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

Adolescent idiopathic scoliosis (AIS) is the most common pediatric spinal disorder and is best understood as a complex polygenic condition. Genome-wide association studies have identified AIS risk loci, including regions near ADGRG6 and SOX9 , yet the mechanisms underlying its heritability remain poorly defined. Here we use spatial transcriptomics to characterize gene expression in the spine of a conditional Adgrg6 mutant mouse model, revealing reduced expression of Sox9 and several extracellular matrix genes in the intervertebral disc. We demonstrate a strong genetic interaction between conditional loss of Adgrg6 and a hypomorphic Sox9 allele that increases the penetrance and severity of scoliosis. We further show that SOX9 occupies open chromatin within the Adgrg6 locus in SOX9+ cells isolated from the mouse disc tissue, consistent with direct transcriptional regulation, and provide evidence for SOX9-dependent and SOX9-independent regulation across a variety of spinal tissues. Together, these findings support a self-reinforcing feedforward circuit in which Adgrg6 and Sox9 are co-regulated to maintain extracellular matrix gene expression in the annulus fibrosus and paraspinal tissues. These results provide mechanistic insight into genes implicated by AIS-associated loci and establish combined Adgrg6–Sox9 insufficiency in mice as a tractable model of polygenic scoliosis susceptibility.