Insights Into Parkinsons Disease Genetics in African Populations: Expanded GWAS Identifies Ancestry-Specific and Cross-Population Risk Loci

IntroductionGenome-wide association studies (GWAS) have identified over 130 risk loci for Parkinsons disease (PD), yet the majority derive from studies performed in European ancestry populations. African (AFR) and African admixed (AAC) ancestry individuals remain underrepresented in PD genetics research, limiting our understanding of ancestry-specific genetic architecture and the generalizability of known risk factors. MethodsWe conducted GWAS in AFR and AAC populations by integrating individual-level genotype data from the Global Parkinsons Genetics Program (GP2) with summary statistics from 23andMe Research Institute and the Million Veterans Program. The combined dataset included 3,975 cases and 319,883 controls, representing a 64% increase in total sample size compared with prior analyses. We performed separate GWAS for AFR and AAC cohorts as well as a combined AFR/AAC meta-analysis. ResultsThe intronic GBA1 variant rs3115534 was the most significant association across all analyses, reaching genome-wide significance in AAC individuals for the first time. In the AFR-only analysis, five loci achieved genome-wide significance: GBA1 (rs3115534), the SNCA signal previously reported in European ancestry GWAS (rs356182), a new protein-coding association at LRRK2 (rs72546327, p.T1410M), a non-coding RPL10P13 variant (rs12302417), and a novel signal on chromosome 16 (rs113244182). The combined AFR/AAC meta-analysis identified four genome-wide significant associations at GBA1 (rs3115534), SNCA (rs356182), SCARB2 (rs11547135), and LRRK2 (rs139283662, which is in LD with p.T1410M). ConclusionsThis study reports the largest GWAS of PD in AFR and AAC populations to date. Our findings confirm trans-ancestry risk loci (GBA1 and SCARB2) and identify an ancestry-enriched coding variant at LRRK2. This convergence of evidence around genes involved in glucocerebrosidase (GCase) trafficking and alpha-synuclein clearance supports current therapeutic strategies targeting this pathway and provides critical targets for developing precision medicine in African ancestry populations. Importantly, the identification of a novel association between a LRRK2 coding variant with disease in the AFR and AAC populations opens up a traditionally underrepresented population for ongoing LRRK2 targeted trials. Furthermore, the identification of novel ancestry-specific loci, including those that are directly relevant to current therapeutic deployment, underlines the importance of understanding the basis of disease in all populations.