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A Risk Factor for Lewy Body Disorders

Ignacio F. Mata, PhD; Ali Samii, MD; Seth H. Schneer; John W. Roberts, MD; Alida Griffith, MD; Berta C. Leis, PhD, RN; Gerard D. Schellenberg, PhD; Ellen Sidransky, MD; Thomas D. Bird, MD; James B. Leverenz, MD; Debby Tsuang, MD, MSc; Cyrus P. Zabetian, MD, MS

Arch Neurol. 2008;65(3):379-382.

Background  Mutations in the glucocerebrosidase (GBA) gene have been reported to modify risk for Parkinson disease (PD) and dementia with Lewy bodies (DLB). However, these findings have not been consistently replicated, and most studies have had substantial methodological shortcomings.

Objective  To better assess the role of GBA variants in altering risk for Lewy body disorders.

Design  Case-control study.

Setting  Four movement disorder clinics in the Seattle, Washington, area.

Participants  Seven hundred twenty-one patients with PD, 554 healthy control subjects, and 57 patients with DLB.

Main Outcome Measures  Disease status and presence or absence of the 2 most common GBA mutations (N370S and L444P).

Results  We observed a significantly higher heterozygote frequency for the 2 mutations in patients with PD (2.9%; P <.001) and those with DLB (3.5%; P = .045) compared with control subjects (0.4%).

Conclusion  Our findings suggest that GBA mutations exert a large effect on susceptibility for Lewy body disorders at the individual level but are associated with a modest (approximately 3%) population-attributable risk in individuals of European ancestry.

Author Affiliations: Department of Neurology, University of Washington School of Medicine (Drs Mata, Samii, Schellenberg, Bird, Leverenz, and Zabetian), Geriatric Research Education and Clinical Center (Drs Mata, Schellenberg, Bird, and Zabetian), Mental Illness Research Education and Clinical Center (Drs Leverenz, Tsuang, and Zabetian), and Parkinson's Disease Research Education and Clinical Center (Drs Samii, Leverenz, and Zabetian), VA Puget Sound Health Care System, Virginia Mason Medical Center (Dr Roberts), and Departments of Medicine (Drs Schellenberg and Bird), Pharmacology (Dr Schellenberg), and Psychiatry and Behavioral Sciences (Drs Leverenz and Tsuang), University of Washington, Seattle; Department of Biology, Oberlin College, Oberlin, Ohio (Mr Schneer); Booth Gardner Parkinson's Care Center, Evergreen Hospital Medical Center, Kirkland, Washington (Drs Griffith and Leis); and Section on Molecular Neurogenetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland (Dr Sidransky).