Genetic Architecture and Biological Mechanisms of Adolescent Idiopathic Scoliosis: From Susceptibility Loci to Functional Pathways

Adolescent idiopathic scoliosis (AIS) is a complex three-dimensional spinal deformity with a substantial but incompletely understood genetic component. Advances in genomic research have shifted the genetic landscape of AIS from early candidate-gene associations toward reproducible genome-wide susceptibility loci, rare variants, and functionally relevant regulatory mechanisms. This review synthesizes current evidence across successive levels of AIS genetic investigation—from candidate-gene studies and genome-wide association studies to rare-variant analyses and functional genomics—and integrates these findings according to the biological pathways through which inherited variation may contribute to disease development. Rather than cataloguing individual susceptibility genes, the review specifically examines how genetic findings of different levels of evidence converge on interconnected developmental, cartilage, extracellular-matrix, hormonal/metabolic, and growth-related mechanisms. Genome-wide association studies have consistently implicated loci including LBX1, GPR126/ADGRG6, PAX1, and SOX6, supporting the involvement of developmental and musculoskeletal pathways. Rare-variant analyses and functional studies have further implicated extracellular-matrix pathways, including evidence involving COL11A1 and COL11A2. Collectively, current genetic evidence converges on interconnected processes involving neural and somitic development, chondrogenesis, extracellular-matrix organization and remodeling, hormonal and metabolic regulation, and skeletal growth. Functional evidence involving PAX1, GPR126/ADGRG6, and COL11A1 provides emerging mechanistic links between genetic variation and spinal development, although the biological consequences of many susceptibility loci remain unresolved. Current evidence supports AIS as a complex polygenic developmental disorder in which common variants, rare variants, and regulatory mechanisms collectively contribute to disease susceptibility. Future research should prioritize functional validation, multi-omics integration, gene–environment interactions, and large multi-ethnic cohorts to advance from genetic association toward a more comprehensive biological understanding of AIS pathogenesis.