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Comparative Study
. 2009 Oct 22;361(17):1651-61.
doi: 10.1056/NEJMoa0901281.

Multicenter Analysis of Glucocerebrosidase Mutations in Parkinson's Disease

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Free PMC article
Comparative Study

Multicenter Analysis of Glucocerebrosidase Mutations in Parkinson's Disease

E Sidransky et al. N Engl J Med. .
Free PMC article

Abstract

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.

Figures

Figure 1
Figure 1
Odds ratios from meta-analyses. Panels correspond to combined risk estimates associated with possessing (A) any GBA mutation, (B) mutation L444P (C) mutation N370S and (D) any GBA mutation excluding Japan and Norway study centers. Horizontal grey lines indicate 95% confidence intervals of estimates. Point estimates per study population are indicated by squares where height is inversely proportional to the standard error of the estimates. Diamonds represent the summary odds ratio whose width indicates the 95% confidence intervals.
Figure 1
Figure 1
Odds ratios from meta-analyses. Panels correspond to combined risk estimates associated with possessing (A) any GBA mutation, (B) mutation L444P (C) mutation N370S and (D) any GBA mutation excluding Japan and Norway study centers. Horizontal grey lines indicate 95% confidence intervals of estimates. Point estimates per study population are indicated by squares where height is inversely proportional to the standard error of the estimates. Diamonds represent the summary odds ratio whose width indicates the 95% confidence intervals.
Figure 1
Figure 1
Odds ratios from meta-analyses. Panels correspond to combined risk estimates associated with possessing (A) any GBA mutation, (B) mutation L444P (C) mutation N370S and (D) any GBA mutation excluding Japan and Norway study centers. Horizontal grey lines indicate 95% confidence intervals of estimates. Point estimates per study population are indicated by squares where height is inversely proportional to the standard error of the estimates. Diamonds represent the summary odds ratio whose width indicates the 95% confidence intervals.
Figure 1
Figure 1
Odds ratios from meta-analyses. Panels correspond to combined risk estimates associated with possessing (A) any GBA mutation, (B) mutation L444P (C) mutation N370S and (D) any GBA mutation excluding Japan and Norway study centers. Horizontal grey lines indicate 95% confidence intervals of estimates. Point estimates per study population are indicated by squares where height is inversely proportional to the standard error of the estimates. Diamonds represent the summary odds ratio whose width indicates the 95% confidence intervals.
Figure 2
Figure 2
The distribution of mutations identified. (A) Ashkenazi Jewish patients with Parkinson disease. 19.6% carried a GBA mutation. Insert demonstrates the distribution of the different mutations identified. (B) Non-Ashkenazi patients with Parkinson disease with full sequencing. 6.9% carried a GBA mutation. The insert shows that among the 117 mutations identified, 54% were not N370S or L444P.
Figure 3
Figure 3
Clinical manifestations of Parkinson disease reported in subjects without (teal) and with (orange) GBA mutations. The number of subjects with data recorded for each symptom is indicated in each respective bar. * = p-value<0.05; significant difference between clinical symptom of patients with and without a GBA mutation.

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