A PAX1 enhancer locus is associated with susceptibility to idiopathic scoliosis in females

Abstract

Idiopathic scoliosis (IS) is a common pediatric musculoskeletal disease that displays a strong female bias. By performing a genome-wide association study (GWAS) of 3,102 individuals we identify significant associations with 20p11.22 SNPs for females (P=6.89×10−9) but not males (P=0.71). This association with IS is also found in independent female cohorts from the USA and Japan (overall P=2.15×10−10, OR=1.30 (rs6137473)). Unexpectedly, the 20p11.22 IS risk alleles were previously associated with protection from early-onset alopecia, another sexually dimorphic condition. The 174 kb associated locus is distal to PAX1 which encodes paired box 1, a transcription factor involved in spine development. We identify a sequence in the associated locus with enhancer activity in zebrafish somitic muscle and spinal cord, an activity that is abolished by IS-associated SNPs. We thus identify a sexually dimorphic IS susceptibility locus, and propose the first functionally-defined candidate mutations in an enhancer that may regulate expression in specific spinal cells.

Genetics and pathogenesis of idiopathic scoliosis

“…An intronic variant within GPR126 and the intergenic variant rs12946942 have also been replicated in different populations, however the precise functional effect of these variants has yet to be elucidated [61, 64]. Two other common variants of interest have recently been found to be associated with IS, but have yet to be replicated (Table 2) [63, 68]. New methodologies such as exome-sequencing have made it possible to identify rare variants associated with idiopathic scoliosis [47–49, 81].…”

“…By performing a GWAS of 3,102 individuals, Sharma et al [68] identified significant association of a locus distal to PAX1 to IS in female patients. PAX1 codes for Paired box 1, a transcription factor involved in spine development.…”

Gene regulation at a distance: From remote enhancers to 3D regulatory ensembles

“…In many cases, the causal variant(s) remained to be identified by follow-up studies, but examples have demonstrated that 1) these regions comprise indeed regulatory enhancers with the corresponding activity in vivo (e.g. [46,54,55]), 2) that genetic variants modifying TF binding and enhancer activity are present in these elements (e.g [56][57][58][59][60]). The MYC locus constitutes a particularly striking illustration of this ( Figure 1).…”

A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis

“…5 A female-specific gene associated with AIS, PAX1 (MIM: 167411), has been reported recently. 6 We previously conducted a genome-wide association study (GWAS) of Japanese females (1,033 affected subjects and 1,473 control subjects) and identified two loci on chromosomes 10q24.31 7 and 6q24.1. 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.…”