Lrrk2 S1647T and BDNF V66M interact with environmental factors to increase risk of Parkinson's disease.

Parkinson's disease (PD) is a complex neurodegenerative disorder contributed by both environmental and genetic factors. The inconsistent findings in genetic association studies may be due to unrecognized interactions with other genetic or environmental factors. Therefore, we assessed the combined effects of genetic variants of three candidate genes of familial PD and environmental exposure on risk of PD in Taiwanese population. A total of 744 study subjects, 453 PD cases and 291 ethnicity-matched controls, were included. The genetic variants on the PINK1, BDNF, and LRRK2 genes were sequenced accordingly. We used a regression approach based on a generalized linear model to evaluate single-locus genotype effects and detection of gene-environment interaction by incorporating interaction terms in the model. We found a significant difference of LRRK2 G2385R and R1628P between PD patients and controls, which confirmed our previous findings. A logistic regression model which included gene-environment interactions was applied. Notably, we identified the variant of LRRK2 T4939A (S1647T) (TT, OR = -0.36, p = 0.03) is associated with increased PD risk, after considering the interaction effects with environmental factors in the model. Additionally, two novel interactions were detected: pesticide exposure with BDNF (OR = -0.85, p = 0.01) and to a lesser extent, with PINK1 (OR = 1.99, p = 0.07). Our findings reinforced the importance that PD risk is modulated by both genetic and environmental exposures. LRRK2 S1647T may be another risk factor for PD development in our ethnicity while considering the joint interaction effects with environmental factors.