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

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 (R 2 =0.1740) compared to coffee and tobacco use (R 2 =0.0243, R 2 =0.0295) or the PGS (R 2 =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.