both genetic and environmental factors. Previous studies have shown associations between DNA methylation and PD risk, but larger-scale studies are needed to identify robust associations independent of blood cell composition. This study aimed to identify DNA methylation markers associated with PD risk by using a larger sample size and accounting for cell type composition differences.

Prior research has explored the link between DNA methylation and Parkinson's Disease (PD). Chung et al. reported 82 epigenome-wide significant CpG probes associated with PD, but these results did not remain significant after adjusting for blood cell composition differences. This highlights the need for larger-scale studies to identify robust methylation probes associated with PD risk independent of cell type. Previous studies have also indicated the importance of investigating the role of specific genes and pathways in PD pathogenesis. Several genes and pathways including those involved in immune function, oxidative stress, and inflammation have been implicated in PD, highlighting the complexity and multifactorial nature of the disease. This study contributes by investigating DNA methylation patterns to further clarify the involvement of specific genes and pathways in PD.

This study utilized data from two independent cohorts: the System Genomics of Parkinson’s Disease (SGPD) consortium and the Parkinson’s disease, Environment and Gene (PEG) cohort. The SGPD cohort included 1638 unrelated European individuals (851 PD cases and 787 controls). The PEG cohort consisted of 493 European individuals (281 PD cases and 212 controls). Blood cell proportions were imputed using the Houseman et al. algorithm. The researchers performed a methylome-wide association study (MWAS) using linear model-based association testing for each CpG probe, employing two methods: MOA and MOMENT. MOA is a mixed model approach, and MOMENT is a more robust method less susceptible to confounding factors. These analyses were performed separately for each cohort and then meta-analyzed. Finally, summary data-based Mendelian Randomization (SMR) was used to investigate the causal relationship between DNA methylation and gene expression. A DNA methylation-based classifier for PD was also developed using the SGPD cohort as a discovery sample and the PEG cohort for validation.

The study identified two epigenome-wide significant associations with PD. One association involved cg00140222 on chromosome 8, and the other involved cg068690548 on chromosome 4, which was near the SLC7A11 gene. Analysis of predicted cell type proportions revealed differences between PD cases and controls. PD cases had a higher proportion of granulocytes and lower proportions of B cells, helper T cells, and natural killer cells. The study found that hypermethylation at cg068690548 was associated with downregulation of SLC7A11. SMR analysis indicated that this association was likely due to environmental factors, not genetic factors affecting methylation or gene expression. The SLC7A11 gene encodes system xc-, an antiporter regulating glutathione levels, a known target of the neurotoxin BMAA. A DNA methylation-based classifier showed moderate accuracy in predicting PD status (AUC ~0.70).

The identification of cg068690548 near the SLC7A11 gene as associated with PD risk through hypermethylation and downregulation of SLC7A11 expression is a key finding. This highlights the potential involvement of oxidative stress and glutamate signaling disruption in PD pathogenesis, aligning with existing literature. The lack of genetic association supports an environmental factor as the cause of this methylation change, and the link to BMAA, a cyanobacterial neurotoxin, raises intriguing possibilities. Further research could explore the role of dietary BMAA exposure in PD risk. The development of a DNA methylation classifier, while showing moderate predictive accuracy, suggests the potential of epigenetic markers for PD diagnostics, though further refinement is needed.

This study identified two novel DNA methylation probes associated with PD risk, one of which is strongly linked to the SLC7A11 gene. The results suggest environmental factors, potentially including BMAA exposure, may play a significant role in PD development. Larger studies and analyses of brain tissue are needed to confirm these findings and investigate the causal relationships more definitively. Epigenetic markers may have utility in PD diagnosis but require further validation.

The study's limitations include the use of whole blood samples, which may not fully reflect methylation patterns in the brain. Also, the DNA methylation classifier showed only moderate predictive accuracy, and the causal relationship between BMAA exposure and PD risk remains to be fully established. The study also used a conservative approach to adjust for blood cell type proportions, which might have missed some true associations.