# Association of LRRK2 p.A419V with Parkinson’s Disease in East Asians and analysis of age at onset

## TL;DR

This study finds that the LRRK2 p.A419V variant increases Parkinson's disease risk in East Asians and is linked to earlier disease onset.

## Contribution

The study identifies p.A419V as a novel PD risk variant in East Asians and links it to ARM domain signaling.

## Key findings

- The LRRK2 p.A419V variant is significantly associated with increased PD risk in East Asians (OR = 2.9).
- p.A419V is linked to a lower age at onset of Parkinson's disease in the study cohort.
- Protein modeling suggests p.A419V is near RAB8A, RAB29, and RAB32 binding sites in the ARM domain.

## Abstract

Common and rare variants in LRRK2 influence Parkinson’s disease (PD) risk across diverse populations, and in this study, the rare p.A419V variant was investigated across multiple ancestry cohorts comprising over 200,000 PD cases and controls. In cases of East Asian (EAS) ancestry, p.A419V was significantly associated with increased risk of PD (OR = 2.9; 95% CI: 1.66–5.10; p = 0.0002), and was not in linkage disequilibrium with other LRRK2 coding variants. The variant was significantly associated with a lower age at PD onset in the study cohort, while a meta-analysis of the EAS cases indicated a similar, albeit non-significant trend. LRRK2 protein modelling prediction indicated that binding sites for RAB8A, RAB29 and RAB32 were in close proximity to the p.A419V variant within the ARM domain. Together, these findings confirm the p.A419V as a significant PD risk factor in EAS populations, as well as highlight disease-relevant variants in the ARM domain and the link with LRRK2-RAB signaling.