Mutations for Gaucher disease confer high susceptibility to Parkinson disease.
BACKGROUND
Increased frequency of pathogenic variants in GBA, the causative gene for Gaucher disease, has been suggested to be associated with Parkinson disease (PD).


OBJECTIVE
To conduct comprehensive resequencing of GBA to identify all sequence variants and to investigate the association of these variants with PD.


METHODS
Case-control study.


METHODS
Multicenter university-based study.


METHODS
Five hundred thirty-four patients with PD, 34 families in which multiple patients with PD are present, and 544 control subjects.


METHODS
Disease status and GBA variations.


RESULTS
Comprehensive resequencing of GBA in 534 patients with PD and 544 controls revealed 27 sequence variants: 11 pathogenic variants associated with Gaucher disease, 11 nonsynonymous variants not associated with Gaucher disease, and 5 synonymous variants. Fifty patients with PD (9.4%) had 1 of the 11 pathogenic variants in the heterozygous state, whereas only 2 controls (0.37%) had such variants (odds ratio, 28.0). Among the pathogenic variants, R120W and L444P/RecNciI were highly prevalent, and each showed a significant association with PD. Furthermore, other rare pathogenic variants were found in 13 patients with PD but not in the controls, further confirming the role of these rare variants in the susceptibility to PD. Patients with PD carrying pathogenic variants were significantly younger than those not carrying them. In addition, concordance of PD states and pathogenic variants was observed in 8 multiplex families with PD.


CONCLUSIONS
Heterozygous pathogenic variants in GBA confer a high risk for sporadic PD, even for familial clustering, and are associated with significantly earlier age at onset of disease.
Mitsui
Jun
J
Department of Neurology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-Ku, Tokyo 113-8655, Japan.
Mizuta
Ikuko
I
Toyoda
Atsushi
A
Ashida
Ryo
R
Takahashi
Yuji
Y
Goto
Jun
J
Fukuda
Yoko
Y
Date
Hidetoshi
H
Iwata
Atsushi
A
Yamamoto
Mitsutoshi
M
Hattori
Nobutaka
N
Murata
Miho
M
Toda
Tatsushi
T
Tsuji
Shoji
S
D017668:Age of Onset; D000368:Aged; D044466:Asian People / Q000235:genetics; D016000:Cluster Analysis; D004252:DNA Mutational Analysis; D005260:Female; D005776:Gaucher Disease / Q000201:enzymology / Q000235:genetics*; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D005962:Glucosylceramidase / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics*; D010375:Pedigree
D005962:Glucosylceramidase