Objective: To advance precision medicine in Parkinson’s disease (PD) by integrating large-scale clinico-genetic data from diverse populations worldwide and establishing a framework to characterize individuals relevant for genetically-stratified trials facilitated by the Global Parkinson’s Genetics Program (GP2).

Background: Disease-modifying trials in PD increasingly target genetically defined individuals, particularly carriers of disease-related GBA1 and LRRK2 variants. However, the global distribution of these individuals remains poorly characterized, limiting equitable implementation of precision medicine strategies.

Method: We analyzed short-read sequencing and array genotyping data from GP2’s most recent data release for carriers of pathogenic and high-risk GBA1 and LRRK2 variants. The cohort included individuals with manifest PD, prodromal features of PD (RBD and hyposmia), and unaffected participants from 11 genetically-defined ancestries. Genetic data were integrated with harmonized clinical and demographic data, where available.

Results: Among 65509 PD individuals, we identified 9019 (13.8%) individuals who were potentially trial-eligible based on genetic status, including 6789 GBA1, 2084 LRRK2, and 146 dual GBA1-LRRK2 carriers. PD patients were further stratified by clinical characteristics to evaluate trial eligibility, including disease duration, motor severity, and cognitive function. Additionally, 319 (6.1%) GBA1 and 26 (0.5%) LRRK2 variant carriers were identified out of 5269 individuals in prodromal PD stages. Finally, out of 45574 unaffected individuals, 3727 (8.2%) carried GBA1 and 786 (1.7%) LRRK2 variants. Notably, our analyses included individuals from targeted recruitment of GBA1 and LRRK2 variant carriers. 

Overall, variant carriers were distributed across multiple global regions, including areas currently underrepresented in gene-targeted trials.

Conclusion: Our findings highlight a substantial global pool of genetically defined individuals with PD potentially eligible for therapeutic trials, while also identifying large numbers of at-risk and prodromal variant carriers relevant for prevention strategies. By facilitating earlier identification of genetically at-risk populations and enabling longitudinal follow-up, GP2 can help accelerate preventive and disease-modifying trials and improve equitable access to emerging precision medicine approaches.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/bridging-genetics-and-precision-medicine-in-parkinsons-disease-through-gp2-translating-genetic-risk-into-trial-eligible-gba1-and-lrrk2-cohorts/