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A Multicenter Study of Glucocerebrosidase Mutations in Dementia With Lewy Bodies

Lookup NU author(s): Dr Marzena Kurzawa-Akanbi, Professor Ian McKeith, Professor Patrick Chinnery, Dr Christopher Morris, Emeritus Professor John Harris

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Abstract

Importance: While mutations in glucocerebrosidase (GBA1) are associated with an increased risk for Parkinson disease (PD), it is important to establish whether such mutations are also a common risk factor for other Lewy body disorders. Objective: To establish whether GBA1 mutations are a risk factor for dementia with Lewy bodies (DLB). DESIGN We compared genotype data on patients and controls from 11 centers. Data concerning demographics, age at onset, disease duration, and clinical and pathological features were collected when available. We conducted pooled analyses using logistic regression to investigate GBA1 mutation carrier status as predicting DLB or PD with dementia status, using common control subjects as a reference group. Random-effects meta-analyses were conducted to account for additional heterogeneity. Setting: Eleven centers from sites around the world performing genotyping. Participants: Seven hundred twenty-one cases met diagnostic criteria for DLB and 151 had PD with dementia. We compared these cases with 1962 controls from the same centers matched for age, sex, and ethnicity. Main Outcome Measures: Frequency of GBA1 mutations in cases and controls. Results: We found a significant association between GBA1 mutation carrier status and DLB, with an odds ratio of 8.28 (95% CI, 4.78-14.88). The odds ratio for PD with dementia was 6.48 (95% CI, 2.53-15.37). The mean age at diagnosis of DLB was earlier in GBA1 mutation carriers than in noncarriers (63.5 vs 68.9 years; P < .001), with higher disease severity scores. Conclusions and Relevance: Mutations in GBA1 are a significant risk factor for DLB. GBA1 mutations likely play an even larger role in the genetic etiology of DLB than in PD, providing insight into the role of glucocerebrosidase in Lewy body disease.


Publication metadata

Author(s): Nalls MA, Duran R, Lopez G, Kurzawa-Akanbi M, McKeith IG, Chinnery PF, Morris CM, Theuns J, Crosiers D, Cras P, Engelborghs S, DeDeyn PP, Van Broeckhoven C, Mann DM, Snowden J, Pickering-Brown S, Halliwell N, Davidson Y, Gibbons L, Harris J, Sheerin UM, Bras J, Hardy J, Clark L, Marder K, Honig LS, Berg D, Maetzler W, Brockmann K, Gasser T, Novellino F, Quattrone A, Annesi G, De Marco EV, Rogaeva E, Masellis M, Black SE, Bilbao JM, Foroud T, Ghetti B, Nichols WC, Pankratz N, Halliday G, Lesage S, Klebe S, Durr A, Duyckaerts C, Brice A, Giasson BI, Trojanowski JQ, Hurtig HI, Tayebi N, Landazabal C, Knight MA, Keller M, Singleton AB, Wolfsberg TG, Sidransky E

Publication type: Article

Publication status: Published

Journal: JAMA Neurology

Year: 2013

Volume: 70

Issue: 6

Pages: 727-735

Print publication date: 01/06/2013

Online publication date: 15/04/2013

Acceptance date: 21/11/2012

ISSN (print): 2168-6149

ISSN (electronic): 2168-6157

Publisher: American Medical Association

URL: http://dx.doi.org/10.1001/jamaneurol.2013.1925

DOI: 10.1001/jamaneurol.2013.1925


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Funding

Funder referenceFunder name
Agence Nationale pour la Recherche
Agency for Innovation by Science and Technology Flanders
Alfonso Martin Escudero Foundation
Canadian Institutes of Health Research
Interuniversity Attraction Poles program of the Belgian Science Policy Office
MRC
New Investigator Award from the Parkinson Society Canada
UK Health Protection Agency
UK Lewy Body Disease Society
Wellcome Trust
Alzheimer Disease Drug Discovery Foundation
Alzheimer's Research Trust as part of the Brains for Dementia Research Project
Alzheimers Research UK
Alzheimer's Society
Alzheimer's Society under the Brains for Dementia Research initiative
Belgian Parkinson Foundation
Centre of Excellence grant from the University Research Fund of the University of Antwerp
Foundation for Alzheimer Research Belgium
High Q
Intramural Research Program of the National Human Genome Research Institute, NIH
Methusalem excellence program of the Flemish government
Panasci Fund for Lewy Body Research
Parkinson's Disease Foundation
Research Foundation Flanders
Reta Lilla Trust
UK National Institute for Health Research (NIHR) Biomedical Research Centre in Ageing and Age Related Diseases
UK National Institute for Health Research (NIHR) Biomedical Research Unit in Lewy Body Disease
1008307National Health and Medical Research Council of Australia
2P30AG010133National Institute on Aging, NIH
5R01NS060113National Institute of Neurological Disorders and Stroke, NIH
241791European Project on Mendelian Forms of Parkinson's Disease grant from the European Community's Seventh Framework Programme
ANR-08-NEUR-004-01National Research Agency in the ERANET NEURON framework
2R56NS037167National Institute on Aging, NIH
630434National Health and Medical Research Council of Australia
ANR-10-IAIHU-06program Investissements d'aveni
FP7/2007-2013European Project on Mendelian Forms of Parkinson's Disease grant from the European Community's Seventh Framework Programme
G1100540UK Medical Research Council (MRC)
K-0901Parkinson's Disease UK
R56NS036630National Institute of Neurological Disorders and Stroke, NIH
NS053488National Institute of Neurological Disorders and Stroke
P50AG08702National Institute on Aging, NIH
WT089698Wellcome Trust/MRC Joint Call in Neurodegeneration
Z01 AG000949-02National Institute on Aging from the Intramural Research Program of the NIH

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