Risk factors associated with age at onset of Parkinson's disease in the UK Biobank

Substantial evidence shown that the age at onset (AAO) of Parkinson's disease (PD) is a major determinant of clinical heterogeneity. However, the mechanisms underlying heterogeneity in the AAO remain unclear. To investigate the risk factors with the AAO of PD, a total of 3156 patients with PD from the UK Biobank were included in this study. We evaluated the effects of polygenic risk scores (PRS), nongenetic risk factors, and their interaction on the AAO using Mann-Whitney U tests and regression analyses. We further identified the genes interacting with nongenetic risk factors for the AAO using genome-wide environment interaction studies. We newly found physical activity (P < 0.0001) was positively associated with AAO and excessive daytime sleepiness (P < 0.0001) was negatively associated with AAO, and reproduced the positive associations of smoking and non-steroidal anti-inflammatory drug intake and the negative association of family history with AAO. In the dose-dependent analyses, smoking duration (P = 1.95 × 10^-6), coffee consumption (P = 0.0150), and tea consumption (P = 0.0008) were positively associated with AAO. Individuals with higher PRS had younger AAO (P = 3.91 × 10^-5). In addition, we observed a significant interaction between the PRS and smoking for AAO (P = 0.0316). Specifically, several genes, including ANGPT1 (P = 7.17 × 10^-7) and PLEKHA6 (P = 4.87 × 10^-6), may influence the positive relationship between smoking and AAO. Our data suggests that genetic and nongenetic risk factors are associated with the AAO of PD and that there is an interaction between the two.