A functional variant in ZNF512B is associated with susceptibility to amyotrophic lateral sclerosis in Japanese

Aritoshi Iida; Atsushi Takahashi; Michiaki Kubo; Susumu Saito; Naoya Hosono; Yozo Ohnishi; Kazuma Kiyotani; Taisei Mushiroda; Masahiro Nakajima; Kouichi Ozaki; Toshihiro Tanaka; Tatsuhiko Tsunoda; Shuichi Oshima; Motoki Sano; Tetsumasa Kamei; Torao Tokuda; Masashi Aoki; Kazuko Hasegawa; Koichi Mizoguchi; Mitsuya Morita; Yuji Takahashi; Masahisa Katsuno; Naoki Atsuta; Hirohisa Watanabe; Fumiaki Tanaka; Ryuji Kaji; Imaharu Nakano; Naoyuki Kamatani; Shoji Tsuji; Gen Sobue; Yusuke Nakamura; Shiro Ikegawa

doi:10.1093/hmg/ddr268

A functional variant in ZNF512B is associated with susceptibility to amyotrophic lateral sclerosis in Japanese

Aritoshi Iida, Atsushi Takahashi, Michiaki Kubo, Susumu Saito, Naoya Hosono, Yozo Ohnishi, Kazuma Kiyotani, Taisei Mushiroda, Masahiro Nakajima, Kouichi Ozaki, Toshihiro Tanaka, Tatsuhiko Tsunoda, Shuichi Oshima, Motoki Sano, Tetsumasa Kamei, Torao Tokuda, Masashi Aoki, Kazuko Hasegawa, Koichi Mizoguchi, Mitsuya MoritaYuji Takahashi, Masahisa Katsuno, Naoki Atsuta, Hirohisa Watanabe, Fumiaki Tanaka, Ryuji Kaji, Imaharu Nakano, Naoyuki Kamatani, Shoji Tsuji, Gen Sobue, Yusuke Nakamura, Shiro Ikegawa

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Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. Several susceptibility genes for ALS have been reported; however, ALS etiology and pathogenesis remain largely unknown. To identify further ALS-susceptibility genes,we conducted a large-scale case-control association study using gene-based tag single-nucleotide polymorphisms (SNPs). A functional SNP (rs2275294) was found to be significantly associated with ALS through a stepwise screening approach (combined P 5 9.3 3 10210, odds ratio 5 1.32). The SNP was located in an enhancer region of ZNF512B, a transcription factor of unknown biological function, and the susceptibility allele showed decreased activity and decreased binding to nuclear proteins. ZNF512B over-expression increased transforming growth factor-b (TGF-b) signaling, while knockdown had the opposite effect. ZNF512B expression was increased in the anterior horn motor neurons of the spinal cord of ALS patients when compared with controls. Our results strongly suggest that ZNF512B is an important positive regulator of TGF-b signaling and that decreased ZNF512B expression increases susceptibility to ALS.

Original language	English
Article number	ddr268
Pages (from-to)	3684-3692
Number of pages	9
Journal	Human molecular genetics
Volume	20
Issue number	18
DOIs	https://doi.org/10.1093/hmg/ddr268
Publication status	Published - 09-2011

All Science Journal Classification (ASJC) codes

Molecular Biology
Genetics
Genetics(clinical)

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Iida, A., Takahashi, A., Kubo, M., Saito, S., Hosono, N., Ohnishi, Y., Kiyotani, K., Mushiroda, T., Nakajima, M., Ozaki, K., Tanaka, T., Tsunoda, T., Oshima, S., Sano, M., Kamei, T., Tokuda, T., Aoki, M., Hasegawa, K., Mizoguchi, K., ... Ikegawa, S. (2011). A functional variant in ZNF512B is associated with susceptibility to amyotrophic lateral sclerosis in Japanese. Human molecular genetics, 20(18), 3684-3692. [ddr268]. https://doi.org/10.1093/hmg/ddr268

Iida, Aritoshi ; Takahashi, Atsushi ; Kubo, Michiaki ; Saito, Susumu ; Hosono, Naoya ; Ohnishi, Yozo ; Kiyotani, Kazuma ; Mushiroda, Taisei ; Nakajima, Masahiro ; Ozaki, Kouichi ; Tanaka, Toshihiro ; Tsunoda, Tatsuhiko ; Oshima, Shuichi ; Sano, Motoki ; Kamei, Tetsumasa ; Tokuda, Torao ; Aoki, Masashi ; Hasegawa, Kazuko ; Mizoguchi, Koichi ; Morita, Mitsuya ; Takahashi, Yuji ; Katsuno, Masahisa ; Atsuta, Naoki ; Watanabe, Hirohisa ; Tanaka, Fumiaki ; Kaji, Ryuji ; Nakano, Imaharu ; Kamatani, Naoyuki ; Tsuji, Shoji ; Sobue, Gen ; Nakamura, Yusuke ; Ikegawa, Shiro. / A functional variant in ZNF512B is associated with susceptibility to amyotrophic lateral sclerosis in Japanese. In: Human molecular genetics. 2011 ; Vol. 20, No. 18. pp. 3684-3692.

