The largest multi-ancestry genetic analysis of Parkinson's disease to date found that the frequency and distribution of disease-causing and risk-associated variants vary substantially across populations. The results highlight the importance of including diverse ancestries in genetic testing, variant interpretation, and recruitment for genotype-directed clinical trials.
Published in The Lancet Neurology, the observational study analyzed genetic data from 99,783 participants in the Global Parkinson's Genetics Program (GP2), including 58,559 patients with Parkinson's disease and 41,224 controls from 11 genetically inferred ancestry groups. Nearly one-third of participants were from historically underrepresented populations, including African, African admixed, East Asian, South Asian, Middle Eastern, Central Asian, and Latino and Indigenous populations of the Americas.
The investigators assessed pathogenic and likely pathogenic variants, copy number variants, and clinically relevant risk variants in 18 established Parkinson's disease and parkinsonism genes, including GBA1, LRRK2, PRKN, PINK1, and SNCA. Data were generated using whole-genome sequencing, whole-exome sequencing, and genotyping across 144 cohorts.
Overall, 2.1 percent of patients carried a causal genetic variant and 11.8 percent carried a clinically relevant risk variant. However, the prevalence differed markedly by ancestry. Causal variants were identified in just 0.4 percent of patients of African ancestry compared with 10.7 percent of those of Ashkenazi Jewish ancestry.
GBA1 variants were the most common finding and were detected in every ancestry group, although both their frequency and mutational spectrum varied. For example, the rs3115534-G variant predominated in African and African admixed populations, whereas p.N409S was most common in Ashkenazi Jewish patients. East Asian and South Asian populations also showed distinct GBA1 variant profiles.
Similarly, LRRK2 variants demonstrated strong ancestry-specific patterns. The pathogenic p.G2019S variant was most common in Ashkenazi Jewish and Middle Eastern populations, whereas East Asian patients more frequently carried the risk variants p.R1628P and p.G2385R. Biallelic PRKN variants were identified in nearly all ancestry groups, while PINK1 variants were most frequent in East Asian, Middle Eastern, and South Asian populations.
Patients carrying GBA1 risk variants developed Parkinson's disease a median of 3 to 8 years earlier than those without these variants across multiple ancestry groups.
Most pathogenicity classifications and many commercial genetic testing panels have been developed using predominantly European datasets, which may reduce diagnostic yield and complicate variant interpretation in underrepresented populations. The study suggests that incorporating ancestry-specific genetic information could improve molecular diagnosis, genetic counseling, and identification of patients eligible for emerging targeted therapies and genotype-directed clinical trials.
The authors concluded that expanding genetic studies in diverse populations will be essential for improving variant classification, increasing diagnostic accuracy, and supporting equitable implementation of precision medicine for Parkinson's disease.
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