Objective: To conduct the largest genome-wide association study (GWAS) of Parkinson’s disease (PD) in African (AFR) and African admixed (AAC) ancestry populations to identify ancestry-specific and cross-population risk loci.

Background: Over 130 PD risk loci have been identified through GWAS, yet the vast majority derive from European ancestry populations. African (AFR) and African admixed (AAC) individuals remain systematically underrepresented, despite harboring the greatest genomic diversity among human populations. Our 2023 publication (Rizig et al., Lancet Neurology) established GBA1 as a driving genetic risk factor in these populations, driven by an intronic variant (rs3115534-G) that disrupts splicing through an RNA-based mechanism.

Method: We integrated individual-level genotype data from the Global Parkinson’s 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 over our prior study. We performed separate GWAS for AFR and AAC cohorts and a combined AFR/AAC meta-analysis, and performed functional follow-up.

Results: The GBA1 intronic 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), SNCA (rs356182), a novel protein-coding LRRK2 variant (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 loci: GBA1, SNCA, SCARB2 (rs11547135), and LRRK2 (rs139283662, in LD with p.T1410M).

Conclusion: This study confirms multi-ancestry risk loci at GBA1, SNCA, and SCARB2, and identifies an ancestry-enriched coding variant at LRRK2 enriched in African ancestry populations. The growing evidence around glucocerebrosidase trafficking and alpha-synuclein clearance genes supports current therapeutic strategies and nominates African ancestry individuals for GBA1- and LRRK2-targeted clinical trials, populations that have been systematically excluded from the genetics underpinning those trials.

References: Rizig, M., Bandres-Ciga, S., Makarious, M. B., Ojo, O. O., Crea, P. W., Abiodun, O. V., et al, Global Parkinson’s Genetics Program (2023). Identification of genetic risk loci and causal insights associated with Parkinson’s disease in African and African admixed populations: a genome-wide association study. The Lancet. Neurology, 22(11), 1015–1025. https://doi.org/10.1016/S1474-4422(23)00283-1

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MDS Abstracts - https://www.mdsabstracts.org/abstract/expanded-parkinsons-disease-gwas-in-african-ancestry-populations-identifies-novel-risk-loci-and-precision-medicine-targets/