Parkinson’s Disease Genetics Across Diverse Ancestries: An Observational Genetic Study of Causal and Risk Variants with Translational Implications

Highlights

• Distinct causal and risk genetic variants for Parkinson’s disease exhibit substantial variation across ancestries, with Ashkenazi Jewish and African ancestries showing marked differences in variant frequencies.

• Risk variants in GBA1 and LRRK2 are prevalent across diverse populations but show ancestry-specific enrichment patterns influencing disease risk and therapeutic targeting.

• Carriers of biallelic PRKN causal variants, including copy number variants, were detected across most ancestries, underscoring the need to consider structural variants in genetic screening.

• Expanding genetic studies beyond European cohorts is essential for improving diagnostic precision and equitable development and application of genotype-driven Parkinson’s disease therapies.

Background

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms, with an increasing global burden due to aging populations. Understanding its genetic architecture has been pivotal in elucidating pathophysiological mechanisms and developing targeted interventions. Historically, genetic studies have predominantly included individuals of European ancestry, limiting the generalizability of findings and therapeutic implications across diverse populations. Genetic variants in genes such as GBA1 and LRRK2 are known to influence PD risk and progression and are targets of emerging clinical trials. Addressing this knowledge gap requires comprehensive multi-ancestry genetic analyses to inform global clinical practice and research equity.

Key Content

Study Design and Population

The Global Parkinson’s Genetics Program (GP2) release 11 (December 2025) provided a unique retrospective, cross-sectional, multi-ancestry dataset of 99,783 individuals, including 58,559 diagnosed PD patients and 41,224 controls. Eleven genetically inferred ancestries were delineated using reference population-based inference methods: African, African admixed, Ashkenazi Jewish, Latino and Indigenous peoples of the Americas, Central Asian, complex admixture, East Asian, European, Finnish, Middle Eastern, and South Asian. PD diagnosis followed established UK Brain Bank or Movement Disorder Society (MDS) criteria, ensuring clinical validity across cohorts. This robust sampling approach enhanced the representation of under-represented populations (29% non-European/Ashkenazi Jewish), strengthening analyses relevant to diverse global populations.

Genetic Variants Investigated

The study comprehensively examined causal and risk variants, including copy number variants (CNVs), in Parkinsonism-associated genes per MDS Task Force nomenclature, covering canonical PD genes such as GBA1, LRRK2, SNCA, VPS35, and rarer causal loci like RAB32, PINK1, PRKN, and others. Analysis incorporated genome sequencing, exome sequencing, and array genotyping modalities, enabling high-resolution variant calling across traditional single nucleotide variants and structural variants.

Population-Specific Variant Distribution

Approximately 2.1% of PD cases carried a recognized causal variant with wide ancestry-dependent variability: from 0.4% in African ancestry to 10.7% in Ashkenazi Jewish individuals. This highlights the disproportionate burden and possible founder effects in certain groups. Risk variants impacting GBA1 and LRRK2 genes were common, identified in 11.8% of PD cases and 8.7% of controls overall, with marked frequency and spectrum differences across ancestries. Notably, GBA1 risk variants were most frequent overall but varied in prevalence—from 4.1% in East Asians to a striking 52.9% among African ancestry individuals.

LRRK2 variant profiles revealed ancestry-specific enrichment: Ashkenazi Jewish and Middle Eastern populations exhibited the highest frequencies of causal variants (10.7% and 4.4%, respectively), whereas East Asian individuals showed predominance of risk variants (12.6%). These data emphasize the non-uniform genetic risk landscapes and their implications for clinical genetic testing and targeted therapeutics.

Biallelic PRKN causal variants, including common CNVs involving deletions and duplications, were detected across most ancestries except Ashkenazi Jewish. The Middle Eastern group demonstrated the highest carrier frequency (1.3%), while frequencies remained below 1% in others, underscoring the importance of structural variant screening in differential genetic diagnostics.

Translational Implications

The genomic variability in PD across ancestries critically impacts the design and applicability of precision medicine approaches. Clinical trials targeting GBA1 and LRRK2 variant carriers largely focus on European and North American cohorts, limiting generalizability and potential benefit in other populations. The documented heterogeneity underscores the necessity for inclusion of diverse ancestries in research, facilitating the development of equitable diagnostic tools, biomarker profiles, and genotype-driven therapies.

For example, the broad distribution but variable spectrum of GBA1 mutations across ancestries suggests the need for ancestry-informed panels in genetic screening and trial enrollment. The high prevalence of LRRK2 risk variants in East Asians prompts investigation into ethnicity-specific pathogenic mechanisms and therapeutic responses.

These findings also advocate for increased genetic counseling resources adapted to diverse populations and highlight the importance of integrating CNV analyses, particularly for PRKN, into clinical screening algorithms.

Expert Commentary

This pioneering multi-ancestry genetic exploration advances our understanding of PD pathogenesis in a globally representative context. The ascertainment of both shared genetic underpinnings and unique population-specific variant spectra refines our conception of genetic risk and causality, which is essential for tailoring diagnostics and therapeutics.

Limitations include retrospective design and varying sequencing modalities, which may influence variant detection sensitivity. Despite large sample size, some ancestries remain under-represented compared to European cohorts, necessitating ongoing recruitment and data sharing efforts.

Guidelines from the Movement Disorder Society and other bodies increasingly emphasize genetic testing in PD; this study advocates for ancestry-specific considerations to avoid misclassification and ensure clinical benefit. It also calls for heightened attention to structural variants, such as PRKN CNVs, which may be under-recognized in certain populations.

From a mechanistic perspective, the data suggest differential penetrance and functional impact of variants according to genetic background, warranting functional genomics studies and longitudinal phenotyping to elucidate disease modifiers.

Conclusion

This comprehensive multi-ancestry genetic study robustly delineates the heterogeneous landscape of causal and risk variants in Parkinson’s disease, highlighting substantial differences across diverse populations. The findings emphasize critical gaps in current research equity and therapeutic targeting, underscoring the imperative for inclusive global genetics initiatives.

Future directions include expanding population recruitment, integrating polygenic risk scores with environmental modifiers, and advancing mechanistic studies to inform culturally competent precision medicine. Such efforts will enhance diagnostic accuracy, unravel ancestral diversity of disease biology, and democratize access to effective genetically informed Parkinson’s therapies worldwide.

References

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