Abstract :
[en] Parkinson's Disease (PD) is the fastest-growing neurodegenerative disorder (Bloem et al., 2021; Dorsey et al., 2018). It is characterized by motor symptoms such as postural instability, rest tremor, bradykinesia and rigidity (Kalia and Lang, 2015). Additionally, PD exhibits non-motor symptoms including cognitive impairment, neuropsychiatric features like hallucinations, depression, and anxiety, as well as sleep disturbances, hyposmia and autonomic dysfunction (Khoo et al., 2013).
While the exact causes of PD remain incompletely understood, research has identified genetic risk factors as important contributing factors in its development. Although PD appears typically as sporadic, approximately 30% of cases can be linked to genetic factors involving monogenic forms (Billingsley et al., 2018). Although motor symptoms can be effectively addressed by pharmacological therapies at least in early disease stages, there is currently no treatment that may interfere with the chronic progressive neurodegeneration. Therefore, there is a strong motivation among clinicians and researchers to perform early diagnoses and identify genetic variants that could lead to future causative and thereby neuroprotective therapies. However, PD is a complex disorder influenced by a combination of environmental and genetic factors. Only a limited subset of genes have been conclusively associated with typical PD, as their causative role in Mendelian forms of PD has been consistently replicated in multiple studies involving large populations of PD patients (Bandres-Ciga et al., 2020). These rare Mendelian forms follow distinct inheritance patterns and have a notable impact on disease development (e.g., SNCA, LRRK2, VPS35, PRKN, PINK1 and PARK7). There are also low-frequency variants with significant effects, such as the GBA1 and LRRK2 genes. These variants are not as rare as monogenic mutations, but their frequency remains relatively low in the general population. Then, there are the common variants that exert minor effects and highlight genetic variants that are prevalent in the population but individually contribute only a modest risk toward PD (Manolio et al., 2009).
Although not as extensively studied as single nucleotide variants, small copy number variants have received considerable interest due to their potential pathogenic implications (La Cognata et al., 2017; Pankratz et al., 2011; Toft and Ross, 2010).
As part of the Luxembourg Parkinson's study, which includes both healthy individuals and patients with PD and atypical parkinsonism, we aim to investigate the genetic background of PD-causal genes (LRRK2, SNCA, VPS35, PRKN, PARK7, PINK1 and ATP13A2) and other known PD-associated genes, looking for rare Single-Nucleotide Variants (SNVs), Copy Number Variation (CNVs), and estimating the effect of multiple common SNVs in predicting an individual's probability of developing PD, using Polygenic Risk Scores (PRS).
The Luxembourg Parkinson's study, a large monocentric longitudinal cohort, included 1791 participants, 911 of whom were diagnosed cases and 880 neurologically healthy controls. The mean age of the control group was 64.7 ± 12.1 years in 2023. The mean age at onset for PD patients was 62.4 ± 11.7 years.
We identified 12.1% of PD patients and 5% of healthy controls carried GBA1 variants. Additionally, four GBA1 variants were discovered in patients with progressive supranuclear palsy and dementia with Lewy bodies. We identified different categories of pathogenic GBA1 variants, including those with severe, mild and risk-associated effects. We then studied the relationships between genotypes and phenotypes, to better understand the impact of each type of variant and how they contribute to disease severity. We discovered a total of 60 rare SNVs within seven PD-causal genes. Notably, nine of these variants were found to be disease-causing in LRRK2, PINK1, and PRKN genes. Additionally, we identified eleven rare CNVs in the PRKN gene, encompassing seven duplications and four deletions.
We showed that the PRSs were significantly associated with PD and highlighted the important role of polygenic background plays in modulating PD risk in carriers of pathogenic GBA1 variants.
Moreover, in an explorative study, where we are looking for loss of function variants, we identified 134 rare variants and eight rare copy number variations in PD-related genes, that could potentially contribute to PD, but these results are not statistically reliable and further analysis is required. The failure to discover novel genetic variants with whole-genome sequencing data can be attributed to the limited power to detect rare variants with small effects, as well as the relatively small sample size of the study.
We carried out an in-depth genetic analysis of the participants in the Luxembourg Parkinson's study. Our findings should help future research to unravel the complex genetic landscape of PD. This knowledge will make it possible to classify participants according to their genetic profile, improving the effectiveness of future precision medicine approaches. These targeted therapies can then be tailored to attack specific molecular targets, paving the way for a new era of personalized treatment strategies.
