The top 20 pathways identified from the pathway analysis are mostly related to growth and/or cancer. The three genes (BMP4, CDON, IGF2BP1) associated with ‘age at first tooth’ in the GWAS meta-analysis are part of the hedgehog-signalling pathway (P = 5 × 10−4), signalling events mediated by the Hedgehog family (P < 10−4) and glypican pathway (P = 4 × 10−4). Hedgehog signalling has been well described in tooth development (43), along with heparan sulphate proteoglycans (44). Growth factors also play a major role in the interaction between dental epithelium and mesenchyme, as well as cell–cell interactions within these tissues during tooth development (45). Several growth factor receptor signalling pathways for the epidermal growth factor receptor and the hepatocyte growth factor receptor were significant in our analysis [signalling events mediated by the hepatocyte growth factor receptor (c-Met) P < 6 × 10−4, EGF receptor (ErbB1) signalling pathway, internalization of ErbB1, ErbB1 downstream signalling, P < 0.0019], which is of interest as their ligands HGF and EGF have been shown to play a role in root development in mice (46,47).
