title: Mutations in GBA are associated with familial Parkinson disease susceptibility and age at onset.
abstract: OBJECTIVE
  To characterize sequence variation within the glucocerebrosidase (GBA) gene in a select subset of our sample of patients with familial Parkinson disease (PD) and then to test in our full sample whether these sequence variants increased the risk for PD and were associated with an earlier onset of disease.
  
  
  METHODS
  We performed a comprehensive study of all GBA exons in one patient with PD from each of 96 PD families, selected based on the family-specific lod scores at the GBA locus. Identified GBA variants were subsequently screened in all 1325 PD cases from 566 multiplex PD families and in 359 controls.
  
  
  RESULTS
  Nine different GBA variants, five previously reported, were identified in 21 of the 96 PD cases sequenced. Screening for these variants in the full sample identified 161 variant carriers (12.2%) in 99 different PD families. An unbiased estimate of the frequency of the five previously reported GBA variants in the familial PD sample was 12.6% and in the control sample was 5.3% (odds ratio 2.6; 95% confidence interval 1.5-4.4). Presence of a GBA variant was associated with an earlier age at onset (p = 0.0001). On average, those patients carrying a GBA variant had onset with PD 6.04 years earlier than those without a GBA variant.
  
  
  CONCLUSIONS
  This study suggests that GBA is a susceptibility gene for familial Parkinson disease (PD) and patients with GBA variants have an earlier age at onset than patients with PD without GBA variants.
authors.affiliation: Associate Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. bill.nichols@cchmc.org
authors.forename: W C
authors.initials: WC
authors.lastname: Nichols
authors.forename: N
authors.initials: N
authors.lastname: Pankratz
authors.forename: D K
authors.initials: DK
authors.lastname: Marek
authors.forename: M W
authors.initials: MW
authors.lastname: Pauciulo
authors.forename: V E
authors.initials: VE
authors.lastname: Elsaesser
authors.forename: C A
authors.initials: CA
authors.lastname: Halter
authors.forename: A
authors.initials: A
authors.lastname: Rudolph
authors.forename: J
authors.initials: J
authors.lastname: Wojcieszek
authors.forename: R F
authors.initials: RF
authors.lastname: Pfeiffer
authors.forename: T
authors.initials: T
authors.lastname: Foroud
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology* / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics; D005962:Glucosylceramidase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000201:enzymology / Q000453:epidemiology* / Q000235:genetics*
chemical_list: D005962:Glucosylceramidase