Objective: To investigate the relationship between a mitochondrial risk score (MRS), lifestyle and age at onset (AAO) in LRRK2 G2019S Parkinson’s disease (PD).

Background: PD is the fastest growing neurological disorder worldwide, and the p.Gly2019Ser mutation in the Leucine-rich repeat kinase 2 (LRRK2) gene is the most common cause for monogenic PD. The penetrance among LRRK2 p.Gly2019Ser mutation carriers is highly age-dependent, and the mechanisms behind disease onset are poorly understood. Genetic, environmental, and lifestyle factors can affect the manifestation of PD. Specifically, mitochondrial DNA damage has been shown to influence the penetrance of LRRK2 p.Gly2019Ser PD.

Method: In our study, we included 486 patients with PD carrying an LRRK2 p.Gly2019Ser mutation from three cohorts: Fox Insight (N=154), AMP-PD (N=127) and a cohort recruited from the Tunisian Arab Berber population (N=205). Genotypes were obtained from genome arrays and whole-genome sequencing data. Mitochondrial polygenic risk score analysis was performed based on a previously published list of genes associated with mitochondrial function that influences PD risk, nominated by a Mendelian randomization study. In addition, lifestyle factors were assessed with the PD risk factor questionnaire (PD-RFQ). Relationships were estimated by linear regression models where the self-declared AAO was used as an outcome.

Results: For patients with LRRK2 p.Gly2019Ser PD, the MRS was associated with AAO (p=4.11×10^-4, β=-66.02, SE=18.56). The higher the MRS, the earlier the AAO. In contrast, the lifestyle factors smoking (p=0.03, β=4.40, SE=1.95) and black tea consumption (p=0.04, β=3.99, SE=1.97) were associated with later AAO. No interaction was found between the MRS and the investigated lifestyle factors. However, when including both lifestyle factors and MRS in the model, the association between MRS and AAO dissipated.

Conclusion: Our data suggest that risk variants within genes associated with mitochondrial function, smoking, and black tea consumption affect the AAO in LRRK2 p.Gly2019Ser mutation carriers. No interaction between lifestyle factors and MRS was apparent. The results highlight the importance of investigating the underlying molecular mechanism and the potential interplay between genetics, environment, and lifestyle.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-mitochondrial-risk-score-and-lifestyle-factors-are-associated-with-age-at-onset-in-lrrk2-p-gly2019ser-parkinsons-disease/