LAUSR

E365K completely accounted for the previously identified GWAS signal (conditional p.E365K rs71628662, P = 0.6234). Within the current data set, the linkage disequilibrium between p.E365K and rs7168662 is very high (D0 = 0.987, r = 0.84). Previously, another noncoding variant (rs114138760) was also identified as an independent signal. In the NeuroX data set, this variant also showed association with disease (P = 0.0001853) and remained significant following adjustment for the primary GWAS variant (P = 0.0001511). In addition, this signal also remained significant following adjustment for p.E365K, p. N409S, and p.T408M (P > 0.007146), and of the 15 rs114138760 risk variant carriers, none carry p.L483P. In summary, this work affirms that functional alleles within GBA (p.E365K and p.T408M) that are insufficient to cause GD variants are robustly associated with PD. Further, we have shown that a previously reported GWAS signal at this locus can be largely explained by protein coding variability withinGBA. These data are consistent with p.E365K being the functional effector allele underlying the original GWA locus (GBA-SYT11 locus), as suggested previously. The results from this current study suggest that efforts directed at replacing or augmenting glucocerebrosidase activity already under way for PD may have wider-ranging applicability than just for individuals with GD-associated mutations in glucocerebrosidase.