rs10738445 — BNC2 BNC2 AIS susceptibility variant

BNC2 rs10738445 — The Enhancer Variant That Tips the Spine

Basonuclin-2 (BNC2) is a zinc finger transcription factor expressed during skeletal development with roles in regulating cell proliferation and differentiation in growth plate cartilage and intervertebral disc tissue. rs10738445 sits in intron 3 of BNC2¹¹ rs10738445 sits in intron 3 of BNC2
an intronic position at chr9:16,680,140 (GRCh38) within a transcriptional enhancer region, not in a protein-coding exon. Despite its non-coding location, this variant exerts a measurable functional effect on gene expression — and that shift in expression is what links it to adolescent idiopathic scoliosis²² adolescent idiopathic scoliosis
AIS — abnormal lateral curvature of the spine developing during the adolescent growth spurt, affecting approximately 2–3% of adolescents worldwide.

AIS is the most common pediatric spinal disorder. Most cases are mild, but roughly 10% of affected individuals develop curves severe enough to require bracing or surgery. The genetic architecture of AIS is complex and polygenic, with rs10738445 being one of the most consistently replicated susceptibility loci — validated across Japanese, Chinese, European, and multi-ethnic international cohorts.

The Mechanism

The C allele at rs10738445 creates an allele-specific transcription factor binding site³³ allele-specific transcription factor binding site
demonstrated by electrophoretic mobility shift assay (EMSA): the C allele binds the transcription factor YY1 approximately 1.3-fold more strongly than the A allele. YY1 (Yin Yang 1) is a ubiquitous zinc finger transcription factor that activates or represses genes depending on cellular context. At this locus, stronger YY1 binding drives higher BNC2 enhancer activity, elevating BNC2 mRNA levels in relevant tissues.

When BNC2 was overexpressed in zebrafish, the animals developed body curvature in a gene-dosage-dependent manner — direct experimental evidence that elevated BNC2 is sufficient to cause a scoliosis-like phenotype in a vertebrate model. In human AIS patients, BNC2 expression in spinal tissue is significantly higher than in controls, and expression magnitude correlates with curve severity (r=0.316, p=0.02), establishing a dose-response relationship between BNC2 expression and disease severity⁴⁴ establishing a dose-response relationship between BNC2 expression and disease severity
Xu et al. 2017, Chinese cohort of 2,645 patients and 2,746 controls.

The intersection with inflammatory pathways is less well characterised, but BNC2 expression is regulated by pro-inflammatory cytokines in growth plate and disc tissue. This may explain, in part, why AIS progression correlates with inflammatory markers and why this variant is catalogued in the innate immunity depth panel.

The Evidence

The discovery study by Ogura et al. 2015⁵⁵ Ogura et al. 2015
"A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis", American Journal of Human Genetics, 2015 identified rs10738445 through GWAS followed by functional validation in 2,109 AIS cases and 11,140 controls from Japanese and Chinese populations. The C allele showed OR=1.21 (p=2.46×10⁻¹³) for AIS susceptibility. This was independently replicated in a Chinese cohort⁶⁶ a Chinese cohort
Xu et al., Molecular Genetics and Genomics, 2017 with 2,645 patients and 2,746 controls (OR=1.14–1.24), and confirmed in an international meta-analysis of 8,756 cases and 27,822 controls⁷⁷ international meta-analysis of 8,756 cases and 27,822 controls
Ogura et al., Scientific Reports, 2018 spanning seven ethnicities (using the linked proxy rs3904778, combined p=3.28×10⁻¹⁸, OR=1.19, 95% CI 1.14–1.24).

The most clinically actionable finding comes from Dai et al. 2025⁸⁸ Dai et al. 2025
"Genetic Variants Can Predict the Outcome of Brace Treatment in Patients With Adolescent Idiopathic Scoliosis", Spine, 2025. In 259 female AIS patients undergoing brace treatment, the C allele was the only significant predictor of treatment failure among five candidate SNPs tested (OR=1.59), with 30.5% of patients experiencing curve progression exceeding 5 degrees. This positions rs10738445 as a potential clinical decision-support marker for predicting which adolescents are likely to fail conservative bracing therapy.

Notably, the BNC2 locus association is specific to adolescent-onset disease: a Japanese cohort study⁹⁹ Japanese cohort study
Takeda et al. 2019 found no significant association with adult spinal deformity, indicating the variant operates through mechanisms tied to growth-phase skeletal development.

Practical Actions

For carriers of the C allele who are parents of adolescents, or who are in the adolescent growth phase themselves, the main implication is heightened awareness: AIS typically develops during the rapid growth spurt (ages 10–15 in girls, 12–16 in boys) and is most successfully treated when detected early. Screening by a paediatric orthopaedist during this window allows intervention before curves progress beyond the bracing threshold (Cobb angle 25–45°).

For adolescents already diagnosed with AIS and undergoing bracing, the Dai 2025 data suggest that C/C homozygotes face a meaningfully higher risk of brace failure (OR=1.59 per allele). This does not mean bracing should be abandoned — it remains first-line treatment — but it justifies closer radiographic monitoring intervals and earlier consideration of surgical consultation if curve progression occurs despite compliant brace use.

Interactions

rs10738445 lies approximately 1.8 kb from rs3904778, the proxy SNP used in most international GWAS and the meta-analysis by Ogura 2018. Both variants tag the same BNC2 locus; rs10738445 has been specifically validated as the functional variant through enhancer assay and YY1 binding experiments, while rs3904778 is the more widely studied GWAS tag. Carriers may have both SNPs genotyped — the two track closely but are not in perfect LD across all populations.

AIS susceptibility is polygenic. Other replicated loci include SOX9/KCNJ2 (rs12946942), TBX1 (rs1978060), and CHD7 (rs1017861). The Dai 2025 study examined these alongside rs10738445 and found only rs10738445 significantly predicted bracing outcome, suggesting it may capture a biologically distinct component of AIS pathogenesis related to the progression-relevant enhancer activity of BNC2.