Variants Near NOG and SOX9 Are Associated with Mandibular Retrognathia

Mandibular retrognathia is a common craniofacial anomaly characterized by a posteriorly positioned mandible, which can affect a person's oral function, esthetics, and quality of life. While facial characteristics are widely acknowledged to have a hereditary component, the etiology of this skeletal anomaly is poorly understood. This study aims to identify genetic loci associated with mandibular retrognathia and help elucidate its causes. Using the FinnGen cohort (2,647 cases, 497,020 controls), a genome-wide association study identified 2 regions of genome-wide significance with lead single-nucleotide polymorphisms rs227727 at NOG locus and rs7225448 at SOX9 locus. Interestingly, both associations were driven by results from females. The rs227727 association was replicated in an independent cohort from Iceland. Functional annotation revealed that rs227727 disrupts an enhancer regulating NOG, a gene important for normal bone and cartilage development and previously implicated in craniofacial anomalies. Morphological analyses of Nog^-/- mice revealed mandibular retrognathia-like features, including reduced mandibular length and condylar width. Variants in linkage disequilibrium with rs7225448 were located within distal enhancers near SOX9, a transcription factor essential for cartilage development. SOX9 mutations are known to cause Robin sequence with its constituent severe mandibular retrognathia. In addition, regional analysis revealed variation in the prevalence of mandibular retrognathia across Finland's 18 administrative regions, which was correlated especially with the rs227727 risk allele regional prevalence. These findings highlight genetic contributors to mandibular retrognathia and emphasize the importance of long-range regulatory elements in craniofacial development. By integrating genetic, functional, and epidemiological data, this study enhances our understanding of the genetic architecture underlying craniofacial anomalies.