Validation of a Mitochondrial Polygenic Score for Parkinson’s Disease

Mitochondrial dysfunction is a key player in Parkinson’s disease (PD) pathogenesis. Mitochondrial polygenic scores (MGS) may be associated with PD but require validation across diverse populations. To validate the association between the MGS, PD status and age-at-onset (AAO) in idiopathic and LRRK2-PD across various ancestries. We analyzed data from 17,129 PD patients and 13,872 healthy individuals across 10 ancestries within the Global Parkinson’s Disease Genetic Program. We used regression models to assess the association between MGS, PD status and AAO. The MGS was associated with iPD in Europeans (β=0.19, SE=0.02, p<2.0×10−16) and Ashkenazi Jews (β=0.26, p=3.7×10-4) but not in other populations. Additionally, the MGS was strongly associated with LRRK2-PD status (β=0.82, p=2.0×10−16). No associations with AAO were observed. The 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.