Genome-wide association studies of adolescent idiopathic scoliosis suggest candidate susceptibility genes

Abstract

Adolescent idiopathic scoliosis (AIS) is an unexplained and common spinal deformity seen in otherwise healthy children. Its pathophysiology is poorly understood despite intensive investigation. Although genetic underpinnings are clear, replicated susceptibility loci that could provide insight into etiology have not been forthcoming. To address these issues, we performed genome-wide association studies (GWAS) of ∼327 000 single nucleotide polymorphisms (SNPs) in 419 AIS families. We found strongest evidence of association with chromosome 3p26.3 SNPs in the proximity of the CHL1 gene (P < 8 × 10(-8) for rs1400180). We genotyped additional chromosome 3p26.3 SNPs and tested replication in two follow-up case-control cohorts, obtaining strongest results when all three cohorts were combined (rs10510181 odds ratio = 1.49, 95% confidence interval = 1.29-1.73, P = 2.58 × 10(-8)), but these were not confirmed in a separate GWAS. CHL1 is of interest, as it encodes an axon guidance protein related to Robo3. Mutations in the Robo3 protein cause horizontal gaze palsy with progressive scoliosis (HGPPS), a rare disease marked by severe scoliosis. Other top associations in our GWAS were with SNPs in the DSCAM gene encoding an axon guidance protein in the same structural class with Chl1 and Robo3. We additionally found AIS associations with loci in CNTNAP2, supporting a previous study linking this gene with AIS. Cntnap2 is also of functional interest, as it interacts directly with L1 and Robo class proteins and participates in axon pathfinding. Our results suggest the relevance of axon guidance pathways in AIS susceptibility, although these findings require further study, particularly given the apparent genetic heterogeneity in this disease.

Association of rs11190870 near LBX1 with adolescent idiopathic scoliosis susceptibility in a Han Chinese population

“…GWAS is a powerful method for the detecting genetic contributions to polygenic diseases, and has been increasingly used to study genetic predisposition in AIS that is regarded as one of the most common complex genetic disorders of the musculoskeletal system [19]. However, this method may produce spurious association [20,21].…”

New disease gene location and high genetic heterogeneity in idiopathic scoliosis

“…Also, although dominant IS genes, yet to be identified, may account for a restricted number of IS cases, they may provide insights into the genetic bases of multifactorial IS, which remain largely unknown. 20,21 Future genetic and functional analyses of candidate genes located within these defined regions will hopefully reveal gene defects accounting for IS, which will allow, in turn, the identification of secondary molecular factors that may point towards yet unrecognised IS pathophysiological pathways.…”

Polygenic Threshold Model with Sex Dimorphism in Adolescent Idiopathic Scoliosis: The Carter Effect

“…In addition to identifying areas of linkage, several studies have provided support for different candidate genes 17 including melatonin-related receptors 18 and estrogen receptors 19,20 . The results of recently reported genome-wide association studies also suggest that AIS is weakly to modestly associated with dozens if not hundreds of common polymorphisms across the genome 21,22 . Despite numerous linkage studies, association studies, and evaluations of candidate genes, no single gene has been established to cause AIS.…”