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

Abstract

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 (P = 4.00×10−8, odds ratio [OR] = 2.05). Its association was replicated in a Chinese population (combined P = 6.43×10−12, OR = 2.21). rs12946942 is on chromosome 17q24.3 near the genes SOX9 and KCNJ2, which when mutated cause scoliosis phenotypes. Our findings will offer new insight into the etiology and progression of AIS.

Candidate gene analysis and exome sequencing confirm LBX1 as a susceptibility gene for idiopathic scoliosis

“…The variant rs6570507 has previously been shown to be associated with idiopathic scoliosis in Japanese, Chinese Han, and European populations (p51.27Â10 À14 , OR 1.27) and rs12946942 in a Japanese and Han Chinese population (p56.43Â10 À12 , OR52.21) [4,6]. Our results lend support to the previously observed associations at a moderate level of genetic effect, but these variants do not appear to have a major effect on scoliosis risk in the Scandinavian population.…”

“…We genotyped the previously reported variants rs10510181, rs11190870, rs12946942, and rs6570507 in 1,739 patients with idiopathic scoliosis and in 1,812 controls from the OPRA and PEAK-25 cohorts [4][5][6][7]. Genotyping was performed at the Mutation Analysis Facility at Karolinska University Hospital (Huddinge, Sweden) using iPLEX Gold chemistry and MassARRAY mass spectrometry system (Agena Bioscience, San Diego, CA, USA) [19].…”

“…Recent genome-wide association studies have identified common genetic variants close to, or within, the ladybird homeobox 1 (LBX1), cell adhesion molecule L1-like (CHL1), and G protein-coupled receptor 126 (GPR126) genes, as well as an intergenic variant on 17q, in Asian and Caucasian populations [4][5][6][7]. One exome sequencing study has identified novel, rare variants associated with idiopathic scoliosis in the Fibrillin 1 and 2 genes in a European population [8].…”

Association Between IL-6 and MMP3 Common Genetic Polymorphisms and Idiopathic Scoliosis in Bulgarian Patients

“…3 In 2013, Miyake et al 4 identified a common variant, rs12946942, near the genes SOX9 and KCNJ2 that showed a significant association with severe AIS in Japanese population. 4 Its association was replicated in Chinese population. 4 With the case-control study design, the candidate gene approach is a strategy for selecting polymorphisms to genotype.…”

“…4 Its association was replicated in Chinese population. 4 With the case-control study design, the candidate gene approach is a strategy for selecting polymorphisms to genotype. Genes with high biological relevance to the disease would be selected as candidates.…”