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

The genetic architecture of Parkinson’s disease (PD) varies considerably across ancestries, yet most genetic studies have focused on individuals of European descent, limiting our insights into the genetic architecture of PD at a global scale. 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, we analyzed sequencing and genotyping data from 69,881 individuals, including 41,139 affected and 28,742 unaffected, from eleven different ancestries, including ∼30% of individuals from non-European ancestries. Our findings revealed shared and ancestry-specific patterns in the prevalence and spectrum of PD-associated variants. Overall, ∼2% of affected individuals carried a causative variant, with substantial variations across ancestries ranging from 10% in Middle Eastern and Ashkenazi Jewish ancestries. Including disease-associated GBA1 and LRRK2 risk variants raised the yield to ∼12.5%, 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 3·4% in Middle Eastern to 51·7% in African ancestry. Similarly, LRRK2 variants showed ancestry-specific enrichment, with G2019S most frequently seen in Middle Eastern and Ashkenazi Jewish, and risk variants predominating in East Asians. However, clinical trials targeting proteins encoded by these genes are primarily based in Europe and North America.