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.
authors.affiliation: Laboratory of Bone and Joint Diseases, Center for Integrative Sciences, RIKEN, Tokyo 108-8639, Japan; Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Ogura
authors.affiliation: Laboratory of Bone and Joint Diseases, Center for Integrative Sciences, RIKEN, Tokyo 108-8639, Japan.
authors.forename: Ikuyo
authors.initials: I
authors.lastname: Kou
authors.affiliation: Department of Cellular Differentiation, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Shigenori
authors.initials: S
authors.lastname: Miura
authors.affiliation: Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: Department of Spine Surgery, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing 210008, China.
authors.forename: Leilei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Laboratory of Bone and Joint Diseases, Center for Integrative Sciences, RIKEN, Tokyo 108-8639, Japan; Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Laboratory of Bone and Joint Diseases, Center for Integrative Sciences, RIKEN, Tokyo 108-8639, Japan; Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Department of Orthopaedic Surgery, Eiju General Hospital, Tokyo 110-8645, Japan.
authors.forename: Katsuki
authors.initials: K
authors.lastname: Kono
authors.affiliation: Department of Orthopaedic Surgery, Meijo Hospital, Nagoya 460-0001, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Kawakami
authors.affiliation: Department of Orthopaedic Surgery, Kobe Medical Center, National Hospital Organization, Kobe 654-0155, Japan.
authors.forename: Koki
authors.initials: K
authors.lastname: Uno
authors.affiliation: Department of Advanced Medicine for Spine and Spinal Cord Disorders, Graduate School of Medicine, Hokkaido University, Sapporo 060-8648, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Ito
authors.affiliation: Department of Orthopaedic Surgery, Seirei Sakura Citizen Hospital, Sakura 285-8765, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Minami
authors.affiliation: Department of Orthopaedic Surgery, School of Medicine, Juntendo University Tokyo 113-8431, Japan.
authors.forename: Ikuho
authors.initials: I
authors.lastname: Yonezawa
authors.affiliation: Department of Orthopaedic Surgery, Fukuoka Children's Hospital, Fukuoka 810-0063, Japan.
authors.forename: Haruhisa
authors.initials: H
authors.lastname: Yanagida
authors.affiliation: Department of Orthopaedic Surgery, School of Medicine, Dokkyo Medical University, Tochigi 321-0293, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Taneichi
authors.affiliation: Department of Spine Surgery, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing 210008, China.
authors.forename: Zezhang
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Orthopaedic Surgery, Meijo Hospital, Nagoya 460-0001, Japan.
authors.forename: Taichi
authors.initials: T
authors.lastname: Tsuji
authors.affiliation: Department of Orthopaedic Surgery, Kobe Medical Center, National Hospital Organization, Kobe 654-0155, Japan.
authors.forename: Teppei
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Advanced Medicine for Spine and Spinal Cord Disorders, Graduate School of Medicine, Hokkaido University, Sapporo 060-8648, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Sudo
authors.affiliation: Department of Orthopaedic Surgery, Seirei Sakura Citizen Hospital, Sakura 285-8765, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kotani
authors.affiliation: Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Naobumi
authors.initials: N
authors.lastname: Hosogane
authors.affiliation: Department of Orthopaedic Surgery, Saiseikai Central Hospital, Tokyo 108-0073, Japan.
authors.forename: Eijiro
authors.initials: E
authors.lastname: Okada
authors.affiliation: Laboratory of Bone and Joint Diseases, Center for Integrative Sciences, RIKEN, Tokyo 108-8639, Japan.
authors.forename: Aritoshi
authors.initials: A
authors.lastname: Iida
authors.affiliation: Laboratory of Bone and Joint Diseases, Center for Integrative Sciences, RIKEN, Tokyo 108-8639, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakajima
authors.affiliation: Department of Orthopaedic Surgery, School of Medicine, Mie University, Tsu 514-8507, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sudo
authors.affiliation: Department of Orthopaedic Surgery, Kitasato University Kitasato Institute Hospital, Tokyo 108-8642, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Chiba
authors.affiliation: Department of Cellular Differentiation, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hiraki
authors.affiliation: Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
authors.affiliation: Department of Spine Surgery, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing 210008, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Department of Molecular Biology and Biochemistry, Division of Basic Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
authors.forename: Chisa
authors.initials: C
authors.lastname: Shukunami
authors.affiliation: Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Kamatani
authors.affiliation: Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Morio
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Laboratory of Bone and Joint Diseases, Center for Integrative Sciences, RIKEN, Tokyo 108-8639, Japan. Electronic address: sikegawa@ims.u-tokyo.ac.jp.
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
mesh_terms: D000293:Adolescent; D000818:Animals; D002681:China; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000378:metabolism / Q000473:pathology; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007564:Japan; D008156:Luciferases; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012600:Scoliosis / Q000235:genetics* / Q000473:pathology; D050986:YY1 Transcription Factor / Q000378:metabolism; D015027:Zebrafish
chemical_list: C484527:BNC2 protein, human; D004268:DNA-Binding Proteins; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; D008156:Luciferases