Identification of a Susceptibility Locus for Severe Adolescent Idiopathic Scoliosis on Chromosome 17q24.3

<div><p>Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity, affecting around 2% of adolescents worldwide. Genetic factors play an important role in its etiology. Using a genome-wide association study (GWAS), we recently identified novel AIS susceptibility loci on chromosomes 10q24.31 and 6q24.1. To identify more AIS susceptibility loci relating to its severity and progression, we performed GWAS by limiting the case subjects to those with severe AIS. Through a two-stage association study using a total of ∼12,000 Japanese subjects, we identified a common variant, rs12946942 that showed a significant association with severe AIS in the recessive model (<i>P</i> = 4.00×10⁻⁸, odds ratio [OR] = 2.05). Its association was replicated in a Chinese population (combined <i>P</i> = 6.43×10⁻¹², OR = 2.21). rs12946942 is on chromosome 17q24.3 near the genes <i>SOX9</i> and <i>KCNJ2</i>, which when mutated cause scoliosis phenotypes. Our findings will offer new insight into the etiology and progression of AIS.</p></div

Linkage disequilibrium (LD) map and <i>P</i>-value plot of the severe adolescent idiopathic scoliosis susceptibility locus at chromosome 17q24.3.

<p>Top panel: The association results shown as – log₁₀ of minimum <i>P</i> values in allele, recessive and dominant models and a focus view of the 130-kb LD block including rs12946942. All SNPs are analyzed in GWAS. Two vertical lines in this graph indicate the range of the LD block. rs12946942 is boxed. Middle panel: The ∼2 Mb LD map (D') around rs12946942 is shown using loci with MAF >0.10 from Phase II HapMap (release 24) JPT individuals. LD score: (dark red) LOD >2, D' = 1; (light red) LOD >2, D'<1; (blue) LOD <2, D' = 1; (white) LOD <2, D'<1. Bottom panel: The position of rs12946942 and the two candidate genes (<i>KCNJ2</i> and <i>SOX9</i>) on chromosome (Chr.) 17.</p

Association of the 27 SNPs in the two-stage association study for AIS in Japanese.

<p>Combined results of GWAS and the replication study. RAF: risk allele frequency. CI: confidence interval.</p>a<p>calculated by <i>x</i>² test. <i>P</i> values below the genome-wide significance level (P<5×10⁻⁸) are in bold.</p

Association of rs12946942 with severe AIS in Japanese and Chinese populations.

<p>RAF: risk allele (T allele) frequency. CI: confidence interval.</p><p>Data of <i>P</i> value, odds ratio (95% CI) and P_BD are for the recessive model (G/G and G/T vs T/T).</p>a<p>by <i>x</i>² test.</p>b<p>homogeneity of odds ratios by the Breslow-Day test.</p>c<p>by the Mantel-Haenszel method.</p