Genetic interaction between Adgrg6 and Sox9 reveals a feedforward mechanism for postnatal spinal stability

Adolescent idiopathic scoliosis (AIS) is the most common spinal disorder in children and is best understood as a complex polygenic condition. Genome-wide association studies (GWAS) have identified several AIS risk loci, including regions near ADGRG6 and SOX9, yet the functional mechanisms underlying AIS heritability remain poorly defined. Here, we use spatial transcriptomics to characterize altered gene expression in the spine of a conditional Adgrg6 mutant mouse model of AIS (Adgrg6-cKO), revealing reduced expression of Sox9 and several components of extracellular matrix organization in the intervertebral disc. We further show that SOX9 occupies regions of open chromatin within the Adgrg6 locus in cells isolated from the mouse intervertebral disc. Finally, we demonstrate a strong genetic interaction between Adgrg6-cKO and a hypomorphic Sox9 allele that increases both the penetrance and severity of AIS-like pathology in mice. Collectively, these findings support a self-reinforcing feedforward regulatory circuit, where Adgrg6 and Sox9 are co-regulated to maintain extracellular matrix gene expression in the annulus fibrosus and paraspinal tissues. These findings provide mechanistic insight into the functional significance of AIS-associated GWAS loci near ADGRG6 and SOX9 and establish combined Adgrg6/Sox9 insufficiency as a tractable model of polygenic scoliosis susceptibility.