The Global Landscape of Genetic Variation in Parkinson’s disease: Multi-Ancestry Insights into Established Disease Genes and their Translational Relevance

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Abstract Background: The genetic architecture of Parkinson’s disease (PD) varies considerably across ancestries, yet most genetic studies have focused on individuals of European descent, limiting insights into the genetic landscape of PD at a global scale. Methods: We conducted a large-scale, multi-ancestry investigation of causal and risk variants in PD-related genes. Using genetic datasets from the Global Parkinson’s Genetics Program (GP2), we analyzed sequencing and genotyping data from 105,588 individuals, including 63,837 affected and 41,751 unaffected, from eleven different ancestries. Approximately 29% of individuals included were from underrepresented populations. Findings: Our findings revealed shared and ancestry-specific patterns in the prevalence and variant spectrum. Overall, ∼2% of PD individuals carried a causative variant, with substantial variations across ancestries ranging from ∼0·5% in African to ∼7% in Middle Eastern and >10% Ashkenazi Jewish ancestries. Including disease-associated GBA1 and LRRK2 risk variants raised the yield to 13·6%, largely driven by GBA1 , except in East Asians, where LRRK2 risk variants dominated. GBA1 variants were most frequent globally, albeit with substantial differences in frequencies and variant spectra. While GBA1 variants were identified across all ancestries, frequencies ranged from ∼5% in Middle Eastern and South Asian to ∼52% in African ancestry. Similarly, LRRK2 variants showed ancestry-specific enrichment, with p.G2019S most frequently seen in Middle Eastern and Ashkenazi Jewish populations, and risk variants predominating in East Asians. Notably, clinical trials targeting specific genetic variants are currently primarily based in Europe and North America. Another globally PD-relevant gene was PRKN , with variant carriers identified across almost all ancestries. Interpretation: This large-scale, multi-ancestry assessment offers crucial insights into the population-specific genetic architecture of PD. It underscores the critical need for increased ancestral diversity in PD research to improve diagnostic accuracy, enhance our understanding of disease mechanisms across populations, and ensure equitable development and application of emerging precision therapies. Funding: Aligning Science Across Parkinson’s (ASAP) Global Parkinson’s Genetics Program (GP2)

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