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 journalArticle

943 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1651-1661
Number of pages11
JournalNew England Journal of Medicine
Volume361
Issue number17
DOIs
Publication statusPublished - 2009 Oct 22

Fingerprint

Glucosylceramidase
Parkinson Disease
Mutation
Jews
Gaucher Disease
Mutation Rate
Logistic Models
Odds Ratio
Israel
Alleles
Genotype

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Sidransky, E., Nalls, M. A., Aasly, J. O., Aharon-Peretz, J., Annesi, G., Barbosa, E. R., ... Ziegler, S. G. (2009). Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. New England Journal of Medicine, 361(17), 1651-1661. https://doi.org/10.1056/NEJMoa0901281

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

In: New England Journal of Medicine, Vol. 361, No. 17, 22.10.2009, p. 1651-1661.

Research output: Contribution to journalArticle

Sidransky, E, Nalls, MA, Aasly, JO, Aharon-Peretz, J, Annesi, G, Barbosa, ER, Bar-Shira, A, Berg, D, Bras, J, Brice, A, Chen, CM, Clark, LN, Condroyer, C, De Marco, EV, Dürr, A, Eblan, MJ, Fahn, S, Farrer, MJ, Fung, HC, Gan-Or, Z, Gasser, T, Gershoni-Baruch, R, Giladi, N, Griffith, A, Gurevich, T, Januario, C, Kropp, P, Lang, AE, Lee-Chen, GJ, Lesage, S, Marder, K, Mata, IF, Mirelman, A, Mitsui, J, Mizuta, I, Nicoletti, G, Oliveira, C, Ottman, R, Orr-Urtreger, A, Pereira, LV, Quattrone, A, Rogaeva, E, Rolfs, A, Rosenbaum, H, Rozenberg, R, Samii, A, Samaddar, T, Schulte, C, Sharma, M, Singleton, A, Spitz, M, Tan, EK, Tayebi, N, Toda, T, Troiano, AR, Tsuji, S, Wittstock, M, Wolfsberg, TG, Wu, YR, Zabetian, CP, Zhao, Y & Ziegler, SG 2009, 'Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease', New England Journal of Medicine, vol. 361, no. 17, pp. 1651-1661. https://doi.org/10.1056/NEJMoa0901281
Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. New England Journal of Medicine. 2009 Oct 22;361(17):1651-1661. https://doi.org/10.1056/NEJMoa0901281
Sidransky, Ellen ; Nalls, Michael A. ; Aasly, Jan O. ; Aharon-Peretz, Judith ; Annesi, Grazia ; Barbosa, Egberto R. ; Bar-Shira, Anat ; Berg, Daniela ; Bras, Jose ; Brice, Alexis ; Chen, Chiung Mei ; Clark, Lorraine N. ; Condroyer, Christel ; De Marco, Elvira V. ; Dürr, Alexandra ; Eblan, Michael J. ; Fahn, Stanley ; Farrer, Matthew J. ; Fung, Hon Chung ; Gan-Or, Ziv ; Gasser, Thomas ; Gershoni-Baruch, Ruth ; Giladi, Nir ; Griffith, Alida ; Gurevich, Tanya ; Januario, Cristina ; Kropp, Peter ; Lang, Anthony E. ; Lee-Chen, Guey Jen ; Lesage, Suzanne ; Marder, Karen ; Mata, Ignacio F. ; Mirelman, Anat ; Mitsui, Jun ; Mizuta, Ikuko ; Nicoletti, Giuseppe ; Oliveira, Catarina ; Ottman, Ruth ; Orr-Urtreger, Avi ; Pereira, Lygia V. ; Quattrone, Aldo ; Rogaeva, Ekaterina ; Rolfs, Arndt ; Rosenbaum, Hanna ; Rozenberg, Roberto ; Samii, Ali ; Samaddar, Ted ; Schulte, Claudia ; Sharma, Manu ; Singleton, Andrew ; Spitz, Mariana ; Tan, Eng King ; Tayebi, Nahid ; Toda, Tatsushi ; Troiano, André R. ; Tsuji, Shoji ; Wittstock, Matthias ; Wolfsberg, Tyra G. ; Wu, Yih Ru ; Zabetian, Cyrus P. ; Zhao, Yi ; Ziegler, Shira G. / Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. In: New England Journal of Medicine. 2009 ; Vol. 361, No. 17. pp. 1651-1661.
@article{473b72a30ab444e8b9244ab265c01e36,
title = "Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease",
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.",
author = "Ellen Sidransky and Nalls, {Michael A.} and Aasly, {Jan O.} and Judith Aharon-Peretz and Grazia Annesi and Barbosa, {Egberto R.} and Anat Bar-Shira and Daniela Berg and Jose Bras and Alexis Brice and Chen, {Chiung Mei} and Clark, {Lorraine N.} and Christel Condroyer and {De Marco}, {Elvira V.} and Alexandra D{\"u}rr and Eblan, {Michael J.} and Stanley Fahn and Farrer, {Matthew J.} and Fung, {Hon Chung} and Ziv Gan-Or and Thomas Gasser and Ruth Gershoni-Baruch and Nir Giladi and Alida Griffith and Tanya Gurevich and Cristina Januario and Peter Kropp and Lang, {Anthony E.} and Lee-Chen, {Guey Jen} and Suzanne Lesage and Karen Marder and Mata, {Ignacio F.} and Anat Mirelman and Jun Mitsui and Ikuko Mizuta and Giuseppe Nicoletti and Catarina Oliveira and Ruth Ottman and Avi Orr-Urtreger and Pereira, {Lygia V.} and Aldo Quattrone and Ekaterina Rogaeva and Arndt Rolfs and Hanna Rosenbaum and Roberto Rozenberg and Ali Samii and Ted Samaddar and Claudia Schulte and Manu Sharma and Andrew Singleton and Mariana Spitz and Tan, {Eng King} and Nahid Tayebi and Tatsushi Toda and Troiano, {Andr{\'e} R.} and Shoji Tsuji and Matthias Wittstock and Wolfsberg, {Tyra G.} and Wu, {Yih Ru} and Zabetian, {Cyrus P.} and Yi Zhao and Ziegler, {Shira G.}",
year = "2009",
month = "10",
day = "22",
doi = "10.1056/NEJMoa0901281",
language = "English",
volume = "361",
pages = "1651--1661",
journal = "New England Journal of Medicine",
issn = "0028-4793",
publisher = "Massachussetts Medical Society",
number = "17",

