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

Abstract

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=4.0x10-4, 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.

The combined effect of lifestyle factors and polygenic scores on age at onset in Parkinson’s disease

“…Since this PGS is based on common variants associated with PD risk, it is pathwayindependent and different mechanisms can lead to the earlier AAO when having a high PGS or the delayed AAO when using protective lifestyle factors. In contrast, pathway-dependent PGSs such as the mitochondrial polygenic score 67,68 have been shown to interact with lifestyle factors such as pesticides or caffeinated beverages.…”

“…www.nature.com/scientificreports/ Thus far, it is not clear how the underlying mechanisms work and if they differ in the different subtypes of PD. However, we have already seen that the effects of environmental and lifestyle factors as well as specific genetic risk factors on AAO vary in different subtypes of PD, especially between monogenic forms of PD and idiopathic PD 67 . To follow up on this, future larger-scale studies including patients with monogenic forms of PD or who carry strong risk factors (e.g., LRRK2-PD, GBA1-PD, or PRKN/PINK1-PD), are important to target the effect of anti-inflammatory lifestyle factors on PD AAO.…”

The combined effect of lifestyle factors and polygenic scores on age at onset in Parkinson’s disease

“…Since this PGS is based on common variants associated with PD risk, it is pathway-independent and different mechanisms can lead to the earlier AAO when having a high PGS or the delayed AAO when using protective lifestyle factors. In contrast, pathway-dependent PGSs such as the mitochondrial polygenic score 46,47 have been shown to interact with lifestyle factors such as pesticides or caffeinated beverages.…”

“…Thus far, it is not clear how the underlying mechanisms work and if they differ in the different subtypes of PD. However, we have already seen that the effects of environmental and lifestyle factors as well as specific genetic risk factors on AAO vary in different subtypes of PD, especially between monogenic forms of PD and idiopathic PD 46 . To follow up on this, future larger-scale studies including patients with monogenic forms of PD or who carry strong risk factors (e.g., LRRK2-PD, GBA1-PD, or PINK1/Parkin-PD), are important to target the effect of anti-inflammatory lifestyle factors on PD AAO.…”