This multi-ancestry, cross-sectional genetic study characterised the distribution of causal and risk variants in 18 Parkinson's disease-associated genes across 99,783 individuals (58,559 with Parkinson's disease, 41,224 controls) from 11 genetically inferred ancestries, using data from the Global Parkinson's Genetics Program (GP2) release 11.
Causal variants were found in 2.1% of PD cases overall, ranging from 0.4% in African to 10.7% in Ashkenazi Jewish ancestry. GBA1 risk variants appeared in 4.1% (east Asian) to 52.9% (African) of PD cases; LRRK2 causal variants peaked in Ashkenazi Jewish (10.7%) and Middle Eastern (4.4%) groups; PRKN biallelic causal variants were highest in Middle Eastern ancestry (1.3%).
- ~71% of PD cases were of European or Ashkenazi Jewish ancestry, limiting statistical power for under-represented groups. - Cross-sectional, observational design precludes causal or longitudinal inference. - Healthy controls were not genetically matched at variant level, and ascertainment methods varied across contributing cohorts.
Genetic testing for PD risk and causal variants should account for ancestry-specific variant spectra — particularly GBA1 in African and LRRK2 in Ashkenazi Jewish and Middle Eastern patients. As GBA1- and LRRK2-targeted trials expand, recruiting ancestrally diverse participants is essential to ensure findings apply broadly.
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