title: Mutations in glucocerebrosidase are a major genetic risk factor for Parkinson's disease and increase susceptibility to dementia in a Flanders-Belgian cohort.
abstract: To investigate the frequency of glucocerebrosidase (GBA) mutations in a Flanders-Belgian Parkinson's disease (PD) patient cohort and to assess genotype-phenotype correlations.
  
  
  
  We performed an in-depth sequencing of all coding exons of GBA in 266 clinically well-characterized PD patients and 536 healthy control individuals.
  
  
  
  We identified rare, heterozygous GBA mutations in 12 PD patients (4.5%) and in 2 healthy control individuals (0.37%), confirming the genetic association of GBA mutations with PD in the Flanders-Belgian population (p<0.001). The patient carriers had a more severe Unified Parkinson's Disease Rating Scale (UPDRS) motor score than non-carriers. Also, GBA mutation status was a significant, independent predictor for the presence of dementia (OR=12.43, 95% CI: 2.27-68.14. p=0.004). Genetic association of PD with the common p.E326K and p.T369M variants in GBA was absent.
  
  
  
  In our Flanders-Belgian cohort, carrier status of a heterozygous GBA mutation was a strong genetic risk factor for PD. The GBA mutation frequency of 4.5% is comparable to previously reported data in other European PD patient cohorts. Furthermore, our clinical data suggest a more severe motor phenotype and a strong predisposition to dementia in GBA mutation carriers.
authors.affiliation: Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Department of Neurology, Antwerp University Hospital, Edegem, Belgium. Electronic address: david.crosiers@uza.be.
authors.forename: David
authors.initials: D
authors.lastname: Crosiers
authors.affiliation: Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Aline
authors.initials: A
authors.lastname: Verstraeten
authors.affiliation: Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Eline
authors.initials: E
authors.lastname: Wauters
authors.affiliation: Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Department of Neurology, Hospital Network Antwerp, Middelheim, Antwerp, Belgium.
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Engelborghs
authors.affiliation: Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Karin
authors.initials: K
authors.lastname: Peeters
authors.affiliation: Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Maria
authors.initials: M
authors.lastname: Mattheijssens
authors.affiliation: Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Department of Neurology, Hospital Network Antwerp, Middelheim, Antwerp, Belgium.
authors.forename: Peter P
authors.initials: PP
authors.lastname: De Deyn
authors.affiliation: Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Jessie
authors.initials: J
authors.lastname: Theuns
authors.affiliation: Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
authors.affiliation: Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Cras
mesh_terms: D000368:Aged; D001530:Belgium; D015331:Cohort Studies; D003704:Dementia / Q000150:complications / Q000235:genetics*; D005091:Exons; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005962:Glucosylceramidase / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010300:Parkinson Disease / Q000150:complications / Q000235:genetics*; D010641:Phenotype; D012307:Risk Factors; D012720:Severity of Illness Index
chemical_list: D005962:Glucosylceramidase
keywords: GBA; Genotype-phenotype correlation; Glucocerebrosidase; Parkinson’s disease