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 Parkinsons 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=4.0x10-4, {beta}=-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, {beta}=-0.38) and caffeinated soda consumption (p=0.03, {beta}=-0.37) in LRRK2-PD and with caffeine soda consumption (p=0.047, {beta}=-0.22) and pesticide exposure (p=0.02, {beta}=-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.