IN PEOPLE with Parkinson’s disease, the genetic variants driving the condition vary substantially by ancestry, according to the largest multi-ancestry genetics study of the disease conducted to date, with clear implications for future gene-targeted therapies.
Researchers conducted a multi-ancestry, observational, cross-sectional genetic study using data from the Global Parkinson’s Genetics Program release 11. The study investigated causal and risk variants, including copy number variants, in 18 established Parkinson’s disease and parkinsonism-associated genes, including GBA1, LRRK2, SNCA, and VPS35, following recommendations from the Movement Disorder Society Task Force on the Nomenclature of Genetic Movement Disorders. Genome and exome sequencing and array genotyping data were analysed from 99,783 individuals, including 58,559 with Parkinson’s disease and 41,224 controls, spanning 11 genetically inferred ancestries.
Around 29% of participants were from under-represented populations, defined as non-European and non-Ashkenazi Jewish. Overall, 1,217 (2.1%) of 58,559 individuals with Parkinson’s disease carried a causal variant, ranging from 0.4% of African individuals to 10.7% of those of Ashkenazi Jewish ancestry. Risk variants in GBA1 and LRRK2 were identified in 11.8% of individuals with Parkinson’s disease and 8.7% of controls. GBA1 risk variants were the most frequent overall, ranging from 4.1% in the east Asian ancestry group to 52.9% in the African ancestry group. LRRK2 causal variants were most frequent in the Ashkenazi Jewish (10.7%) and Middle Eastern (4.4%) ancestry groups, while LRRK2 risk variants were most common in the east Asian ancestry group (12.6%). Biallelic causal variants in PRKN were identified across all ancestries except Ashkenazi Jewish, with the highest frequency, 1.3%, in the Middle Eastern group.
These findings have offered crucial insights into the population-specific genetic architecture of Parkinson’s disease, revealing shared genetic contributors across ancestries and ancestry-specific differences in variant frequency and spectrum. As clinical trials targeting GBA1 and LRRK2 variant carriers have primarily been conducted in Europe and the United States, the authors have suggested that greater ancestral diversity in Parkinson’s disease genetics research will be crucial to improving diagnostic accuracy and ensuring equitable access to emerging genetically informed therapies.
Lange LM et al. Parkinson’s disease genetics across diverse ancestries: an observational genetic study of causal and risk variants with translational implications. Lancet Neurol. 2026;25(8):741-54.
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