Validation of a Mitochondrial Polygenic Score for Parkinson's Disease

BackgroundMitochondrial dysfunction is a key player in Parkinsons disease (PD) pathogenesis. Mitochondrial polygenic scores (MGS) may be associated with PD but require validation across diverse populations. ObjectiveTo validate the association between the MGS, PD status and age-at-onset (AAO) in idiopathic and LRRK2-PD across various ancestries. MethodsWe analyzed data from 17,129 PD patients and 13,872 healthy individuals across 10 ancestries within the Global Parkinsons Disease Genetic Program. We used regression models to assess the association between MGS, PD status and AAO. ResultsThe MGS was associated with iPD in Europeans ({beta}=0.19, SE=0.02, p<2.0x10-16) and Ashkenazi Jews ({beta}=0.26, p=3.7x10-4) but not in other populations. Additionally, the MGS was strongly associated with LRRK2-PD status ({beta}=0.82, p=2.0x10-16). No associations with AAO were observed. ConclusionsThe MGS is robustly associated with iPD status in Europeans and Ashkenazi Jews and with LRRK2-PD status. Population-specific MGS are needed to improve accuracy in other ancestries.