title: GBA mutations increase risk for Lewy body disease with and without Alzheimer disease pathology.
abstract: OBJECTIVE
  Mutations in the GBA gene occur in 7% of patients with Parkinson disease (PD) and are a well-established susceptibility factor for PD, which is characterized by Lewy body disease (LBD) neuropathologic changes (LBDNCs). We sought to determine whether GBA influences risk of dementia with LBDNCs, Alzheimer disease (AD) neuropathologic changes (ADNCs), or both.
  
  
  METHODS
  We screened the entire GBA coding region for mutations in controls and in subjects with dementia and LBDNCs and no or low levels of ADNCs (pure dementia with Lewy bodies [pDLB]), LBDNCs and high-level ADNCs (LBD-AD), and high-level ADNCs but without LBDNCs (AD).
  
  
  RESULTS
  Among white subjects, pathogenic GBA mutations were identified in 6 of 79 pDLB cases (7.6%), 8 of 222 LBD-AD cases (3.6%), 2 of 243 AD cases (0.8%), and 3 of 381 controls (0.8%). Subjects with pDLB and LBD-AD were more likely to carry mutations than controls (pDLB: odds ratio [OR] = 7.6; 95% confidence interval [CI] = 1.8-31.9; p = 0.006; LBD-AD: OR = 4.6; CI = 1.2-17.6; p = 0.025), but there was no significant difference in frequencies between the AD and control groups (OR = 1.1; CI = 0.2-6.6; p = 0.92). There was a highly significant trend test across groups (χ(2)(1) = 19.3; p = 1.1 × 10(-5)), with the likelihood of carrying a GBA mutation increasing in the following direction: control/AD < LBD-AD < pDLB.
  
  
  CONCLUSIONS
  GBA is a susceptibility gene across the LBD spectrum, but not in AD, and appears to convey a higher risk for PD and pDLB than for LBD-AD. PD and pDLB might be more similar to one another in genetic determinants and pathophysiology than either disease is to LBD-AD.
authors.affiliation: Veterans Affairs Puget Sound Health Care System Seattle, WA, USA. dwt1@uw.edu
authors.forename: Debby
authors.initials: D
authors.lastname: Tsuang
authors.forename: James B
authors.initials: JB
authors.lastname: Leverenz
authors.forename: Oscar L
authors.initials: OL
authors.lastname: Lopez
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Hamilton
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.forename: Julie A
authors.initials: JA
authors.lastname: Schneider
authors.forename: Aron S
authors.initials: AS
authors.lastname: Buchman
authors.forename: Eric B
authors.initials: EB
authors.lastname: Larson
authors.forename: Paul K
authors.initials: PK
authors.lastname: Crane
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Kaye
authors.forename: Patricia
authors.initials: P
authors.lastname: Kramer
authors.forename: Randy
authors.initials: R
authors.lastname: Woltjer
authors.forename: Walter
authors.initials: W
authors.lastname: Kukull
authors.forename: Peter T
authors.initials: PT
authors.lastname: Nelson
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Jicha
authors.forename: Janna H
authors.initials: JH
authors.lastname: Neltner
authors.forename: Doug
authors.initials: D
authors.lastname: Galasko
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.forename: Dora
authors.initials: D
authors.lastname: Yearout
authors.forename: Haley
authors.initials: H
authors.lastname: Huston
authors.forename: Allison
authors.initials: A
authors.lastname: Fritts-Penniman
authors.forename: Ignacio F
authors.initials: IF
authors.lastname: Mata
authors.forename: Jia Y
authors.initials: JY
authors.lastname: Wan
authors.forename: Karen L
authors.initials: KL
authors.lastname: Edwards
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
authors.forename: Cyrus P
authors.initials: CP
authors.lastname: Zabetian
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications / Q000473:pathology*; D004252:DNA Mutational Analysis; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology; D005962:Glucosylceramidase / Q000235:genetics*; D006801:Humans; D020961:Lewy Body Disease / Q000150:complications / Q000235:genetics*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009154:Mutation; D059645:Mutation Rate; D012307:Risk Factors; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D051844:alpha-Synuclein; D005962:Glucosylceramidase