Objective: To identify the genetic determinants of Parkinson’s disease (PD) age at onset (AAO) within and across genetically determined European ancestries (European, Ashkenazi Jewish, Finnish, and Icelandic) using data from the Global Parkinson’s Genetic Program (GP2, http://gp2.org/), previously published PD GWAS (IPDGC), the Fox Insight Genetics Study (FIGS), and national biobanks UK Biobank (UKB), and deCODE.

Background: Recent research has continued to add to our knowledge of the complex genetic contribution to PD, however the genetic risk factors linked to AAO remain limited. The largest AAO meta-analysis of European ancestry identified two genome-wide significant associations, SNCA and TMEM175, both known PD risk loci1. The strongest predictor of PD AAO is currently a polygenic risk score (PRS) derived from cumulative genetic risk for PD, suggesting a substantial genetic overlap between PD susceptibility and AAO, but additional large studies and replication are needed to identify these overlapping signals.

Method: We performed a series of GWAS using genotyped imputed data from GP2 release 9 (DOI: 10.5281/zenodo.14510099), IPDGC, and Fox Insight within and across three ancestry groups: European (EUR), Ashkenazi Jewish (AJ), and Finnish (FIN). We meta-analyzed these results with summary statistics from an Icelandic population (ICE) provided by deCODE. Genetically-defined ancestry groups for GP2, IPDGC, and Fox Insight were defined by the GP2 ancestry and QC pipeline (https://pypi.org/project/the-real-genotools/1.2.1/). Meta-analyses were performed in stages, splitting by ancestry and biobank data sources. The last stage combined all European ancestry groups in a final pan-European meta-analysis for AAO.

Results: In our preliminary analysis, we identified several hits and estimated heritability for AAO with common variants. An updated PRS from the most recent PD meta-analysis was found to be a significant predictor of AAO. Genetic variability in AAO between males and females was also investigated.

Conclusion: We have conducted the largest GWAS to date on PD AAO. Our findings demonstrate the importance of examining risk for AAO at a more granular population level. Expanding GWAS with larger sample sizes, improved genotyping, and enhanced imputation will help identify new risk factors and refine our knowledge of the disease.

References: 1. Blauwendraat, C. et al. Parkinson’s disease age at onset genome-wide association study: Defining heritability, genetic loci, and α-synuclein mechanisms. Mov. Disord. 34, 866–875 (2019).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/assessing-genome-wide-genetic-risk-for-parkinsons-disease-age-at-onset-in-european-sub-populations-from-the-global-parkinsons-genetics-program/