Interaction of Mitochondrial Polygenic Score and Lifestyle Factors in LRRK2 p.Gly2019Ser Parkinsonism

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Abstract
Background: A mitochondrial polygenic score (MGS) is composed of genes related to mitochondrial function and found to be associated with Parkinson's disease (PD) risk.Objective: To investigate the impact of the MGS and lifestyle/environment on age at onset (AAO) in LRRK2 p.Gly2019Ser parkinsonism (LRRK2‐PD) and idiopathic PD (iPD).Methods: We included N = 486 patients with LRRK2‐PD and N = 9259 with iPD from the Accelerating Medicines Partnership® Parkinson's Disease Knowledge Platform (AMP‐PD), Fox Insight, and a Tunisian Arab‐Berber founder population. Genotyping data were used to perform the MGS analysis. Additionally, lifestyle/environmental data were obtained from the PD Risk Factor Questionnaire (PD‐RFQ). Linear regression models were used to assess the relationship between MGS, lifestyle/environment, and AAO.Results: Our derived MGS was significantly higher in PD cases compared with controls (P = 1.1 × 10−8). We observed that higher MGS was significantly associated with earlier AAO in LRRK2‐PD (P = 0.047, β = −1.40) and there was the same trend with a smaller effect size in iPD (P = 0.231, β = 0.22). There was a correlation between MGS and AAO in LRRK2‐PD patients of European descent (P = 0.049, r = −0.12) that was visibly less pronounced in Tunisians (P = 0.449, r = −0.05). We found that the MGS interacted with caffeinated soda consumption (P = 0.003, β = −5.65) in LRRK2‐PD and with tobacco use (P = 0.010, β = 1.32) in iPD. Thus, patients with a high MGS had an earlier AAO only if they consumed caffeinated soda or were non‐smokers.Conclusions: The MGS was more strongly associated with earlier AAO in LRRK2‐PD compared with iPD. Caffeinated soda consumption or tobacco use interacted with MGS to predict AAO. Our study suggests gene–environment interactions as modifiers of AAO in LRRK2‐PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Funding Information
  • Deutsche Forschungsgemeinschaft (FOR2488)
  • Michael J. Fox Foundation for Parkinson's Research (MJFF‐021227 & MJFF‐019271)

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