Journal
JAMA NEUROLOGY
Volume 70, Issue 6, Pages 727-735Publisher
AMER MEDICAL ASSOC
DOI: 10.1001/jamaneurol.2013.1925
Keywords
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Funding
- UK Medical Research Council (MRC) [G1100540]
- 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
- Alzheimer's Society
- Alzheimer's Research Trust as part of the Brains for Dementia Research Project
- Parkinson's Disease UK [K-0901]
- National Research Agency in the ERANET NEURON framework [ANR-08-NEUR-004-01]
- program Investissements d'aveni [ANR-10-IAIHU-06]
- UK Lewy Body Disease Society
- UK Health Protection Agency
- Methusalem excellence program of the Flemish government
- Centre of Excellence grant from the University Research Fund of the University of Antwerp
- Research Foundation Flanders
- Agency for Innovation by Science and Technology Flanders
- Interuniversity Attraction Poles program of the Belgian Science Policy Office
- Foundation for Alzheimer Research Belgium
- Belgian Parkinson Foundation
- Alzheimers Research UK
- Alzheimer's Society under the Brains for Dementia Research initiative
- MRC
- Wellcome Trust
- Wellcome Trust/MRC Joint Call in Neurodegeneration [WT089698]
- Alfonso Martin Escudero Foundation
- Reta Lilla Trust
- National Institute of Neurological Disorders and Stroke, NIH [5R01NS060113, R56NS036630]
- National Institute on Aging, NIH [P50AG08702, 2R56NS037167, 2P30AG010133]
- Panasci Fund for Lewy Body Research
- Alzheimer Disease Drug Discovery Foundation
- Parkinson's Disease Foundation
- European Project on Mendelian Forms of Parkinson's Disease grant from the European Community's Seventh Framework Programme [241791, FP7/2007-2013]
- Canadian Institutes of Health Research
- New Investigator Award from the Parkinson Society Canada
- National Health and Medical Research Council of Australia [630434, 1008307]
- Agence Nationale pour la Recherche
- High Q
- National Institute of Neurological Disorders and Stroke [NS053488]
- Intramural Research Program of the National Human Genome Research Institute, NIH
- National Institute on Aging from the Intramural Research Program of the NIH [Z01 AG000949-02]
- MRC [G0701075, MR/L016451/1, G1100479, MC_PC_09003, MC_G1000735, G1100540, G0400074, G0502157, G0900652, MR/K000608/1, MC_G0901330] Funding Source: UKRI
- Medical Research Council [G1100479, MC_PC_09003, MR/K000608/1, MC_G1000735, G0701075, G0400074, G0502157, G1100540, MR/L016451/1, G0900652, MC_G0901330] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0509-10011, NF-SI-0611-10048] Funding Source: researchfish
- Parkinson's UK [G-1107] Funding Source: researchfish
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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.
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