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 (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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by The Michael J. Fox Foundation for Parkinson's Research (MJFF-019271 and MJFF-021227). This project was further supported by the Institute of Neurogenetics at the University of Lübeck. Grant support was received from the DFG RU ProtectMove (FOR2488). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Data used in the preparation of this manuscript were obtained from the Accelerating Medicine Partnership Parkinson's Disease (AMP PD) Knowledge Platform, the Fox Insight database by the Michael J. Fox Foundation, and the Parkinson's Progression Markers Initiative (PPMI) database by the Michael J. Fox Foundation. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors and with permission of the Accelerating Medicine Partnership Parkinson's Disease Knowledge Platform and the Michael J. Fox Foundation.