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.

Genetics and pathogenesis of idiopathic scoliosis

“…An intronic variant within GPR126 and the intergenic variant rs12946942 have also been replicated in different populations, however the precise functional effect of these variants has yet to be elucidated [61, 64]. Two other common variants of interest have recently been found to be associated with IS, but have yet to be replicated (Table 2) [63, 68]. New methodologies such as exome-sequencing have made it possible to identify rare variants associated with idiopathic scoliosis [47–49, 81].…”

“…BNC2 overexpression induced body curvature in developing zebrafish in a gene-dosage-dependent manner [63]. …”

Summary of the first inaugural joint meeting of the International Consortium for scoliosis genetics and the International Consortium for vertebral anomalies and scoliosis, March 16–18, 2017, Dallas, Texas

“…Shiro Ikegawa: Genome-wide association studies (GWASs) have identified a transcription network of the genes related with the susceptibility for adolescent idiopathic scoliosis (AIS), including LBX1 (Takahashi et al, 2011), GPR126 (Kou et al, 2013), BNC2 (Ogura et al, 2015), and PAX1 (Sharma et al, 2015). LBX1 influences dorsal spinal cord neural development through Wnt/β-catenin signaling (Guo et al, 2016).…”

“…Both CS and IS are considered to represent developmental defects of spine formation. Ogura et al, 2015), and PAX1 (Sharma et al, 2015). LBX1 influences dorsal spinal cord neural development through Wnt/β-catenin signaling (Guo et al, 2016).…”

Mutant MAPK7-Induced Idiopathic Scoliosis is Linked to Impaired Osteogenesis

“…AIS afflicts 2-3% of school-age children and accounts for about 85% of all idiopathic patients [1]. Previous studies have revealed a strong genetic etiology, and recent genome-wide association studies and whole exome sequencing (WES) studies have identified several variants in genes associated with AIS, such as GPR126 [2], BNC2 [3], PAX1 [4], LBX1AS1 [5], POC5 [6], and AKAP2 [7]. However, the precise biological pathways underlying the predisposition of these variants to AIS are unknown.…”