Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease.
OBJECTIVE
To evaluate the frequency of glucocerebrosidase (GBA) mutations in cases and controls enrolled in the Genetic Epidemiology of Parkinson's Disease (GEPD) study.


METHODS
We sequenced all exons of the GBA gene in 278 Parkinson disease (PD) cases and 179 controls enrolled in GEPD, with a wide range of age at onset (AAO), and that included a subset of 178 Jewish cases and 85 Jewish controls. Cases and controls were recruited without knowledge of family history of PD, and cases were oversampled in the AAO < 50 years category.


RESULTS
13.7% of PD cases (38/278) carried GBA mutations, compared with 4.5% of controls (8/179) (odds ratio [OR] 3.4, 95% CI 1.5 to 7.4). The frequency of GBA mutations was 22.2% in 90 cases with AAO < or = 50 years, compared with 9.7% in 185 cases with AAO > 50 years (OR 2.7, 95% CI 1.3 to 5.3). Adjusting for age at the time of evaluation, sex, family history of PD, and Jewish ancestry, GBA carriers had a 1.7-year-earlier AAO of PD (95% CI 0.5 to 3.3, p < 0.04) than noncarriers. The average AAO of PD was 2.5 years earlier in carriers with an AAO < or = 50 years compared with noncarriers (95% CI 0.6 to 4.5, p < 0.01) and this was not seen in the AAO > 50 years group. The frequency of GBA mutations was higher in a subset of 178 cases that reported four Jewish grandparents (16.9%) than in cases who did not report Jewish ancestry (8.0%) (p < 0.01). Nine different GBA mutations were identified in PD cases, including 84insGG, E326K, T369M, N370S, D409H, R496H, L444P, RecNciI, and a novel mutation, P175P.


CONCLUSIONS
This study suggests that the Glucocerebrosidase gene may be a susceptibility gene for Parkinson disease and that Glucocerebrosidase mutations may modify age at onset.
Clark
L N
LN
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. lc654@columbia.edu
Ross
B M
BM
Wang
Y
Y
Mejia-Santana
H
H
Harris
J
J
Louis
E D
ED
Cote
L J
LJ
Andrews
H
H
Fahn
S
S
Waters
C
C
Ford
B
B
Frucht
S
S
Ottman
R
R
Marder
K
K
D017668:Age of Onset; D000368:Aged; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D005962:Glucosylceramidase / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics; D007585:Jews / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000201:enzymology* / Q000208:ethnology / Q000235:genetics*
D005962:Glucosylceramidase