Our data suggest that GBA mutations might represent a significant risk factor for Lewy body disorders. However, although the effect sizes observed in our case-control sample were large (odds ratios in the 8-10 range), the frequency of mutation carriers among both the PD and DLB groups was low (). Thus, we estimate that the population-attributable risk for GBA mutations in Lewy body disorders is only approximately 3% in individuals of European ancestry ().
Most patients with PD heterozygous for GBA
mutations in our cohort had sporadic, late-onset disease that was responsive to levodopa, consistent with previously published data ().4,11,12
This finding is in contrast to some parkinsonian patients with Gaucher disease in whom parkinsonism was of early onset and refractory to treatment.1
Our work has 3 major strengths compared with 6 previously published studies6-11
mutations in PD populations of primarily European origin. First, our study had a large sample size. A frequent observation among genetic association analyses is the initial report of a large effect in a small sample followed by more powerful studies that typically fail to reproduce the initial results or occasionally validate the effect, but at a more modest level.16
Of the 6 studies on GBA
previously mentioned, the first study9
reported a mutation frequency of 14% among 57 patients with PD and 0% among 44 control samples derived from US brain banks. The 5 subsequent studies6-8,10,11
have observed effects of marginal or no significance, but 4 of these have included a PD cohort of fewer than 100 patients and were thus underpowered. Our study addressed this issue by using a PD cohort that exceeded the combined sample size of patients with PD across all 6 studies and suggests a potentially bona fide but more modest effect than originally reported.9
Second, our study limited the sample to individuals of European ancestry. The N370 mutation has a much higher prevalence among Ashkenazi Jews than in individuals of European origin.4,5,9-11
Thus, spurious associations might arise if cases and control subjects are drawn differentially from these populations.16
We collected detailed information on ancestry from patients with PD and control subjects at the time of enrollment and were thus able to account for this important confounder. In contrast, such data were largely lacking in previous studies.
Third, we included a matched control group. Some studies have failed to include a control group and have instead relied on previous estimates of GBA
mutation frequencies derived indirectly from epidemiologic studies on Gaucher disease.7,8
Another derived control subjects from brain banks with minimal data available on ancestry.9
These approaches are subject to substantial bias and confounding. We used a control group screened for parkinsonism and matched closely for age, ancestry, and area of residence.
Our study also had several limitations. Although more than 200 pathogenic GBA
mutations have been reported,17
we genotyped only the 2 most common ones, which together account for approximately 70% of the disease alleles in white patients with Gaucher disease (excluding Ashkenazi Jews; International Collaborative Gaucher Group Gaucher Registry, unpublished data, September 2006). Thus, we might have underestimated the true mutation frequency. The sample size of the DLB group was small, and there was insufficient information to separate individuals of European ancestry from those of other white populations. Thus, findings from our analysis of the DLB group must be interpreted with caution, but these data suggest that the remarkably high mutation frequency (23%) observed in a previous DLB sample (n=35) might be an overestimate.8
Common variants in many genes have been nominated as risk factors for PD in populations of European origin, but arguably all but 2 (SNCA
) have later failed validation.18-20
This phenomenon has engendered a healthy skepticism in evaluating newly nominated susceptibility genes, and GBA
is no exception. Given the large burden of proof incumbent on candidate gene studies, our findings should not be considered definitive replication but indicate that the role of GBA
in Lewy body disorders merits intensive study. This will require large-scale collaborative efforts and well-designed studies on thousands of individuals.