Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease

Ellen Sidransky, Michael A. Nalls, Jan O. Aasly, Judith Aharon-Peretz, Grazia Annesi, Egberto R. Barbosa, Anat Bar-Shira, Daniela Berg, Jose Bras, Alexis Brice, Chiung Mei Chen, Lorraine N. Clark, Christel Condroyer, Elvira V. De Marco, Alexandra Dürr, Michael J. Eblan, Stanley Fahn, Matthew J. Farrer, Hon Chung Fung, Ziv Gan-OrThomas Gasser, Ruth Gershoni-Baruch, Nir Giladi, Alida Griffith, Tanya Gurevich, Cristina Januario, Peter Kropp, Anthony E. Lang, Guey Jen Lee-Chen, Suzanne Lesage, Karen Marder, Ignacio F. Mata, Anat Mirelman, Jun Mitsui, Ikuko Mizuta, Giuseppe Nicoletti, Catarina Oliveira, Ruth Ottman, Avi Orr-Urtreger, Lygia V. Pereira, Aldo Quattrone, Ekaterina Rogaeva, Arndt Rolfs, Hanna Rosenbaum, Roberto Rozenberg, Ali Samii, Ted Samaddar, Claudia Schulte, Manu Sharma, Andrew Singleton, Mariana Spitz, Eng King Tan, Nahid Tayebi, Tatsushi Toda, André R. Troiano, Shoji Tsuji, Matthias Wittstock, Tyra G. Wolfsberg, Yih Ru Wu, Cyrus P. Zabetian, Yi Zhao, Shira G. Ziegler

Research output: Contribution to journalArticlepeer-review

1599 Scopus citations


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.

Original languageEnglish
Pages (from-to)1651-1661
Number of pages11
JournalNew England Journal of Medicine
Issue number17
StatePublished - 22 Oct 2009
Externally publishedYes

ASJC Scopus subject areas

  • General Medicine


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