No abstract

Dental morphology is highly diverse among individuals and between human populations. Although it is thought that genetic factors mainly determine common dental variations, only a few such genetic factors have been identified. One study demonstrated that a nonsynonymous single-nucleotide polymorphism (370V/A, rs3827760) in the ectodysplasin A receptor gene (EDAR) is associated with shoveling and double-shoveling grades of upper first incisors and tooth crown size. Here, we examined the association of EDAR 370V/A with several dental characters in Korean and Japanese subjects. A meta-analysis that combined analyses of Korean and Japanese subjects revealed that the Asian-specific 370A allele is associated with an increase in the grades of shoveling and double shoveling, as previously found. We also showed a highly significant association between EDAR 370V/A genotype and crown size, especially mesiodistal diameters of anterior teeth. Moreover, we found that the 370A allele was associated with the presence of hypoconulids of lower second molars. These results indicated that the EDAR polymorphism is responsible, in part, for the Sinodonty and Sundadonty dichotomy in Asian populations, and clearly demonstrated that the EDAR polymorphism has pleiotropic effects on tooth morphology. As the 370A allele is known to be a most likely target of positive selection in Asian populations, some phenotypes associated with the variant may be 'hitchhiking phenotypes', while others may be actual targets of selection.

No abstract

Massively parallel sequencing of target regions, exomes, and complete genomes has begun to increase the opportunities for identifying genetic variants underlying rare and common diseases dramatically. Here we applied exome resequencing to primary failure of tooth eruption (PFE) to identify the genetic causality of the disease. Two Japanese families having PFE were recruited and examined by genome-wide linkage study and subsequently exome analyses. Linkage analyses of these two families comprising eight affected individuals and two unaffected individuals revealed linkage signals at 10 loci with a maximum LOD score of 1.5. Four affected individuals in one family were pooled and further processed for exome analysis, followed by massive parallel sequencing. After three-step filtering including annotation and functional expectation, three variants were found to be candidates for PFE. Among the three variants, only a novel variant of parathyroid hormone 1 receptor gene (PTH1R), R383Q, was cosegregated in the first PFE family. Accordingly, we screened the gene for variants at all coding exons and the respective intron-exon boundaries in the second family and two sporadic individuals with PFE. We also identified a novel missense variant, P119L, cosegregating in the second family and missense variants P132L and R147C in the sporadic cases. These variants all were in the highly conserved region across zebrafish to chimpanzee and not observed in 192 unrelated controls, supporting the pathogenicity of the variants. The combination of linkage and exome analyses employed in this study provides a powerful strategy for identifying genes responsible for Mendelian disorders. ß

No abstract