Mutations in glucocerebrosidase are a major genetic risk factor for Parkinson’s disease and increase susceptibility to dementia in a Flanders-Belgian cohort

• GBA mutations are a strong genetic risk factor for Parkinson disease (PD).
• A heterozygous GBA mutation was identified in 4.5% of PD patients.
• More severe PD motor symptoms are observed in GBA mutation carriers.
• GBA mutation status is an independent predictor for dementia in PD patients.

ObjectiveTo investigate the frequency of glucocerebrosidase (GBA) mutations in a Flanders-Belgian Parkinson’s disease (PD) patient cohort and to assess genotype-phenotype correlations.MethodsWe performed an in-depth sequencing of all coding exons of GBA in 266 clinically well-characterized PD patients and 536 healthy control individuals.ResultsWe 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.ConclusionIn 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.