A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis

被引：110

作者：

Ogura, Yoji ^{[1
,2
]}

Kou, Ikuyo ^{[1
]}

Miura, Shigenori ^{[3
]}

Takahashi, Atsushi ^{[4
]}

Xu, Leilei ^{[5
]}

Takeda, Kazuki ^{[1
,2
]}

Takahashi, Yohei ^{[1
,2
]}

Kono, Katsuki ^{[6
]}

Kawakami, Noriaki ^{[7
]}

Uno, Koki ^{[8
]}

Ito, Manabu ^{[9
]}

Minami, Shohei ^{[10
]}

Yonezawa, Ikuho ^{[11
]}

Yanagida, Haruhisa ^{[12
]}

Taneichi, Hiroshi ^{[13
]}

Zhu, Zezhang ^{[5
]}

Tsuji, Taichi ^{[7
]}

Suzuki, Teppei ^{[8
]}

Sudo, Hideki ^{[9
]}

Kotani, Toshiaki ^{[10
]}

Watanabe, Kota ^{[2
]}

Hosogane, Naobumi ^{[2
]}

Okada, Eijiro ^{[14
]}

Iida, Aritoshi ^{[1
]}

Nakajima, Masahiro ^{[1
]}

Sudo, Akihiro ^{[15
]}

Chiba, Kazuhiro ^{[16
]}

Hiraki, Yuji

Toyama, Yoshiaki ^{[2
]}

Qiu, Yong ^{[5
]}

Shukunami, Chisa ^{[17
]}

Kamatani, Yoichiro ^{[4
]}

Kubo, Michiaki ^{[18
]}

Matsumoto, Mono ^{[2
]}

Ikegawal, Shiro ^{[1
]}

机构：

[1] RIKEN, Lab Bone & Joint Dis, Ctr Integrat Sci, Tokyo 1088639, Japan

[2] Keio Univ, Dept Orthopaed Surg, Sch Med, Tokyo 1608582, Japan

[3] Kyoto Univ, Dept Cellular Differentiat, Inst Frontier Med Sci, Kyoto 6068507, Japan

[4] RIKEN, Lab Stat Anal, Ctr Integrat Med Sci, Yokohama, Kanagawa 2300045, Japan

[5] Nanjing Univ, Sch Med, Dept Spine Surg, Nanjing Drum Tower Hosp, Nanjing 210008, Jiangsu, Peoples R China

[6] Eiju Gen Hosp, Dept Orthopaed Surg, Tokyo 1108645, Japan

[7] Meijo Hosp, Dept Orthopaed Surg, Nagoya, Aichi 4600001, Japan

[8] Natl Hosp Org, Dept Orthopaed Surg, Kobe Med Ctr, Kobe, Hyogo 6540155, Japan

[9] Hokkaido Univ, Dept Adv Med Spine & Spinal Cord Disorders, Grad Sch Med, Sapporo, Hokkaido 0608648, Japan

[10] Seirei Sakura Citizen Hosp, Dept Orthopaed Surg, Sakura 2858765, Japan

[11] Juntendo Univ, Dept Orthopaed Surg, Sch Med, Tokyo 1138431, Japan

[12] Fukuoka Childrens Hosp, Dept Orthopaed Surg, Fukuoka 8100063, Japan

[13] Dokkyo Med Univ, Dept Orthopaed Surg, Sch Med, Tochigi 3210293, Japan

[14] Saiseikai Cent Hosp, Dept Orthopaed Surg, Tokyo 1080073, Japan

[15] Mie Univ, Dept Orthopaed Surg, Sch Med, Tsu, Mie 5148507, Japan

[16] Kitasato Univ, Kitasato Inst Hosp, Dept Orthopaed Surg, Tokyo 1088642, Japan

[17] Hiroshima Univ, Dept Mol Biol & Biochem, Div Basic Life Sci, Inst Biomed & Hlth Sci, Hiroshima 7348553, Japan

[18] RIKEN, Lab Genotyping Dev, Ctr Integrat Med Sci, Yokohama, Kanagawa 2300045, Japan

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2015年 / 97卷 / 02期

关键词：

GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; LBX1; CHINESE; IDENTIFICATION; POPULATION; RS11190870; BASONUCLIN; ZEBRAFISH; VARIANTS;

D O I：

10.1016/j.ajhg.2015.06.012

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 x 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.

