Objective: This study aimed to identify novel genetic modifiers of age at onset (AAO) for Parkinson’s disease (PD) including common variants and rare variants using genome-wide association analysis and gene-level burden tests in Chinese population.

Background: PD is a complex neurodegenerative disorder characterized by motor and non-motor symptoms, with AAO varying widely among individuals. Research on genetic factors affecting AAO of PD is still very limited so far, especially rare genetic variants in populations other than European-ancestry.

Method: We conducted a comprehensive study utilizing data from 14,393 Chinese PD patients across four cohorts, using whole genome sequencing (WGS), whole exome sequencing (WES), and target region sequencing (TRS). Genome-wide association study (GWAS) and rare variant burden tests were performed to identify genetic modifiers associated with PD AAO. Moreover, polygenic risk scores (PRS) based on PD risk loci were calculated and correlated with AAO [figure1].

Results: Our analyses identified a novel significant locus associated with earlier onset of PD. Additionally, rare variants in one gene were found to influence PD AAO. The PRS based on PD risk loci showed an inverse association with AAO, suggesting shared genetic architecture between PD risk and AAO.

Conclusion: Our study enhances the understanding of genetic determinants influencing PD AAO in the Chinese population. The identification of novel genetic modifiers provides insights into the biological mechanisms underlying PD onset and may inform personalized treatment strategies. Further functional studies are warranted to validate the role of these genetic modifiers in PD pathogenesis.

Figure 1. Graphical workflow of the analysis.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-modifiers-of-age-at-onset-for-parkinsons-disease-in-chinese-population/