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

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.

Fig. 1. LRRK2 p.A419V and age at onset.

Association of LRRK2 p.A419V with age at onset were conducted using generalized linear models (GLM) with linear regression under an additive model.

Fig. 2. Mutation sites and predicted RAB binding of LRRK2.

A Visualization of the predicted LRRK2 structure with different colored domains (armadillo repeat (ARM) domain in brown/tan, ankyrin repeat (ANK) domain in pink, leucine-rich repeat (LRR) domain in blue, ROC (Ras of complex proteins) GTPase domain in yellow, COR (C-terminal of ROC) domain in orange, kinase domain in green, and the WD40 domain in red). The alanine residue at position 419, substituted by valine in the p.A419V variant, is indicated by a red sphere within the ARM domain. Binding predictions of the different RAB proteins with LRRK2: B RAB8A, C RAB10, D RAB29, E RAB32.