Interaction of mitochondrial polygenic score and environmental factors in LRRK2 p.Gly2019Ser parkinsonism

The objective of our study was to investigate the impact of the mitochondrial polygenic score (MGS) and lifestyle/environmental data on age at onset in LRRK2 p.Gly2019Ser parkinsonism ( LRRK2 -PD) and idiopathic Parkinson’s disease (iPD). In this study, we included N=486 patients with LRRK2 -PD and N=9259 patients with iPD from AMP-PD, Fox Insight, and a Tunisian Arab-Berber founder population. Genotyping data was utilized to perform the MGS analysis, using 14 Single Nucleotide Polymorphisms (SNPs) from genes causally associated with mitochondrial function and PD risk. Additionally, lifestyle and environmental data were obtained from the PD risk factor questionnaire (PD-RFQ). Correlation analyses and linear regression models were used to assess the relationship between MGS, lifestyle/environment, and AAO. We observed that higher MGS was associated with earlier AAO in patients with LRRK2 -PD (p=4.0×10−4, β=-0.18) but not in patients with iPD. A correlation between MGS and AAO was visibly stronger in European ancestry LRRK2 -PD patients (p=0.01, r=-0.16) than in Tunisian Arab-Berber patients (p=0.44, r=-0.05). We found that the MGS interacted with coffee (p=0.03, β=-0.38) and caffeinated soda consumption (p=0.03, β=-0.37) in LRRK2 -PD and with caffeine soda consumption (p=0.047, β=-0.22) and pesticide exposure (p=0.02, β=-0.37) in iPD. Thus, patients with a high MGS had an earlier AAO only if they consumed caffeine or were exposed to pesticides. The MGS related to mitochondrial function was associated with AAO in LRRK2 -PD but not iPD with an ethnic-specific effect. Caffeine consumption or pesticide exposure interacted with MGS to predict PD AAO. Our study suggests gene-environment interactions as modifiers of AAO in LRRK2 -PD. ### Competing Interest Statement CK serves as a medical advisor to Centogene and Retromer Therapeutics and received speaking honoraria from Desitin. The remaining authors declare no conflict of interest. ### Funding Statement This project was supported by the DFG RU ProtectMove (DFG FOR2488), the Michael J. Fox Foundation (MJFF-021227 & MJFF-019271), and the Else Kroener-Fresenius-Stiftung. ### 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: Ethical permission was given by the Ethical Committee of the Institut National de Neurologie and certified by the Ministry of Health, Tunisia. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data sharing is not applicable to this article as no new data were created or analysed in this study. Data used in the preparation of this manuscript were obtained from the Fox Insight database () on 18/10/2020. For up-to-date information on the study, visit . Data used in the preparation of this article were obtained from the Accelerating Medicine Partnership (AMP) Parkinson's Disease (AMP PD) Knowledge Platform. For up-to-date information on the study, visit .