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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.

Pubmed ID: 19846850 RIS Download

Mesh terms: Aged | Case-Control Studies | Genotype | Glucosylceramidase | Humans | Jews | Logistic Models | Middle Aged | Multivariate Analysis | Mutation | Odds Ratio | Parkinson Disease

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Associated grants

  • Agency: Intramural NIH HHS, Id: ZIA HG200336-06
  • Agency: NINDS NIH HHS, Id: NS060113
  • Agency: NINDS NIH HHS, Id: NS050487
  • Agency: NCRR NIH HHS, Id: UL1 RR024156
  • Agency: Intramural NIH HHS, Id: ZIA HG200336-07
  • Agency: Intramural NIH HHS, Id: Z01 AG000957-05
  • Agency: NINDS NIH HHS, Id: NS40256
  • Agency: NINDS NIH HHS, Id: R56 NS036630
  • Agency: Intramural NIH HHS, Id: Z99 HG999999
  • Agency: NIA NIH HHS, Id: Z01 AG000957
  • Agency: NINDS NIH HHS, Id: R01 NS036630

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