Abstract
Idiopathic scoliosis (IS) is a common paediatric 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 United States of America 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.
Highlights
Idiopathic scoliosis (IS) is a common paediatric musculoskeletal disease that displays a strong female bias
Research subjects included in the two-stage genome-wide association study (GWAS) were ascertained in Paediatric Orthopedic Clinics at the Texas Scottish Rite Hospital for Children (TSRHC)
Combining the two stages in this way yielded increased evidence for association with IS in the 20p11.22 region, with a combined Fisher’s P 1⁄4 1.33 Â 10 À 8 (Fig. 2 and Table 1) and ORs depicted in Supplementary Fig. 3
Summary
Idiopathic scoliosis (IS) is a common paediatric musculoskeletal disease that displays a strong female bias. Girls and boys exhibit a striking difference in the prevalence of progressive IS, with girls having approximately tenfold greater risk of progressive curves that require operative treatment[11] This dichotomy in female/ male disease expression, and its correlation with the adolescent growth spurt have prompted investigations of hormonal influences in the development and progression of female IS6. Gene discovery efforts centred on applying traditional linkage mapping methods to search for causal genes in such extended pedigrees These studies defined five IS candidate loci as noted in the Online Mendelian Inheritance in Man (OMIM): OS1 (OMIM 181800, chr19p13.3), OS2 (OMIM 607354, chr 17p11), OS3 (OMIM 608765, chr 8q12.1-12.2), OS4 (OMIM 612238, chr 9q31-q34) and OS5 (OMIM 612239, chr 17q25-qter). The causal genes and mutations encoded within familial IS disease loci have not been forthcoming, most likely due to issues of genetic heterogeneity in IS that can confound traditional gene discovery approaches[20]
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