Glucocerebrosidase as a genetic modifier influencing susceptibility and phenotype of Parkinson‘s disease

Abstract

Evaluation of: Sidransky E, Nalls MA, Aasly JO et al.: Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N. Engl. J. Med. 361, 1651–1661 (2009). This study aimed to substantiate the role of glucocerebrosidase (GBA) mutations in Parkinson’s disease (PD) by pooling clinical and genotypic data for 5691 PD patients and 4898 unaffected individuals from 16 international centers. Genotyping was performed for either two mutations (N370S and L444P) or for three to eight GBA mutations. One of the N370S and L444P mutations was found in 15 and 3% of PD patients of Ashkenazi and non-Ashkenazi Jewish origin, respectively. Whole gene sequencing performed in a subgroup of these patients revealed a combined odds ratio of carrying any GBA mutation of 5.43. Genotype–phenotype correlations verified that GBA mutation carriers were more likely to develop PD at an earlier age, have affected relatives and show increased incidence of cognitive changes compared with PD patients without mutations. This study provides evidence that heterozygosity for GBA mutations is the most common susceptibility factor for the onset of PD symptoms to date. It also highlights the need for further studies using large numbers of patients and controls in order to elucidate the effect(s) of GBA mutations on PD clinical manifestations and their role in the molecular mechanisms of PD pathogenesis.