Two genes identified in this study that have been implicated repeatedly in animal and human models of tooth development are BMP4 and EDA. BMP4 is a member of the transforming growth factor beta-1 superfamily of secretory signalling molecules that play essential roles in embryonic development, including mesoderm induction, tooth development, limb formation, bone induction and fracture repair (14). Mutations in BMP4 can cause eye, brain and digit developmental anomalies (14). BMP4 is expressed early in tooth development and has an expression profile which coincides with the shift of odontogenic potential from the epithelium to the mesenchyme during development of the tooth bud (15). Recent data suggest that BMP4 signalling suppresses tooth developmental inhibitors in the tooth mesenchyme, including Dkk2 and Osr2, and synergizes with Msx1 to activate mesenchymal odontogenic potential for tooth morphogenesis and sequential tooth formation (16). Given BMP4's important role in tooth development, it is perhaps not surprising that SNPs at this locus also associate with timing of tooth eruption. Interestingly, variants within BMP4 have previously been associated with Parkinson's disease (17) and colorectal cancer in other GWASs (18) suggesting pleiotropic actions of this gene.
