A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis

Am J Hum Genet. 2015 Aug 6;97(2):337-42. doi: 10.1016/j.ajhg.2015.06.012. Epub 2015 Jul 23.


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.

MeSH terms

  • Adolescent
  • Animals
  • China
  • Chromosomes, Human, Pair 9 / genetics*
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Embryo, Nonmammalian / metabolism
  • Embryo, Nonmammalian / pathology
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Humans
  • Japan
  • Luciferases
  • Odds Ratio
  • Phenotype*
  • Polymorphism, Single Nucleotide / genetics*
  • Scoliosis / genetics*
  • Scoliosis / pathology
  • YY1 Transcription Factor / metabolism
  • Zebrafish


  • BNC2 protein, human
  • DNA-Binding Proteins
  • YY1 Transcription Factor
  • YY1 protein, human
  • Luciferases