Genome-wide association study identifies 14 previously unreported susceptibility loci for adolescent idiopathic scoliosis in Japanese

Abstract

Adolescent idiopathic scoliosis (AIS) is the most common pediatric spinal deformity. Several AIS susceptibility loci have been identified; however, they could explain only a small proportion of AIS heritability. To identify additional AIS susceptibility loci, we conduct a meta-analysis of the three genome-wide association studies consisting of 79,211 Japanese individuals. We identify 20 loci significantly associated with AIS, including 14 previously not reported loci. These loci explain 4.6% of the phenotypic variance of AIS. We find 21 cis-expression quantitative trait loci-associated genes in seven of the fourteen loci. By a female meta-analysis, we identify additional three significant loci. We also find significant genetic correlations of AIS with body mass index and uric acid. The cell-type specificity analyses show the significant heritability enrichment for AIS in multiple cell-type groups, suggesting the heterogeneity of etiology and pathogenesis of AIS. Our findings provide insights into etiology and pathogenesis of AIS.

Fig. 1

Manhattan plot showing the –log₁₀ P value for the SNPs in the AIS GWAS. P values were derived from the meta-analysis by using the inverse-variance method under a fixed-effect model. The red line represents the genome-wide significance threshold (P = 5 × 10⁻⁸). The genetic loci that satisfied the genome-wide significance threshold in the meta-analysis of the three GWAS are labeled

Fig. 2

Relationship between effect size and minor allele frequency. The meta-analysis effect size (y axis) and the minor allele frequency (x axis) for 20 significant SNPs. Red circles represent the SNPs at previously unreported loci (n = 14) and blue circles represent the SNPs at previously reported loci (n = 6). Effect sizes are measured as odds ratios, which give the odds of the outcome given exposure to one risk allele compared with those to no risk allele

Fig. 3

Allelic difference of functional variant, rs1978060 in Chr.22q11.21. a Reporter assays in MCF-7 cells. There was a significantly decreased transcriptional activity for the risk G-allele of rs1978060 compared to the non-risk A-allele. Error bars show standard deviation (S.D.) for each variant. Asterisks indicate statistically significant changes in paired comparison (t-test P < 0.01). n = 2 independent experiments. b Electrophoretic mobility shift assays with nuclear extracts from MCF-7 cells. There was specific bands for A-allele probe (lane 1, black arrow) and the G-allele probe (lane 2, white arrow) of rs1978060. Competition analyses were performed using an excess of the unlabeled A-allele probe (lane 3, lane 6) and G-allele probe (lane 4, lane 5) as competitors. c A super-shift assay using the FOXA2 antibody. The black arrow indicates a super-shifted FOXA2 complex in lane 3. Source data are provided as a Source Data file