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

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 our insights into the genetic architecture 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, 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.

FINDINGS

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 <0·5% in African, African-admixed, and Central Asian to >10% in Middle Eastern and Ashkenazi Jewish ancestries. Including disease-associated and risk variants raised the yield to ∼12.5%, largely driven by , except in East Asians, where risk variants dominated. variants were most frequent globally, albeit with substantial differences in frequencies and variant spectra. While variants were identified across all ancestries, frequencies ranged from 3·4% in Middle Eastern to 51·7% in African ancestry. Similarly, 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.

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 diversity in PD genetic research to improve diagnostic accuracy, enhance our understanding of disease mechanisms across populations, and ensure the equitable development and application of emerging precision therapies.

FUNDING

Aligning Science Across Parkinson's (ASAP) Global Parkinson's Genetics Program (GP2).

PUTTING RESEARCH INTO CONTEXT

Genetic discoveries have drastically advanced our understanding of Parkinson's disease (PD), including the identification of rare monogenic causes and common risk variants. However, according to our PubMed-based ( https://pubmed.ncbi.nlm.nih.gov/ ) literature review, the majority of genetic data has been generated in PD cohorts of European ancestry. The sample sets of two recent comprehensive, large-scale genetic screening studies, the PD GENEration North America and the Rostock International Parkinson's disease (ROPAD) study, comprised 85% and 96% of White participants, respectively. Moreover, a global survey of monogenic PD, published in 2023, reported that 91% of genetically confirmed individuals with PD were of European ancestry, underscoring the major gap in ancestral representation in PD genetics research. Although ancestry-specific variants and founder effects have been reported for select PD-associated genes such as , , and , comprehensive, globally- and ancestry-representative studies are missing, thereby constraining the applicability of genetic diagnostics and the development and inclusivity of equitable, ancestry-informed therapeutic strategies. This study, conducted within the framework of the Global Parkinson's Genetics Program (GP2), represents the largest multi-ancestry exploratory genetic investigation of PD to date, including nearly 70,000 individuals from around the world, with more than 20,000 participants of non-European ancestry (representing ∼30% of the study cohort). By exploring the genetic landscape of pathogenic variants in established PD-linked genes and PD risk-associated variants across 11 diverse genetically defined ancestry groups, it provides crucial insights into the global genetic landscape of PD. This work highlights both shared and ancestry-specific contributions and emphasizes the need to consider genetic diversity in research and clinical practice. Our findings highlight the importance of as a globally relevant genetic contributor to PD risk, with variant carriers identified across all investigated populations, reinforcing it as a relevant therapeutic target across ancestries. Similarly, variant carriers, currently already targeted in clinical trials, and individuals with alterations, increasingly being explored as a therapeutic target in preclinical studies, were identified across multiple ancestral groups. However, overall, investigating variants in known PD-linked genes resulted in substantially different yields across ancestries, underscoring the limited applicability of current PD gene and variant panels across ancestries and suggesting yet unexplored population-specific variations, especially in currently underrepresented populations, where newly identified variants in established PD-genes often remain of uncertain significance due to limited sample size and reference data. As precision medicine approaches are increasingly integrated into PD research and clinical trials, it is critical to ensure that emerging therapies are applicable and accessible to individuals of all ancestral backgrounds. Current trials targeting gene variant carriers predominantly enroll participants of European or Ashkenazi Jewish ancestry, raising concerns about equity and efficacy in a global multi-ancestry context. This study underscores the importance of globally inclusive genetic efforts like GP2 to close these existing gaps, improve diagnostic equity, and enable more representative and effective implementation of precision neurology worldwide.