Parkinson's disease genetics across diverse ancestries: an observational genetic study of causal and risk variants with translational implications.
Level 4 - case-series / case-control
Case-control and cross-sectional observational genetic study
PubMed 42456684 · doi:10.1016/S1474-4422(26)00198-5
What was done
Researchers conducted a multi-ancestry, retrospective cross-sectional observational genetic study using data from the Global Parkinson's Genetics Program (GP2 release 11). They evaluated causal and risk-associated variants (including copy number variants) across 18 established Parkinson's disease-associated genes (including GBA1, LRRK2, SNCA, and PRKN) using genome sequencing, exome sequencing, and array genotyping. The dataset comprised 99,783 individuals (58,559 diagnosed with Parkinson's disease by Parkinson's UK Brain Bank or Movement Disorder Society criteria, and 41,224 healthy controls) across 11 genetically inferred ancestry groups. Allele and carrier frequencies were calculated overall and stratified by ancestry.
What was found
Under-represented populations (non-European and non-Ashkenazi Jewish) accounted for 29.1% (29,001 of 99,783) of the cohort. Monogenic causal variants were found in 2.1% (1,217 of 58,559) of cases overall, varying from 0.4% (10 of 2,844) in African ancestry to 10.7% (251 of 2,343) in Ashkenazi Jewish ancestry. Risk variants in GBA1 and LRRK2 were present in 11.8% (6,893 of 58,559) of cases and 8.7% (3,578 of 41,224) of controls. GBA1 risk variant frequencies in cases ranged from 4.1% (195 of 4,773) in East Asian ancestry to 52.9% (1,505 of 2,844) in African ancestry. LRRK2 causal variants peaked in Ashkenazi Jewish (10.7%, 250 of 2,343) and Middle Eastern (4.4%, 59 of 1,347) cohorts, while LRRK2 risk variants peaked in East Asian individuals (12.6%, 601 of 4,773). PRKN biallelic causal variants were identified in under 1% of most ancestries but reached 1.3% (17 of 1,347) in Middle Eastern individuals.
Why it matters
Targeted clinical trials and precision therapies for Parkinson's disease predominantly recruit European-ancestry populations. Demonstrating that causal and druggable risk variants differ markedly across global populations provides an empirical imperative to diversify genetic screening and trial enrollment.
Limits
The study is retrospective and cross-sectional, combining diverse cohorts with mixed genotyping platforms and sequencing approaches. Clinical phenotypes, age at onset, environmental exposures, and longitudinal outcomes were not reported in the abstract. Sample sizes for certain non-European ancestral groups (such as Middle Eastern, n=1,347) were substantially smaller than European groups.
Cited by
- supports In the Parkinson's Foundation PD GENEration study of 8,000 individuals with Parkinson's published in Brain, 13% carried a known genetic cause or risk factor, meaning 87% had no known genetic cause or risk factor.