Brain-derived neurotrophic factor (BDNF) genetic polymorphism greatly increases risk of leucine-rich repeat kinase 2 (LRRK2) for Parkinson's disease

Abstract

Parkinson's disease (PD) is a complex neurodegenerative disorder. Although the p.G2385R allele of leucine-rich repeat kinase 2 (LRRK2) has been recently reported as a common genetic variant that increases the risk for typical PD exclusively among Asian population, its genetic modifiers is yet to be studied. Brain-derived neurotrophic factor (BDNF) has been shown to play an important role in the survival of dopaminergic neurons and its genetic polymorphism was associated with an increased risk for PD at an older age onset. The current case–control study was performed to investigate the interaction between LRRK2 p.G2385R and BDNF p.V66M in a Chinese PD cohort. A total of 464 PD patients and 549 controls were involved in this study. LRRK2 p.G2385R variant (odds ratio [OR] = 3.2; 95% confidence interval [CI] = 1.96–5.15, p < 0.0001), not BDNF p.V66M alone significantly increased the risk of PD. However, the simultaneous presence of both LRRK2 and BDNF variants significantly enhanced the risk for PD (OR = 4.033; 95% CI = 2.188–7.435, p < 0.0001), particularly in patients with an onset age of older than 60 (OR = 6.439; 95% CI = 3.096–13.389, p < 0.0001). Our results further support that LRRK2 variants are an independent genetic risk factor for typical PD, but BDNF variants can greatly increase LRRK2-induced risk for patients with an onset age of older than 60 indicating an additive effect between the 2 genes, which might aid in studying the mechanism underlying LRRK2 parkinsonism and developing potential therapeutic strategies.