}

TY - JOUR

T1 - Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease

AU - Sidransky, Ellen

AU - Nalls, Michael A.

AU - Aasly, Jan O.

AU - Aharon-Peretz, Judith

AU - Annesi, Grazia

AU - Barbosa, Egberto R.

AU - Bar-Shira, Anat

AU - Berg, Daniela

AU - Bras, Jose

AU - Brice, Alexis

AU - Chen, Chiung Mei

AU - Clark, Lorraine N.

AU - Condroyer, Christel

AU - De Marco, Elvira V.

AU - Dürr, Alexandra

AU - Eblan, Michael J.

AU - Fahn, Stanley

AU - Farrer, Matthew J.

AU - Fung, Hon Chung

AU - Gan-Or, Ziv

AU - Gasser, Thomas

AU - Gershoni-Baruch, Ruth

AU - Giladi, Nir

AU - Griffith, Alida

AU - Gurevich, Tanya

AU - Januario, Cristina

AU - Kropp, Peter

AU - Lang, Anthony E.

AU - Lee-Chen, Guey Jen

AU - Lesage, Suzanne

AU - Marder, Karen

AU - Mata, Ignacio F.

AU - Mirelman, Anat

AU - Mitsui, Jun

AU - Mizuta, Ikuko

AU - Nicoletti, Giuseppe

AU - Oliveira, Catarina

AU - Ottman, Ruth

AU - Orr-Urtreger, Avi

AU - Pereira, Lygia V.

AU - Quattrone, Aldo

AU - Rogaeva, Ekaterina

AU - Rolfs, Arndt

AU - Rosenbaum, Hanna

AU - Rozenberg, Roberto

AU - Samii, Ali

AU - Samaddar, Ted

AU - Schulte, Claudia

AU - Sharma, Manu

AU - Singleton, Andrew

AU - Spitz, Mariana

AU - Tan, Eng King

AU - Tayebi, Nahid

AU - Toda, Tatsushi

AU - Troiano, André R.

AU - Tsuji, Shoji

AU - Wittstock, Matthias

AU - Wolfsberg, Tyra G.

AU - Wu, Yih Ru

AU - Zabetian, Cyrus P.

AU - Zhao, Yi

AU - Ziegler, Shira G.

PY - 2009/10/22

Y1 - 2009/10/22

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=70350319531&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70350319531&partnerID=8YFLogxK

U2 - 10.1056/NEJMoa0901281

DO - 10.1056/NEJMoa0901281

M3 - Article

C2 - 19846850

AN - SCOPUS:70350319531

VL - 361

SP - 1651

EP - 1661

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 17

ER -