Genetic Analyses of Enamel Hypoplasia in Multiethnic Cohorts

Enamel hypoplasia causes a reduction in the thickness of affected enamel and is one of the most common dental anomalies. This defect is caused by environmental and/or genetic factors that interfere with tooth formation, emphasizing the importance of investigating enamel hypoplasia on an epidemiological and genetic level.

A genome-wide association of enamel hypoplasia was performed in multiple cohorts, overall comprising 7,159 individuals ranging in age from 7 to 82 years. Mixed models were used to test for genetic association while simultaneously accounting for relatedness and genetic population structure. Meta-analysis was then performed. More than 5 million single-nucleotide polymorphisms were tested in individual cohorts.

Analyses of the individual cohorts and meta-analysis identified association signals close to genome-wide significance (p < 5 × 10-8), and many suggestive association signals (5 × 10-8 < p < 5 × 10-6) near genes with plausible roles in tooth/enamel development.

The strongest association signal (p = 1.57 × 10-9) was observed near BMP2K in one of the individual cohorts. Additional suggestive signals were observed near genes with plausible roles in tooth development in the meta-analysis, such as SLC4A4 which can influence enamel hypoplasia. Additional human genetic studies are needed to replicate these results and functional studies in model systems are needed to validate our findings.