Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis

Abstract

Adolescent idiopathic scoliosis (AIS) is the most common pediatric skeletal disease. We previously reported a locus on chromosome 10q24.31 associated with AIS susceptibility in Japanese using a genome-wide association study (GWAS) consisting of 1,033 cases and 1,473 controls. To identify additional AIS-associated loci, we expanded the study by adding X-chromosome SNPs in the GWAS and increasing the size of the replication cohorts. Through a stepwise association study including 1,819 cases and 25,939 controls, we identified a new susceptibility locus on chromosome 6q24.1 in Japanese (P = 2.25 × 10(-10); odds ratio (OR) = 1.28). The most significantly associated SNP, rs6570507, was in GPR126 (encoding G protein-coupled receptor 126). Its association was replicated in Han Chinese and European-ancestry populations (combined P = 1.27 × 10(-14); OR = 1.27). GPR126 was highly expressed in cartilage, and the knockdown of gpr126 in zebrafish caused delayed ossification of the developing spine. Our results should provide insights into the etiology and pathogenesis of AIS.

International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein–Coupled Receptors

“…ADGRG6 (GPR126) SNPs are also coupled to human skeletal frame size. The SNP rs6570507 has the potential to regulate transcriptional activity and is associated inversely with trunk length (Soranzo et al, 2009) and adolescent idiopathic scoliosis, the most common pediatric skeletal disease (Kou et al, 2013). These data suggest that alterations in ADGRG6 (GPR126) levels result in abnormal skeletal growth.…”

A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis

“…8 The association of these loci with AIS was replicated in Chinese and Caucasian populations; 9-11 however, these loci only explain~1% of the total genetic variance in AIS. 8 To identify additional susceptibility gene(s) for AIS, we extended our GWAS by increasing the numbers of subjects (Table S1) and conducting a whole-genome imputation. A total of 2,142 AIS-affected subjects were recruited for the GWAS from ten collaborating hospitals (Japanese Scoliosis Clinical Research Group), according to the criteria previously described.…”

Functional variants of POC5 identified in patients with idiopathic scoliosis

“…However, the results of genome-wide linkage studies in multiplex families were inconclusive, suggesting that IS is genetically heterogeneous (8)(9)(10). GWAS in case/control samples were recently used to identify candidate loci for IS susceptibility (11)(12)(13); however, functional variants unambiguously causing IS have not yet been identified. In the present study, we sought to refine the search for IS susceptibility loci and to identify the disease-causing gene in a large family with a high prevalence of IS.…”