Variants associated with Gaucher disease in multiple system atrophy

Jun Mitsui, Takashi Matsukawa, Hidenao Sasaki, Ichiro Yabe, Masaaki Matsushima, Alexandra Dürr, Alexis Brice, Hiroshi Takashima, Akio Kikuchi, Masashi Aoki, Hiroyuki Ishiura, Tsutomu Yasuda, Hidetoshi Date, Budrul Ahsan, Atsushi Iwata, Jun Goto, Yaeko Ichikawa, Yasuo Nakahara, Yoshio Momose, Yuji Takahashi & 51 others Kenju Hara, Akiyoshi Kakita, Mitsunori Yamada, Hitoshi Takahashi, Osamu Onodera, Masatoyo Nishizawa, Hirohisa Watanabe, Mizuki Ito, Gen Sobue, Kinya Ishikawa, Hidehiro Mizusawa, Kazuaki Kanai, Takamichi Hattori, Satoshi Kuwabara, Kimihito Arai, Shigeru Koyano, Yoshiyuki Kuroiwa, Kazuko Hasegawa, Tatsuhiko Yuasa, Kenichi Yasui, Kenji Nakashima, Hijiri Ito, Yuishin Izumi, Ryuji Kaji, Takeo Kato, Susumu Kusunoki, Yasushi Osaki, Masahiro Horiuchi, Tomoyoshi Kondo, Shigeo Murayama, Nobutaka Hattori, Mitsutoshi Yamamoto, Miho Murata, Wataru Satake, Tatsushi Toda, Alessandro Filla, Thomas Klockgether, Ullrich Wüllner, Garth Nicholson, Sid Gilman, Caroline M. Tanner, Walter A. Kukull, Mathew B Stern, Virginia M Y Lee, John Q. Trojanowski, Eliezer Masliah, Phillip A. Low, Paola Sandroni, Laurie J Ozelius, Tatiana Foroud, Shoji Tsuji

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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 9 10(-3)). Interpretation: The findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA.

Original languageEnglish
Pages (from-to)417-426
Number of pages10
JournalAnnals of Clinical and Translational Neurology
Volume2
Issue number4
DOIs
Publication statusPublished - Apr 2015

Bibliographical note

Copyright the Author(s) 2015. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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    Mitsui, J., Matsukawa, T., Sasaki, H., Yabe, I., Matsushima, M., Dürr, A., ... Tsuji, S. (2015). Variants associated with Gaucher disease in multiple system atrophy. Annals of Clinical and Translational Neurology, 2(4), 417-426. https://doi.org/10.1002/acn3.185