Variants associated with Gaucher disease in multiple system atrophy

Abstract

Objective: Glucocerebrosidase gene (GBA) variants that cause Gaucher disease are associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). To investigate the role of GBA variants in multiple system atrophy (MSA), we analyzed GBA variants in a large case-control series.

Methods: We sequenced coding regions and flanking splice sites of GBA in 969 MSA patients (574 Japanese, 223 European, and 172 North American) and 1509 control subjects (900 Japanese, 315 European, and 294 North American). We focused solely on Gaucher-disease-causing GBA variants.

Results: In the Japanese series, we found nine carriers among the MSA patients (1.65%) and eight carriers among the control subjects (0.89%). In the European series, we found three carriers among the MSA patients (1.35%) and two carriers among the control subjects (0.63%). In the North American series, we found five carriers among the MSA patients (2.91%) and one carrier among the control subjects (0.34%). Subjecting each series to a Mantel-Haenszel analysis yielded a pooled odds ratio (OR) of 2.44 (95% confidence interval [CI], 1.14-5.21) and a P-value of 0.029 without evidence of significant heterogeneity. Logistic regression analysis yielded similar results, with an adjusted OR of 2.43 (95% CI 1.15-5.37) and a P-value of 0.022. Subtype analysis showed that Gaucher-disease-causing GBA variants are significantly associated with MSA cerebellar subtype (MSA-C) patients (P = 7.3 × 10(-3)).

Interpretation: The findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA.

Figure 1

Odds ratios for GD-causing GBA variants among MSA patients, as compared with controls, at each case–control series and overall. Shown are the combined estimates (on a log₁₀ scale) of the odds ratios for carrying GD variants. The odds ratio estimate is marked with a solid black square. The lines represent the 95% confidence interval of odds ratio estimate. The size of the square represents the weight that the corresponding series exerts in the Mantel–Haenszel analysis. Confidence intervals of pooled odds ratios are displayed as a horizontal line through the diamond. The heterogeneity of odds ratio of each series from the Mantel–Haenszel analysis was not significant (Cochran Q = 1.80, P = 0.41; Breslow-Day = 1.99, P = 0.37; I² = 0%), indicating that there is no effect modification by the series (population). GBA, Glucocerebrosidase; MSA, multiple system atrophy; GD, Gaucher disease.

Figure 2

Identification of Gaucher-disease-causing GBA variants in sib-pairs with coincidence of MSA and PD. Squares represent men; circles, women; black symbols, individuals with MSA; gray symbols, individuals with PD; open symbols, unaffected individuals; dots, genomic DNAs available. GBA, Glucocerebrosidase; MSA-C, multiple system atrophy of the cerebellar type; MSA-P, multiple system atrophy with predominant parkinsonism; PD, Parkinson disease; NM, nonmutated allele.

Figure 3

Identification of Gaucher-disease-causing GBA variants in a multiplex family with MSA. The diagnosis of definite MSA in III-6 in Family 8 was confirmed by autopsy findings. Squares represent men; circles, women; black symbols, individuals with MSA; gray symbols, individuals with PD; open symbols, unaffected individuals; dots, genomic DNAs available. GBA, Glucocerebrosidase; MSA-P, multiple system atrophy with predominant parkinsonism; PD, Parkinson disease; NM, nonmutated allele.