The combined effect of lifestyle factors and polygenic scores on age at onset in Parkinson’s disease

Abstract

Objective To investigate the association between a Parkinson's disease (PD)-specific polygenic score (PGS) and protective lifestyle factors on age at onset (AAO) in PD. Methods We included data from 4375 patients with idiopathic PD, 167 patients with GBA1-PD, and 3091 healthy controls of European ancestry from AMP-PD, PPMI, and Fox Insight cohorts. The PGS was calculated based on a previously proposed composition of 1805 variants. The association between PGS and lifestyle factors (i.e., coffee, tobacco, and aspirin) on AAO was assessed with linear and Cox proportional hazards models. Results The PGS showed a negative association with AAO (β=-1.07, p=6x10-7). The use of one, two, or three of the protective lifestyle factors showed a reduction in the hazard ratio by 21% (p=0.0001), 45% (p<2x10-16), and 55% (p<2x10-16), respectively, compared to no use. An additive effect of aspirin (β=7.61, p=8x10-7) and PGS (β=-1.63, p=0.0112) was found for AAO without an interaction (p=0.9789) in the linear regressions, and similar effects were seen for tobacco. Aspirin is shown to be a better predictor of AAO (R2=0.1740) compared to coffee and tobacco use (R2=0.0243, R2=0.0295) or the PGS (R2=0.0141). In contrast, no association between aspirin and AAO was found in GBA1-PD (p>0.05). Interpretation In our cohort, coffee, tobacco, aspirin, and PGS are independent predictors of PD AAO. Additionally, lifestyle factors seem to have a greater influence on AAO than common genetic risk variants with aspirin presenting the largest effect. External validation of our findings is needed.