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Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease

From the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain (L.N.C., B.M.R., E.D.L., K.M.), Department of Pathology (L.N.C.), Gertrude H. Sergievsky Center (H.M.-S., E.D.L., L.J.C., H.A., R.O., K.M.), Department of Neurology (J.H., E.D.L., L.J.C., S.F., C.W., B.F., S.F., K.M.), Department of Psychiatry (H.A., R.O., K.M.), and Department of Epidemiology (R.O.), College of Physicians and Surgeons, Columbia University; Department of Statistics (Y.W.), Columbia University; and The Epidemiology of Brain Disorders Department (R.O.), New York State Psychiatric Institute, New York, NY.

Address correspondence and reprint requests to Dr. Lorraine N. Clark, Department of Pathology, Columbia University, P&S Bldg., 14-434, 630 W. 168th St., New York, NY 10032

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 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 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.

GLOSSARY: AAO = age at onset; cDNA = complementary DNA; GBA = glucocerebrosidase; GD = Gaucher disease; GEPD = Genetic Epidemiology of Parkinson’s Disease; MMSE = Mini-Mental State Examination; NA = not applicable; DLB = dementia with Lewy bodies; OR = odds ratio; PD = Parkinson disease; SNP = single nucleotide polymorphism; UPDRS = Unified Parkinson’s Disease Rating Scale.

lc654{at}columbia.edu

Supplemental data at www.neurology.org

Supported by NIH NS50487 (L.N.C.) and NS36630 and RR00645 (K.M.) and the Parkinson’s Disease foundation (L.N.C. and K.M.).

Disclosure: The authors report no conflicts of interest.

Received November 1, 2006. Accepted in final form April 16, 2007.

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