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Original Contribution |

A Multicenter Study of Glucocerebrosidase Mutations in Dementia With Lewy Bodies

Michael A. Nalls, PhD; Raquel Duran, PhD; Grisel Lopez, MD; Marzena Kurzawa-Akanbi, PhD; Ian G. McKeith, FMedSci; Patrick F. Chinnery, PhD; Christopher M. Morris, PhD; Jessie Theuns, PhD; David Crosiers, MD, PhD; Patrick Cras, MD, PhD; Sebastiaan Engelborghs, MD, PhD; Peter Paul De Deyn, MD, PhD; Christine Van Broeckhoven, PhD, DSc; David M. A. Mann, PhD; Julie Snowden, PhD; Stuart Pickering-Brown, PhD; Nicola Halliwell, BSc; Yvonne Davidson, MSc; Linda Gibbons, MSc; Jenny Harris, BSc; Una-Marie Sheerin, MD; Jose Bras, PhD; John Hardy, PhD; Lorraine Clark, PhD; Karen Marder, MD, MPH; Lawrence S. Honig, MD, PhD; Daniela Berg, MD; Walter Maetzler, MD; Kathrin Brockmann, MD; Thomas Gasser, MD; Fabiana Novellino, MD; Aldo Quattrone, MD; Grazia Annesi, PhD; Elvira Valeria De Marco, PhD; Ekaterina Rogaeva, PhD; Mario Masellis, MD, PhD; Sandra E. Black, MD; Juan M. Bilbao, MD; Tatiana Foroud, PhD; Bernardino Ghetti, MD; William C. Nichols, PhD; Nathan Pankratz, PhD; Glenda Halliday, PhD; Suzanne Lesage, PhD; Stephan Klebe, MD, PhD; Alexandra Durr, MD, PhD; Charles Duyckaerts, MD, PhD; Alexis Brice, MD; Benoit I. Giasson, PhD; John Q. Trojanowski, MD, PhD; Howard I. Hurtig, MD; Nahid Tayebi, PhD; Claudia Landazabal; Melanie A. Knight, PhD; Margaux Keller, BA; Andrew B. Singleton, PhD; Tyra G. Wolfsberg, PhD; Ellen Sidransky, MD
JAMA Neurol. 2013;70(6):727-735. doi:10.1001/jamaneurol.2013.1925.
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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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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.

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