We found a frequency of 6.1% (14/230) known pathogenic mutations in the PD series and 0.7% (3/430) in the control group. These results represent a significantly higher frequency of mutations in GBA in PD patients when compared to controls (p<0.001; OR=9.2; 95% CI 2.6-32.4). Of note, the control group shows no mutations associated with severe GD; while they exist in the PD group – 4/14 patients with L444P or D409H. If we consider the variants of unknown pathogenicity (p.K13R; p.R41L and p.E427K) as potentially causative, this association still remains (p<0.001; OR=4.9; 95% CI 1.9-12.9).
The most common mutation identified was N370S, the most frequently identified pathogenic mutation in Ashkenazi Jewish as well as Portuguese patients with GD. Based on screening of 2000 random cord blood samples in Portugal, the carrier frequency of this mutation is estimated to be 0.0043 in this population (Lacerda et al. 1994
). This mutation is believed to account for 63% of the mutant alleles in Portuguese patients with GD. Although the N370S mutation was three times more frequent in the PD group when compared to controls, we did not have sufficient power to identify a statistically significant association analyzing this mutation alone (P=0.079; OR 3.3; 95% CI 0.75-13.4). Mutation N396T, encountered in 5 subjects in this study, was first identified in Portugal and has proven to be a relatively common mutation in this population (Amaral et al. 2000
This study substantiates the need to sequence GBA in non-Ashkenazi cohorts in order to accurately determine the frequency of mutations in this gene. Had we screened only for common Gaucher mutations, we would have missed 43% of the mutant alleles in this population.
The association of GBA mutations with PD in the Portuguese population is particularly interesting when it is noted that the mutation driving this association is one associated with Jewish ancestry, and that another PD causing mutation, p.G2019S of LRRK2, underlying ~6% of Portuguese PD cases (Bras et al. 2005
), is also associated with Ashkenazi Jewish ancestry; these data clearly illustrate the contribution of Jewish ancestry to the modern Portuguese population.
In summary using a cohort with a different and defined ethnicity, we demonstrate that GBA mutations are significantly more common in patients with PD than in neurologically normal controls. These findings illustrate that the identification of such an association requires large sample series, even when using populations where GBA mutations are enriched; thus detection of such an association in populations with non-Ashkenazi ancestry is likely to require thousands of samples.