A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis

Yoji Ogura; Ikuyo Kou; Shigenori Miura; Atsushi Takahashi; Leilei Xu; Kazuki Takeda; Yohei Takahashi; Katsuki Kono; Noriaki Kawakami; Koki Uno; Manabu Ito; Shohei Minami; Ikuho Yonezawa; Haruhisa Yanagida; Hiroshi Taneichi; Zezhang Zhu; Taichi Tsuji; Teppei Suzuki; Hideki Sudo; Toshiaki Kotani; Kota Watanabe; Naobumi Hosogane; Eijiro Okada; Aritoshi Iida; Masahiro Nakajima; Akihiro Sudo; Kazuhiro Chiba; Yuji Hiraki; Yoshiaki Toyama; Yong Qiu; Chisa Shukunami; Yoichiro Kamatani; Michiaki Kubo; Morio Matsumoto; Shiro Ikegawa

doi:10.1016/j.ajhg.2015.06.012

A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis

Yoji Ogura, Ikuyo Kou, Shigenori Miura, Atsushi Takahashi, Leilei Xu, Kazuki Takeda, Yohei Takahashi, Katsuki Kono, Noriaki Kawakami, Koki Uno, Manabu Ito, Shohei Minami, Ikuho Yonezawa, Haruhisa Yanagida, Hiroshi Taneichi, Zezhang Zhu, Taichi Tsuji, Teppei Suzuki, Hideki Sudo, Toshiaki KotaniKota Watanabe, Naobumi Hosogane, Eijiro Okada, Aritoshi Iida, Masahiro Nakajima, Akihiro Sudo, Kazuhiro Chiba, Yuji Hiraki, Yoshiaki Toyama, Yong Qiu, Chisa Shukunami, Yoichiro Kamatani, Michiaki Kubo, Morio Matsumoto, Shiro Ikegawa

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Abstract

Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity. We previously conducted a genome-wide association study (GWAS) and detected two loci associated with AIS. To identify additional loci, we extended our GWAS by increasing the number of cohorts (2,109 affected subjects and 11,140 control subjects in total) and conducting a whole-genome imputation. Through the extended GWAS and replication studies using independent Japanese and Chinese populations, we identified a susceptibility locus on chromosome 9p22.2 (p = 2.46 × 10^-13; odds ratio = 1.21). The most significantly associated SNPs were in intron 3 of BNC2, which encodes a zinc finger transcription factor, basonuclin-2. Expression quantitative trait loci data suggested that the associated SNPs have the potential to regulate the BNC2 transcriptional activity and that the susceptibility alleles increase BNC2 expression. We identified a functional SNP, rs10738445 in BNC2, whose susceptibility allele showed both higher binding to a transcription factor, YY1 (yin and yang 1), and higher BNC2 enhancer activity than the non-susceptibility allele. BNC2 overexpression produced body curvature in developing zebrafish in a gene-dosage-dependent manner. Our results suggest that increased BNC2 expression is implicated in the etiology of AIS.

Original language	English
Article number	1911
Pages (from-to)	337-342
Number of pages	6
Journal	American Journal of Human Genetics
Volume	97
Issue number	2
DOIs	https://doi.org/10.1016/j.ajhg.2015.06.012
Publication status	Published - 06-08-2015
Externally published	Yes

All Science Journal Classification (ASJC) codes

Genetics
Genetics(clinical)

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10.1016/j.ajhg.2015.06.012

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Ogura, Y., Kou, I., Miura, S., Takahashi, A., Xu, L., Takeda, K., Takahashi, Y., Kono, K., Kawakami, N., Uno, K., Ito, M., Minami, S., Yonezawa, I., Yanagida, H., Taneichi, H., Zhu, Z., Tsuji, T., Suzuki, T., Sudo, H., ... Ikegawa, S. (2015). A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis. American Journal of Human Genetics, 97(2), 337-342. Article 1911. https://doi.org/10.1016/j.ajhg.2015.06.012

@article{fd178c3ec550463dbffaf5f03c4123c4,

title = "A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis",

abstract = "Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity. We previously conducted a genome-wide association study (GWAS) and detected two loci associated with AIS. To identify additional loci, we extended our GWAS by increasing the number of cohorts (2,109 affected subjects and 11,140 control subjects in total) and conducting a whole-genome imputation. Through the extended GWAS and replication studies using independent Japanese and Chinese populations, we identified a susceptibility locus on chromosome 9p22.2 (p = 2.46 × 10-13; odds ratio = 1.21). The most significantly associated SNPs were in intron 3 of BNC2, which encodes a zinc finger transcription factor, basonuclin-2. Expression quantitative trait loci data suggested that the associated SNPs have the potential to regulate the BNC2 transcriptional activity and that the susceptibility alleles increase BNC2 expression. We identified a functional SNP, rs10738445 in BNC2, whose susceptibility allele showed both higher binding to a transcription factor, YY1 (yin and yang 1), and higher BNC2 enhancer activity than the non-susceptibility allele. BNC2 overexpression produced body curvature in developing zebrafish in a gene-dosage-dependent manner. Our results suggest that increased BNC2 expression is implicated in the etiology of AIS.",

