The Genetic Architecture of Adolescent Idiopathic Scoliosis

Adolescent idiopathic scoliosis (AIS) is the most common pediatric spinal deformity, affecting 2–3% of school-age children worldwide. This disease is typically classified by age at onset, with the great majority occurring around the time of the adolescent growth spurt, the so-called AIS. AIS can progress rapidly, threatening pain, deformity, and pulmonary dysfunction. Heritability of AIS is high, and population studies have consistently found that AIS is best explained by a polygenic inheritance model, in which many genetic risk factors combine to cause the disease. Population studies have associated AIS with genetic markers near interesting candidate genes, including the homeobox transcription factor LBX1, the G protein-coupled receptor GPR126, the paired box transcription factors PAX1 and PAX3, as well as the SRY-box SOX9. Moreover, gene targeting in zebrafish and mouse model systems have identified candidate genes, which offer an exciting new area of investigation into molecular mechanisms of AIS. AIS candidate genes thus far identified function in muscle, nerve, and cartilage specification in early development, suggesting neuromuscular and/or cartilage disease origins, but their role in later human development and growth of the axial spine is an unexplored area of developmental biology. Continued gene discovery efforts, aided by next-generation genomic platforms, are a priority for the field and will provide the tools for biological investigations of AIS pathogenesis.