Penetrance of LRRK2 G2385R and R1628P is modified by common PD-associated genetic variants

Variants in the LRRK2 gene are well-characterized genetic predisposing factors for PD worldwide, and LRRK2-associated PD is often indistinguishable from idiopathic PD (IPD). However, considerable heterogeneity of LRRK2-PD suggests the existence of additional genetic and/or environmental modifiers for LRRK2 carriers, which have yet to be confirmed by large-scale human studies. In a Chinese cohort consisting of 2013 sporadic PD patients and 1971 controls, we investigated the modification of the two Asian-specific LRRK2 variants, G2385R and R1628P, by variants of five other PD-associated genes/loci (SNCA, MAPT, GBA, BST1, PARK16). Of all the PD patients, 13.1% carried LRRK2 G2385R and/or R1628P variant. Among these carriers, a total of 15 different polygenic genotypes were detected representing different combination patterns between LRRK2 variants and those of the other genes/loci, which, alone or in combination, significantly modified the LRRK2-related risk for PD and the patients' ages at onset (AAOs). These results not only represent the largest replication data affirming the association between PD and all the six genes/loci in Chinese, but for the first time suggest that multiple PD-associated genetic factors modify both the penetrance and AAO of LRRK2 parkinsonism. This finding may have important implications for elucidating pathophysiologic mechanisms relevant to both LRRK2-associated and idiopathic PD. However, testing interactions among multiple genes by genetic association studies is still challenging. Future studies with much larger sample sizes are needed to confirm our findings. (C) 2012 Elsevier Ltd. All rights reserved.