引用

页码：337 / 342

页数：6

共 26 条

[11] Nakamura Yusuke, 2007, Clin Adv Hematol Oncol, V5, P696
[12] Identification of Basonuclin2, a DNA-binding zinc-finger protein expressed in germ tissues and skin keratinocytes
Romano, RA
Li, HX
Tummala, R
Maul, R
Sinha, S
[J]. GENOMICS, 2004, 83 (05) : 821 - 833
[13] JASPAR:: an open-access database for eukaryotic transcription factor binding profiles
Sandelin, A
Alkema, W
Engström, P
Wasserman, WW
Lenhard, B
[J]. NUCLEIC ACIDS RESEARCH, 2004, 32 : D91 - D94
[14] A PAX1 enhancer locus is associated with susceptibility to idiopathic scoliosis in females
Sharma, Swarkar
Londono, Douglas
Eckalbar, Walter L.
Gao, Xiaochong
Zhang, Dongping
Mauldin, Kristen
Kou, Ikuyo
Takahashi, Atsushi
Matsumoto, Morio
Kamiya, Nobuhiro
Murphy, Karl K.
Cornelia, Reuel
Herring, John A.
Burns, Dennis
Ahituv, Nadav
Ikegawa, Shiro
Gordon, Derek
Wise, Carol A.
[J]. NATURE COMMUNICATIONS, 2015, 6
[15] A genome-wide association study identifies two new susceptibility loci for lung adenocarcinoma in the Japanese population
Shiraishi, Kouya
Kunitoh, Hideo
Daigo, Yataro
Takahashi, Atsushi
Goto, Koichi
Sakamoto, Hiromi
Ohnami, Sumiko
Shimada, Yoko
Ashikawa, Kyota
Saito, Akira
Watanabe, Shun-ichi
Tsuta, Koji
Kamatani, Naoyuki
Yoshida, Teruhiko
Nakamura, Yusuke
Yokota, Jun
Kubo, Michiaki
Kohno, Takashi
[J]. NATURE GENETICS, 2012, 44 (08) : 900 - +
[16] A genome-wide association study identifies common variants near LBX1 associated with adolescent idiopathic scoliosis
Takahashi, Yohei
Kou, Ikuyo
Takahashi, Atsushi
Johnson, Todd A.
Kono, Katsuki
Kawakami, Noriaki
Uno, Koki
Ito, Manabu
Minami, Shohei
Yanagida, Haruhisa
Taneichi, Hiroshi
Tsuji, Taichi
Suzuki, Teppei
Sudo, Hideki
Kotani, Toshiaki
Watanabe, Kota
Chiba, Kazuhiro
Hosono, Naoya
Kamatani, Naoyuki
Tsunoda, Tatsuhiko
Toyama, Yoshiaki
Kubo, Michiaki
Matsumoto, Morio
Ikegawa, Shiro
[J]. NATURE GENETICS, 2011, 43 (12) : 1237 - U96
[17] Lack of Association between Adolescent Idiopathic Scoliosis and Previously Reported Single Nucleotide Polymorphisms in MATN1, MTNR1B, TPH1, and IGF1 in a Japanese Population
Takahashi, Yohei
Matsumoto, Morio
Karasugi, Tatsuki
Watanabe, Kota
Chiba, Kazuhiro
Kawakami, Noriaki
Tsuji, Taichi
Uno, Koki
Suzuki, Teppei
Ito, Manabu
Sudo, Hideki
Minami, Shohei
Kotani, Toshiaki
Kono, Katsuki
Yanagida, Haruhisa
Taneichi, Hiroshi
Takahashi, Atsushi
Toyama, Yoshiaki
Ikegawa, Shiro
[J]. JOURNAL OF ORTHOPAEDIC RESEARCH, 2011, 29 (07) : 1055 - 1058
[18] Genetic epidemiology and heritability of AIS: A study of 415 Chinese female patients
Tang, Nelson L. S.
Yeung, Hiu-Yan
Hung, Vivian W. Y.
Di Liao, Chen
Lam, Tsz-Ping
Yeung, Hau-Man
Lee, Kwong-Man
Bobby Kin-Wah Ng
Cheng, Jack Chun-Yiu
[J]. JOURNAL OF ORTHOPAEDIC RESEARCH, 2012, 30 (09) : 1464 - 1469
[19] A 5-year epidemiological study on the prevalence rate of idiopathic scoliosis in Tokyo: school screening of more than 250,000 children
Ueno, Masaki
Takaso, Masashi
Nakazawa, Toshiyuki
Imura, Takayuki
Saito, Wataru
Shintani, Ryousuke
Uchida, Kentaro
Fukuda, Michinari
Takahashi, Kazuhisa
Ohtori, Seiji
Kotani, Toshiaki
Minami, Shohei
[J]. JOURNAL OF ORTHOPAEDIC SCIENCE, 2011, 16 (01) : 1 - 6
[20] Basonuclin 2: An extremely conserved homolog of the zinc finger protein basonuclin
Vanhoutteghem, A
Djian, P
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (10) : 3468 - 3473

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