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, 2 (4), 417-26

Variants Associated With Gaucher Disease in Multiple System Atrophy

Jun Mitsui  1 Takashi Matsukawa  1 Hidenao Sasaki  2 Ichiro Yabe  2 Masaaki Matsushima  2 Alexandra Dürr  3 Alexis Brice  3 Hiroshi Takashima  4 Akio Kikuchi  5 Masashi Aoki  5 Hiroyuki Ishiura  1 Tsutomu Yasuda  1 Hidetoshi Date  1 Budrul Ahsan  1 Atsushi Iwata  1 Jun Goto  1 Yaeko Ichikawa  1 Yasuo Nakahara  1 Yoshio Momose  1 Yuji Takahashi  1 Kenju Hara  6 Akiyoshi Kakita  7 Mitsunori Yamada  8 Hitoshi Takahashi  7 Osamu Onodera  6 Masatoyo Nishizawa  6 Hirohisa Watanabe  9 Mizuki Ito  9 Gen Sobue  9 Kinya Ishikawa  10 Hidehiro Mizusawa  10 Kazuaki Kanai  11 Takamichi Hattori  11 Satoshi Kuwabara  11 Kimihito Arai  12 Shigeru Koyano  13 Yoshiyuki Kuroiwa  14 Kazuko Hasegawa  15 Tatsuhiko Yuasa  16 Kenichi Yasui  17 Kenji Nakashima  17 Hijiri Ito  18 Yuishin Izumi  19 Ryuji Kaji  19 Takeo Kato  20 Susumu Kusunoki  21 Yasushi Osaki  22 Masahiro Horiuchi  23 Tomoyoshi Kondo  24 Shigeo Murayama  25 Nobutaka Hattori  26 Mitsutoshi Yamamoto  27 Miho Murata  28 Wataru Satake  29 Tatsushi Toda  29 Alessandro Filla  30 Thomas Klockgether  31 Ullrich Wüllner  31 Garth Nicholson  32 Sid Gilman  33 Caroline M Tanner  34 Walter A Kukull  35 Mathew B Stern  36 Virginia M-Y Lee  37 John Q Trojanowski  37 Eliezer Masliah  38 Phillip A Low  39 Paola Sandroni  39 Laurie J Ozelius  40 Tatiana Foroud  41 Shoji Tsuji  1
Affiliations

Variants Associated With Gaucher Disease in Multiple System Atrophy

Jun Mitsui et al. Ann Clin Transl Neurol.

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.

Figures

Figure 1
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 = 1.80, = 0.41; Breslow-Day = 1.99, = 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
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
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.

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