Objective: To develop a publicly accessible web browser that allows users to easily explore the distribution of LRRK2 variants in both Parkinson’s disease (PD) and healthy controls across diverse ancestries, with integrated clinical and functional data to support variant interpretation and inform LRRK2-targeting precision medicine efforts and clinical trials.

Background: LRRK2 is implicated in both monogenic and complex PD, harboring rare causal variants and common risk variants. While thousands of missense variants have been reported, only a fraction are considered disease-causing. In the context of PD, pathogenic LRRK2 variants typically act via gain-of-function mechanisms that lead to increased kinase activity. Functional assays measuring phosphorylation of substrates such as Rab10 have helped classify variants of previously uncertain significance as pathogenic or benign. Importantly, LRRK2 variant frequencies substantially differ across ancestries, necessitating globally representative analyses for equitable diagnostic accuracy and gene-targeted therapies.

Method: We analyzed data from the Global Parkinson’s Genetics Program’s (GP2) Release 11 (122,317 individuals), including array genotyping, clinical-exome, and whole-genome sequencing. Participants were assigned to genetically determined ancestry groups. We extracted LRRK2 variants using PLINK, performed annotation with ANNOVAR, and used RShiny to develop the browser.

Results: The LRRK2 Browser displays allele frequencies for each LRRK2 variant, stratified by PD status, ancestry, and dataset. Where available, we linked variants to LRRK2 kinase activity as well as other pathogenicity measurements. Further, we extracted family history status and age at onset for affected variant carriers. As expected, the frequency of many LRRK2 variants, including established pathogenic and risk variants, varies substantially across ancestries. We additionally provide visuals such as protein and cDNA diagrams and a kinase activity bar plot, as well as variant-specific age and family history distribution plots, for refined variant interpretation.

Conclusion: LRRK2 variation differs markedly by ancestry, underscoring the importance of inclusive research on its impact in PD. We developed the publicly available LRRK2 Browser to integrate genetic, clinical, and functional data across ancestries, supporting improved variant interpretation and advancing equitable adoption of LRRK2-targeted therapies.

« Back to 2026 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/lrrk2-in-focus-a-global-browser-linking-genetic-diversity-to-functional-effects/