Objective: In response to these limitations, we are proposing the China Parkinson’s Disease 10,000 Genomes Project (CPD10KGP), which aims to delineate the genetic architecture of PD within the Chinese population.

Background: PD is a multifaceted neurodegenerative disorder marked by a notable genetic involvement. Presently, the available data on the spectrum and prevalence of pathogenic variants in PD across various populations are constrained and subject to bias.

Method: We conducted a comprehensive genetic analysis of PD within a large, multicenter Chinese cohort comprising 6,911 unrelated PD patients (51.87% male; mean age-at-onset 54.72 ± 11.34 years old; 12.25% with positive family history). Utilizing multiplex ligation-dependent probe amplification (MLPA), whole-exome sequencing (WES) or whole-genome sequencing (WGS), we screened for variants in 35 established PD-associated genes, as well as 523 Movement disorders (MD)-associated genes.

Results: We detected pathogenic or likely pathogenic variants in 263 (3.81%) patients across known PD-associated genes, with the most prevalent being PRKN (n = 133), PLA2G6 (n = 20), LRRK2 (n = 19), PINK1 (n = 16), SNCA (n = 12), and DAGLB (n = 9). Moreover, the median age-at-onset (MAO) for patients with a molecular diagnosis (median, 36.0 years) was approximately two decades earlier than those without a molecular diagnosis (median, 56.0 years). Furthermore, 284 (4.11%) patients harbored severe, mild, or risk variants in the GBA1 gene (median, 49.5 years) with an MAO about 6.5 years earlier. Additionally, 304 (4.40%) patients carried P/LP variants in MD-associated genes, including those related to Spinocerebellar ataxias (SCA) (n = 67), Frontotemporal dementia/ Amyotrophic lateral sclerosis (FTD/ALS) (n = 67), Spastic paraplegias (SPG) (n = 42). Of these, 70 variants had been previously reported, affecting 31 distinct genes.

Conclusion: Through the expansion of the CPD10KGP datasets to encompass nearly 7,000 PD cases, this investigation characterizes the mutation spectrum of established PD-associated genes. It also elucidates the pivotal role of MD gene variants within the PD cohort, suggesting a shared pathogenic mechanism. Our research highlights the significant contribution of genetic factors in PD pathogenesis and elucidates the genetic intersections with other movement disorders.

Fig 1. Research workflow of the present study.

Fig 2. Mutational frequencies of each gene

Fig 3. Mutational frequencies

Fig 4. AAO spectrum

Fig 5. Circular visualization

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MDS Abstracts - https://www.mdsabstracts.org/abstract/unveiling-parkinsons-disease-variants-in-the-chinese-population-the-cpd10kgp-study/