Multicenter Analysis of Glucocerebrosidase Mutations in Parkinson`s Disease

Background Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher`s disease, among patients with Parkinson`s disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson`s disease. Methods Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson`s disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers. Results All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations. Conclusions Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson`s disease.

National Institutes of Health (NIH)[Z01AG000957-05]

U.S. National Institutes of Health (NIH)

U.S. National Institutes of Health (NIH)

National Institute of Neurological Disorders and Stroke and the National Center for Research Resources (NINDS/NIH)[NS050487]

National Institute of Neurological Disorders and Stroke and the National Center for Research Resources (NINDS/NIH)[NS060113]

U.S. National Institutes of Health (NIH)

National Institute of Neurological Disorders and Stroke and the National Center for Research Resources (NINDS/NIH)[NS40256]

U.S. National Institutes of Health (NIH)

Parkinson`s Disease Foundation

Parkinson`s Disease Foundation

Department of Veterans Affairs, Seattle

Department of Veterans Affairs, Seattle

German National Genome Network, German Ministry for Education and Research

German National Genome Network, German Ministry for Education and Research[01GS08134]

French Parkinson`s Disease Genetics Study Group

French Parkinson`s Disease Genetics Study Group

Duke-National University of Singapore (NUS) Graduate Medical School, National Medical Research Council, Biomedical Research Council, Singapore Millennium Foundation

Duke-National University of Singapore (NUS) Graduate Medical School, National Medical Research Council, Biomedical Research Council, Singapore Millennium Foundation

SingHealth, Singapore General Hospital, National Neuroscience Institute

SingHealth, Singapore General Hospital, National Neuroscience Institute

Tel Aviv Sourasky Medical Center Grant of Excellence

Tel Aviv Sourasky Medical Center Grant of Excellence

Wolfson and Kahn Foundations

Wolfson and Kahn Foundations

Fundação para a Ciência e a Tecnologia de Portugal (FCT)

Portuguese Fundacao para a Ciencia e a Tecnologia

National Science Council, Executive Yuan, Taiwan

National Science Council, Executive Yuan, Taiwan[NSC-95-2314-B-182A-061]

Ministry of Education, Culture, Sports, Science, and Technology of Japan

Ministry of Education, Culture, Sports, Science and Technology of Japan