author = "Yoji Ogura and Ikuyo Kou and Shigenori Miura and Atsushi Takahashi and Leilei Xu and Kazuki Takeda and Yohei Takahashi and Katsuki Kono and Noriaki Kawakami and Koki Uno and Manabu Ito and Shohei Minami and Ikuho Yonezawa and Haruhisa Yanagida and Hiroshi Taneichi and Zezhang Zhu and Taichi Tsuji and Teppei Suzuki and Hideki Sudo and Toshiaki Kotani and Kota Watanabe and Naobumi Hosogane and Eijiro Okada and Aritoshi Iida and Masahiro Nakajima and Akihiro Sudo and Kazuhiro Chiba and Yuji Hiraki and Yoshiaki Toyama and Yong Qiu and Chisa Shukunami and Yoichiro Kamatani and Michiaki Kubo and Morio Matsumoto and Shiro Ikegawa",

note = "Publisher Copyright: {\textcopyright} 2015 The American Society of Human Genetics.",

year = "2015",

month = aug,

day = "6",

doi = "10.1016/j.ajhg.2015.06.012",

language = "English",

volume = "97",

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Ogura, Y, Kou, I, Miura, S, Takahashi, A, Xu, L, Takeda, K, Takahashi, Y, Kono, K, Kawakami, N, Uno, K, Ito, M, Minami, S, Yonezawa, I, Yanagida, H, Taneichi, H, Zhu, Z, Tsuji, T, Suzuki, T, Sudo, H, Kotani, T, Watanabe, K, Hosogane, N, Okada, E, Iida, A, Nakajima, M, Sudo, A, Chiba, K, Hiraki, Y, Toyama, Y, Qiu, Y, Shukunami, C, Kamatani, Y, Kubo, M, Matsumoto, M & Ikegawa, S 2015, 'A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis', American Journal of Human Genetics, vol. 97, no. 2, 1911, pp. 337-342. https://doi.org/10.1016/j.ajhg.2015.06.012

TY - JOUR

T1 - A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis

AU - Ogura, Yoji

AU - Kou, Ikuyo

AU - Miura, Shigenori

AU - Takahashi, Atsushi

AU - Xu, Leilei

AU - Takeda, Kazuki

AU - Takahashi, Yohei

AU - Kono, Katsuki

AU - Kawakami, Noriaki

AU - Uno, Koki

AU - Ito, Manabu

AU - Minami, Shohei

AU - Yonezawa, Ikuho

AU - Yanagida, Haruhisa

AU - Taneichi, Hiroshi

AU - Zhu, Zezhang

AU - Tsuji, Taichi

AU - Suzuki, Teppei

AU - Sudo, Hideki

AU - Kotani, Toshiaki

AU - Watanabe, Kota

AU - Hosogane, Naobumi

AU - Okada, Eijiro

AU - Iida, Aritoshi

AU - Nakajima, Masahiro

AU - Sudo, Akihiro

AU - Chiba, Kazuhiro

AU - Hiraki, Yuji

AU - Toyama, Yoshiaki

AU - Qiu, Yong

AU - Shukunami, Chisa

AU - Kamatani, Yoichiro

AU - Kubo, Michiaki

AU - Matsumoto, Morio

AU - Ikegawa, Shiro

PY - 2015/8/6

Y1 - 2015/8/6

N2 - Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity. We previously conducted a genome-wide association study (GWAS) and detected two loci associated with AIS. To identify additional loci, we extended our GWAS by increasing the number of cohorts (2,109 affected subjects and 11,140 control subjects in total) and conducting a whole-genome imputation. Through the extended GWAS and replication studies using independent Japanese and Chinese populations, we identified a susceptibility locus on chromosome 9p22.2 (p = 2.46 × 10-13; odds ratio = 1.21). The most significantly associated SNPs were in intron 3 of BNC2, which encodes a zinc finger transcription factor, basonuclin-2. Expression quantitative trait loci data suggested that the associated SNPs have the potential to regulate the BNC2 transcriptional activity and that the susceptibility alleles increase BNC2 expression. We identified a functional SNP, rs10738445 in BNC2, whose susceptibility allele showed both higher binding to a transcription factor, YY1 (yin and yang 1), and higher BNC2 enhancer activity than the non-susceptibility allele. BNC2 overexpression produced body curvature in developing zebrafish in a gene-dosage-dependent manner. Our results suggest that increased BNC2 expression is implicated in the etiology of AIS.

AB - Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity. We previously conducted a genome-wide association study (GWAS) and detected two loci associated with AIS. To identify additional loci, we extended our GWAS by increasing the number of cohorts (2,109 affected subjects and 11,140 control subjects in total) and conducting a whole-genome imputation. Through the extended GWAS and replication studies using independent Japanese and Chinese populations, we identified a susceptibility locus on chromosome 9p22.2 (p = 2.46 × 10-13; odds ratio = 1.21). The most significantly associated SNPs were in intron 3 of BNC2, which encodes a zinc finger transcription factor, basonuclin-2. Expression quantitative trait loci data suggested that the associated SNPs have the potential to regulate the BNC2 transcriptional activity and that the susceptibility alleles increase BNC2 expression. We identified a functional SNP, rs10738445 in BNC2, whose susceptibility allele showed both higher binding to a transcription factor, YY1 (yin and yang 1), and higher BNC2 enhancer activity than the non-susceptibility allele. BNC2 overexpression produced body curvature in developing zebrafish in a gene-dosage-dependent manner. Our results suggest that increased BNC2 expression is implicated in the etiology of AIS.

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U2 - 10.1016/j.ajhg.2015.06.012

DO - 10.1016/j.ajhg.2015.06.012

M3 - Article

C2 - 26211971

AN - SCOPUS:84938969495

SN - 0002-9297

VL - 97

SP - 337

EP - 342

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 2

M1 - 1911

ER -

A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis

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