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 & 15 others 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

Research output: Contribution to journalArticle

48 Citations (Scopus)

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 languageEnglish
Article number1911
Pages (from-to)337-342
Number of pages6
JournalAmerican Journal of Human Genetics
Volume97
Issue number2
DOIs
Publication statusPublished - 06-08-2015
Externally publishedYes

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Genome-Wide Association Study
Scoliosis
Single Nucleotide Polymorphism
Alleles
Transcription Factors
Yin-Yang
Gene Dosage
Quantitative Trait Loci
Zinc Fingers
Zebrafish
Introns
Chromosomes
Odds Ratio
Genome
Population

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Ogura, Y., Kou, I., Miura, S., Takahashi, A., Xu, L., Takeda, K., ... Ikegawa, S. (2015). A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis. American Journal of Human Genetics, 97(2), 337-342. [1911]. https://doi.org/10.1016/j.ajhg.2015.06.012
Ogura, Yoji ; Kou, Ikuyo ; Miura, Shigenori ; Takahashi, Atsushi ; Xu, Leilei ; Takeda, Kazuki ; Takahashi, Yohei ; Kono, Katsuki ; Kawakami, Noriaki ; Uno, Koki ; Ito, Manabu ; Minami, Shohei ; Yonezawa, Ikuho ; Yanagida, Haruhisa ; Taneichi, Hiroshi ; Zhu, Zezhang ; Tsuji, Taichi ; Suzuki, Teppei ; Sudo, Hideki ; Kotani, Toshiaki ; Watanabe, Kota ; Hosogane, Naobumi ; Okada, Eijiro ; Iida, Aritoshi ; Nakajima, Masahiro ; Sudo, Akihiro ; Chiba, Kazuhiro ; Hiraki, Yuji ; Toyama, Yoshiaki ; Qiu, Yong ; Shukunami, Chisa ; Kamatani, Yoichiro ; Kubo, Michiaki ; Matsumoto, Morio ; Ikegawa, Shiro. / A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis. In: American Journal of Human Genetics. 2015 ; Vol. 97, No. 2. pp. 337-342.
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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.",
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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

A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis. / Ogura, Yoji; Kou, Ikuyo; Miura, Shigenori; Takahashi, Atsushi; Xu, Leilei; Takeda, Kazuki; Takahashi, Yohei; Kono, Katsuki; Kawakami, Noriaki; Uno, Koki; Ito, Manabu; Minami, Shohei; Yonezawa, Ikuho; Yanagida, Haruhisa; Taneichi, Hiroshi; Zhu, Zezhang; Tsuji, Taichi; Suzuki, Teppei; Sudo, Hideki; Kotani, Toshiaki; Watanabe, Kota; Hosogane, Naobumi; Okada, Eijiro; Iida, Aritoshi; Nakajima, Masahiro; Sudo, Akihiro; Chiba, Kazuhiro; Hiraki, Yuji; Toyama, Yoshiaki; Qiu, Yong; Shukunami, Chisa; Kamatani, Yoichiro; Kubo, Michiaki; Matsumoto, Morio; Ikegawa, Shiro.

In: American Journal of Human Genetics, Vol. 97, No. 2, 1911, 06.08.2015, p. 337-342.

Research output: Contribution to journalArticle

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

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JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

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