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Adolescent Idiopathic Scoliosis (AIS) is a condition featuring curvature of the spine. It affects tens of millions of children worldwide. Now, scientists at the RIKEN Center in collaboration with Keio University, have identified a gene linked to the condition. Image Credit: Nevit Dilmen

Genetic roots of scoliosis

Adolescent idiopathic scoliosis (AIS) — or curvature of the spine — affects tens of millions of children worldwide. Now, scientists have discovered a gene with links to the condition.

"AIS is a complex and mysterious disease with awkward spinal deformities that can be a nightmare for affected people," explains team leader Shiro Ikegawa. "We were excited to find a single nucleotide polymorphism located on human chromosome number nine that is significantly associated with the disease."

The RIKEN Center for Integrative Medical Sciences collaborating with Keio University, both in Japan, have published details on how the gene is associated with increased expression (or "turning on") of a protein BNC2 regulated by another protein called YY1.

The work is published in the American Journal of Human Genetics. The discovery began with a genome-wide association study using more than ten thousand volunteers with and without scoliosis. This type of study looks for small differences in genes — called single nucleotide polymorphisms, or SNPs — that appear more frequently in people with the AIS disorder. They went on to confirm the association between this particular SNP (pronounced "snip") in two additional independent populations — one in Japan and one in China. Then the scientists isolated it near a part of the DNA code producing the protein BNC2. After more analysis, they discovered that when this particular SNP is present, BNC2 protein is highly expressed in the uterus, spinal cord, bone, and cartilage.

"This result told us we were on the right track. Evidence that the SNP variation is associated with higher levels of BNC2, tells us this SNP has the potential to regulate expression — turn on or turn off the protein called BNC2."

Shiro Ikegawa PhD, team leader, Laboratory of Bone and Joint Diseases, Center for Integrative Sciences, RIKEN, Tokyo

The team tested their hypothesis in zebrafish finding that not only was BNC2 triggered by the protein YY1 BNC2— which binds to a specific location on chromosome 9p22.2 — but that genes with this at-risk SNP, produced a greater amount of BNC2 when YY1 was present — much greater than from genes with a non-risk variant.

The BNC2 gene is found across many diverse species, and plays roles in a variety of tissues. To test how its over-expression affects development, the team over expressed it in zebrafish embryos. This resulted in severe spinal curvature in the fish correlated to the amount of BNC2.

These results, and the abundance of BNC2 in AIS patients' spine and bones, make it likely that adolescents with the disease-associated SNP begin to produce excess BNC2 at puberty — when other genetic changes and/or environmental factors also take place.

The next step is to understand why AIS is so much more prevalent in women than in men. "The expression of BNC2 in the uterus and changes that occur during puberty could help explain the large sex difference," thinks Ikegawa. "Additionally, knowing what genes are downstream of BNC2 will provide us with potential targets for therapeutic interventions."

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.

Reference: Ogura et al. (2015) A functional SNP in BNC2 is associated with adolescent idiopathic scoliosis. American Journal of Human Genetics. doi: 10.1016/j.ajhg.2015.06.012.

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