Genetic Modifiers of Age at Onset for Parkinson's Disease in Asians: A Genome-Wide Association Study.

ABSTRACT

BACKGROUND: Age at onset (AAO) is an essential feature of Parkinson's disease (PD) and can help predict disease progression and mortality. Identification of genetic variants influencing AAO of PD could lead to a better understanding of the disease's biological mechanism and provide clinical guidance. However, genetic determinants for AAO of PD remain mostly unknown, especially in the Asian population. OBJECTIVES: To identify genetic determinants for AAO of PD in the Asian population. METHODS: We performed a genome-wide association meta-analysis on AAO of PD in 5166 Chinese patients with PD (Ndiscovery  = 3628, Nreplication  = 1538). We then conducted a further cross-ethnic meta-analysis using our results and summary statistics for the AAO of PD from the European population. RESULTS: The total heritability of AAO of PD was around 0.10 ~ 0.14, similar to that (~0.11) estimated in populations of European ancestry. One novel significant intergenic locus rs9783733 (NDN; PWRN4) was identified (P = 3.14E-09, beta = 2.30, SE = 0.39). Remarkably, this variant could delay AAO of PD by ~2.43 years, with a more considerable effect on males (~3.18 years) than females (~1.45 years). The variant was suggestively significant in the cross-ethnic meta-analysis and suggested a positive selection in the East Asian population. Additionally, cross-ethnic meta-analysis identified a significant locus rs356203 in SNCA (P = 2.35E-11, beta = -0.71, SE = 0.01). CONCLUSIONS: These findings improve the current understanding of the genetic etiology of AAO of PD in different ethnic groups, and provide a new target for further research on PD pathogenesis and potential therapeutic options. © 2021 International Parkinson and Movement Disorder Society.