Background: Parkinson’s disease (PD) is a neurodegenerative disorder, and literature suggests that genetics and lifestyle/environmental factors may play a key role in the triggering of the disease. This study aimed to evaluate the predictive performance of a 12-Single Nucleotide Polymorphisms (SNPs) polygenic risk score (PRS) in combination with already established PD-environmental/lifestyle factors. Methods: Genotypic and lifestyle/environmental data on 235 PD-patients and 464 controls were obtained from a previous study carried out in the Cypriot population. A PRS was calculated for each individual. Univariate logistic-regression analysis was used to assess the association of PRS and each risk factor with PD-status. Stepwise-regression analysis was used to select the best predictive model for PD combining genetic and lifestyle/environmental factors. Results: The 12-SNPs PRS was significantly increased in PD-cases compared to controls. Furthermore, univariate analyses showed that age, head injury, family history, depression, and Body Mass Index (BMI) were significantly associated with PD-status. Stepwise-regression suggested that a model which includes PRS and seven other independent lifestyle/environmental factors is the most predictive of PD in our population. Conclusions: These results suggest an association between both genetic and environmental factors and PD, and highlight the potential for the use of PRS in combination with the classical risk factors for risk prediction of PD.

Parkinson’s Disease (PD) is a multifactorial neurodegenerative disease characterized by motor and non-motor symptoms. The etiology of PD remains unclear. However, several studies have demonstrated the interplay of genetic, epigenetic, and environmental factors in PD. Early-onset PD (EOPD) is a subgroup of PD diagnosed between the ages of 21 and 50. Population genetic studies have demonstrated great genetic variability amongst EOPD patients. Hence, this study aimed to obtain a genetic landscape of EOPD in the Cypriot population. Greek-Cypriot EOPD patients (n = 48) were screened for variants in the six most common EOPD-associated genes (PINK1, PRKN, FBXO7, SNCA, PLA2G6, and DJ-1). This included DNA sequencing and Multiplex ligation-dependent probe amplification (MLPA). One previously described frameshift variant in PINK1 (NM_032409.3:c.889del) was detected in five patients (10.4%)—the largest number to be detected to date. Copy number variations in the PRKN gene were identified in one homozygous and 3 compound heterozygous patients (8.3%). To date, the pathogenic variants identified in this study have explained the PD phenotype for 18.8% of the EOPD cases. The results of this study may contribute to the genetic screening of EOPD in Cyprus.

There is accumulating evidence that distinct mitochondrial DNA (mtDNA) methylation and hydroxymethylation patterns exist in Parkinson’s disease (PD). However, most studies have been limited to the investigation of specific target regions, rather than the entire mtDNA, and have been further hindered by other methodological discrepancies and the lack of non-CpG context investigation. Here, we provide a comprehensive profile of methylation and hydroxymethylation levels across the mitochondrial genome, at global and single-base resolution, in CpG and non-CpG (CHG, CHH) contexts in blood samples from early-onset PD (EOPD) patients (n = 39) and age- and sex-matched controls (n = 63). Bisulfite (BS) and oxidative-bisulfite (oxBS) conversions in parallel workflows followed by next-generation sequencing (NGS) using Illumina’s Novaseq 6000 sequencing system identified mitochondrial 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in all contexts. Global mtDNA methylation was significantly higher in EOPD patients vs. matched controls in the CpG context (p = 5.63 × 10⁻³) in the BS status, and in all contexts [CpG (p = 2.67 × 10⁻⁴), CHG (p = 0.015), CHH (p = 0.012)] in the oxBS status, i.e., “true methylation”. At single-base resolution, the most statistically significant sites across the mitogenome, in the D-loop region, and CpG context, were primarily hypomethylated in EOPD patients compared to matched controls. Upon further validation, both global and base resolution mtDNA (hydroxy)methylation results could act as blood-based biomarkers for EOPD.