@article{86a63438f68d430fa21fc7512b295192,

title = "A functional variant in ZNF512B is associated with susceptibility to amyotrophic lateral sclerosis in Japanese",

abstract = "Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. Several susceptibility genes for ALS have been reported; however, ALS etiology and pathogenesis remain largely unknown. To identify further ALS-susceptibility genes,we conducted a large-scale case-control association study using gene-based tag single-nucleotide polymorphisms (SNPs). A functional SNP (rs2275294) was found to be significantly associated with ALS through a stepwise screening approach (combined P 5 9.3 3 10210, odds ratio 5 1.32). The SNP was located in an enhancer region of ZNF512B, a transcription factor of unknown biological function, and the susceptibility allele showed decreased activity and decreased binding to nuclear proteins. ZNF512B over-expression increased transforming growth factor-b (TGF-b) signaling, while knockdown had the opposite effect. ZNF512B expression was increased in the anterior horn motor neurons of the spinal cord of ALS patients when compared with controls. Our results strongly suggest that ZNF512B is an important positive regulator of TGF-b signaling and that decreased ZNF512B expression increases susceptibility to ALS.",

author = "Aritoshi Iida and Atsushi Takahashi and Michiaki Kubo and Susumu Saito and Naoya Hosono and Yozo Ohnishi and Kazuma Kiyotani and Taisei Mushiroda and Masahiro Nakajima and Kouichi Ozaki and Toshihiro Tanaka and Tatsuhiko Tsunoda and Shuichi Oshima and Motoki Sano and Tetsumasa Kamei and Torao Tokuda and Masashi Aoki and Kazuko Hasegawa and Koichi Mizoguchi and Mitsuya Morita and Yuji Takahashi and Masahisa Katsuno and Naoki Atsuta and Hirohisa Watanabe and Fumiaki Tanaka and Ryuji Kaji and Imaharu Nakano and Naoyuki Kamatani and Shoji Tsuji and Gen Sobue and Yusuke Nakamura and Shiro Ikegawa",

note = "Funding Information: This work was supported by grants from the Leading Project of Ministry of Education, Culture, Sports, Science and Technology Japan; Health and Labour, Sciences Research Grants for Research on Measures for Intractable Diseases and Comprehensive Research on Aging and Health from the Ministry of Health, Labour and Welfare, Japan; and by a Grant-in-Aid for Scientific Research (C) (19500314) from the Ministry of Education, Culture, Sports, Science and Technology Japan (A.I.).",

year = "2011",

month = sep,

doi = "10.1093/hmg/ddr268",

language = "English",

volume = "20",

pages = "3684--3692",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "18",

}

Iida, A, Takahashi, A, Kubo, M, Saito, S, Hosono, N, Ohnishi, Y, Kiyotani, K, Mushiroda, T, Nakajima, M, Ozaki, K, Tanaka, T, Tsunoda, T, Oshima, S, Sano, M, Kamei, T, Tokuda, T, Aoki, M, Hasegawa, K, Mizoguchi, K, Morita, M, Takahashi, Y, Katsuno, M, Atsuta, N, Watanabe, H, Tanaka, F, Kaji, R, Nakano, I, Kamatani, N, Tsuji, S, Sobue, G, Nakamura, Y & Ikegawa, S 2011, 'A functional variant in ZNF512B is associated with susceptibility to amyotrophic lateral sclerosis in Japanese', Human molecular genetics, vol. 20, no. 18, ddr268, pp. 3684-3692. https://doi.org/10.1093/hmg/ddr268

A functional variant in ZNF512B is associated with susceptibility to amyotrophic lateral sclerosis in Japanese. / Iida, Aritoshi; Takahashi, Atsushi; Kubo, Michiaki; Saito, Susumu; Hosono, Naoya; Ohnishi, Yozo; Kiyotani, Kazuma; Mushiroda, Taisei; Nakajima, Masahiro; Ozaki, Kouichi; Tanaka, Toshihiro; Tsunoda, Tatsuhiko; Oshima, Shuichi; Sano, Motoki; Kamei, Tetsumasa; Tokuda, Torao; Aoki, Masashi; Hasegawa, Kazuko; Mizoguchi, Koichi; Morita, Mitsuya; Takahashi, Yuji; Katsuno, Masahisa; Atsuta, Naoki; Watanabe, Hirohisa; Tanaka, Fumiaki; Kaji, Ryuji; Nakano, Imaharu; Kamatani, Naoyuki; Tsuji, Shoji; Sobue, Gen; Nakamura, Yusuke; Ikegawa, Shiro.

