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.