期刊
NEW ENGLAND JOURNAL OF MEDICINE
卷 361, 期 17, 页码 1651-1661出版社
MASSACHUSETTS MEDICAL SOC
DOI: 10.1056/NEJMoa0901281
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资金
- National Institutes of Health [Z01AG000957-05]
- National Institute of Neurological Disorders and Stroke and the National Center for Research Resources [NS050487, NS060113, NS40256]
- Parkinson's Disease Foundation
- Department of Veterans Affairs, Seattle
- German National Genome Network, German Ministry for Education and Research [01GS08134]
- 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
- SingHealth, Singapore General Hospital, National Neuroscience Institute
- Tel Aviv Sourasky Medical Center Grant of Excellence
- Wolfson and Kahn Foundations
- Portuguese Fundacao para a Ciencia e a Tecnologia
- National Science Council, Executive Yuan, Taiwan [NSC-95-2314-B-182A-061]
- Ministry of Education, Culture, Sports, Science and Technology of Japan
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.
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