In: Human molecular genetics, Vol. 20, No. 18, ddr268, 09.2011, p. 3684-3692.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - A functional variant in ZNF512B is associated with susceptibility to amyotrophic lateral sclerosis in Japanese

AU - Iida, Aritoshi

AU - Takahashi, Atsushi

AU - Kubo, Michiaki

AU - Saito, Susumu

AU - Hosono, Naoya

AU - Ohnishi, Yozo

AU - Kiyotani, Kazuma

AU - Mushiroda, Taisei

AU - Nakajima, Masahiro

AU - Ozaki, Kouichi

AU - Tanaka, Toshihiro

AU - Tsunoda, Tatsuhiko

AU - Oshima, Shuichi

AU - Sano, Motoki

AU - Kamei, Tetsumasa

AU - Tokuda, Torao

AU - Aoki, Masashi

AU - Hasegawa, Kazuko

AU - Mizoguchi, Koichi

AU - Morita, Mitsuya

AU - Takahashi, Yuji

AU - Katsuno, Masahisa

AU - Atsuta, Naoki

AU - Watanabe, Hirohisa

AU - Tanaka, Fumiaki

AU - Kaji, Ryuji

AU - Nakano, Imaharu

AU - Kamatani, Naoyuki

AU - Tsuji, Shoji

AU - Sobue, Gen

AU - Nakamura, Yusuke

AU - Ikegawa, Shiro

N1 - Funding Information: This work was supported by grants from the Leading Project of Ministry of Education, Culture, Sports, Science and Technology Japan; Health and Labour, Sciences Research Grants for Research on Measures for Intractable Diseases and Comprehensive Research on Aging and Health from the Ministry of Health, Labour and Welfare, Japan; and by a Grant-in-Aid for Scientific Research (C) (19500314) from the Ministry of Education, Culture, Sports, Science and Technology Japan (A.I.).

PY - 2011/9

Y1 - 2011/9

N2 - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. Several susceptibility genes for ALS have been reported; however, ALS etiology and pathogenesis remain largely unknown. To identify further ALS-susceptibility genes,we conducted a large-scale case-control association study using gene-based tag single-nucleotide polymorphisms (SNPs). A functional SNP (rs2275294) was found to be significantly associated with ALS through a stepwise screening approach (combined P 5 9.3 3 10210, odds ratio 5 1.32). The SNP was located in an enhancer region of ZNF512B, a transcription factor of unknown biological function, and the susceptibility allele showed decreased activity and decreased binding to nuclear proteins. ZNF512B over-expression increased transforming growth factor-b (TGF-b) signaling, while knockdown had the opposite effect. ZNF512B expression was increased in the anterior horn motor neurons of the spinal cord of ALS patients when compared with controls. Our results strongly suggest that ZNF512B is an important positive regulator of TGF-b signaling and that decreased ZNF512B expression increases susceptibility to ALS.

AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. Several susceptibility genes for ALS have been reported; however, ALS etiology and pathogenesis remain largely unknown. To identify further ALS-susceptibility genes,we conducted a large-scale case-control association study using gene-based tag single-nucleotide polymorphisms (SNPs). A functional SNP (rs2275294) was found to be significantly associated with ALS through a stepwise screening approach (combined P 5 9.3 3 10210, odds ratio 5 1.32). The SNP was located in an enhancer region of ZNF512B, a transcription factor of unknown biological function, and the susceptibility allele showed decreased activity and decreased binding to nuclear proteins. ZNF512B over-expression increased transforming growth factor-b (TGF-b) signaling, while knockdown had the opposite effect. ZNF512B expression was increased in the anterior horn motor neurons of the spinal cord of ALS patients when compared with controls. Our results strongly suggest that ZNF512B is an important positive regulator of TGF-b signaling and that decreased ZNF512B expression increases susceptibility to ALS.

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UR - http://www.scopus.com/inward/citedby.url?scp=80052253329&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddr268

DO - 10.1093/hmg/ddr268

M3 - Article

C2 - 21665992

AN - SCOPUS:80052253329

VL - 20

SP - 3684

EP - 3692

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 18

M1 - ddr268

ER -

A functional variant in ZNF512B is associated with susceptibility to amyotrophic lateral sclerosis in Japanese

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