A multicenter study of glucocerebrosidase mutations in dementia with Lewy bodies

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Crosiers reports receiving travel support from Abbott and Boehringer Ingelheim. Dr Brockmann reports receiving speaker honoraria from Deutsche Gesellschaft für klinische Neurophysiologie, GlaxoSmithKline, and Orion Corporation. Dr Berg reports receiving consultation fees from UCB Schwarz Pharma, Merz, and Novartis; payment for lectures from Teva, GSC, Lundbeck, and UCB Schwarz Pharma; and grant support from Janssen Pharmaceutica, Teva, Michael J. Fox Foundation, the Federal Ministry of Education and Research, Abbott, Boehringer, German Parkinson’s Disease Association, and the Center for Integrative Neurosciences. Dr Gasser reports receiving consultation fees from Cefalon Pharma and Merck-Serono; lecture fees from Valeant Pharma, Merck-Serono, UCB-Pharma, and Boehringer; and grant support from Novartis Pharma, European Union, Helmholtz Association, and the Federal Ministry of Education and Research. Dr Maetzler reports receiving lecture fees from GlaxoSmithKline and grant support from the Robert Bosch Foundation. Dr Masellis reports receiving speaker honoraria from Novartis and EMD Serono, Inc; serving as an associate editor for Current Pharmacogenomics and Personalized Medicine; receiving publishing royalties from Henry Stewart Talks; serving as a consultant for Bioscape Medical Imaging CRO; and receiving research support from the Canadian Institutes of Health Research, Parkinson Society Canada, an Early Researcher Award from the Ministry of Economic Development and Innovation of Ontario, Teva Pharmaceutical Industries Ltd, and the Department of Medicine, Sunnybrook Health Sciences Centre. Dr Black reports receiving contract research funds to the Cognitive Neurology Research and Stroke Research Units from Roche, GlaxoSmithKline, Novartis, Myriad, Pfizer, sanofi-aventis, Boehringer Ingelheim, Lundbeck, Novo Nordisk, and AstraZeneca and honoraria from Janssen-Ortho, Novartis, Lundbeck, Pfizer, Eisai, Myriad, GlaxoSmithKline, Roche, Schering-Plough, Elan, Wyeth, and Bristol-Myers Squibb. Dr Ghetti reports receiving support from Elan and Bayer Schering Pharma AG. Dr Nichols reports receiving support from the National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH).

Figures

Figure

Forest plots detailing study analyses. A, Stratification by genotyping method differentiated by depth of screening. B, Stratification by clinically vs pathologically based diagnoses. OR indicates odds ratio.