Validation of a Mitochondrial Polygenic Score for Parkinson’s Disease

Background 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. Competing Interest Statement The authors have declared no competing interest. Funding Statement This project was supported by the Global Parkinson's Genetics Program (GP2; https://gp2.org). GP2 is funded by the Aligning Science Across Parkinson's (ASAP) initiative and implemented by The Michael J. Fox Foundation for Parkinson's Research (MJFF). For a complete list of GP2 members see doi.org/10.5281/zenodo.7904831 Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Data used in the preparation of this manuscript were obtained from the Global Parkinson's Genetics Program (GP2) database accessed via the Terra platform (https://app.terra.bio/#workspaces). For up-to-date information on GP2 data acquisition, access, and policies, visit https://gp2.org/. This project was supported by the Global Parkinson's Genetics Program (GP2; https://gp2.org). GP2 is funded by the Aligning Science Across Parkinson's (ASAP) initiative and implemented by The Michael J. Fox Foundation for Parkinson's Research (MJFF). For a complete list of GP2 members see doi.org/10.5281/zenodo.7904831 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability Statement Data sharing is not applicable to this article as no new data were created or analyzed in this study. Data used in the preparation of this manuscript were obtained from the Global Parkinson’s Genetics Program (GP2) database accessed via the Terra platform (https://app.terra.bio/#workspaces). For up-to-date information on GP2 data acquisition, access, and policies, visit https://gp2.org/. All code generated for this article, and the identifiers for all software programs and packages used, are available on GitHub (https://github.com/GP2code/GP2-mitochondrial-PRS) and were given a persistent identifier via Zenodo (https://doi.org/10.5281/zenodo.15013765).