Genetic Analyses of Enamel Hypoplasia in Multiethnic Cohorts

Introduction: 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. Methods: 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. Results: 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. Conclusion: 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.Fil: Alotaibi, Rasha N.. University of Pittsburgh; Estados UnidosFil: Howe, Brian J.. University of Pittsburgh; Estados UnidosFil: Moreno Uribe, Lina M.. University of Iowa; Estados UnidosFil: Sanchez, Carla A.. University of Pittsburgh; Estados UnidosFil: Deleyiannis, Frederic W. B.. University of Pittsburgh; Estados UnidosFil: Padilla, Carmencita D.. University of Pittsburgh; Estados UnidosFil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; ArgentinaFil: Orioli, Ieda M.. Universidade Federal do Rio de Janeiro; BrasilFil: Buxó, Carmen J.. University of Iowa; Estados UnidosFil: Wehby, George L.. University of Pittsburgh; Estados UnidosFil: Vieira, Alexandre R.. University of Iowa; Estados UnidosFil: Murray, Jeffrey. University of Pittsburgh; Estados UnidosFil: Valencia Ramírez, Consuelo. University of Pittsburgh; Estados UnidosFil: Restrepo Muñeton, Claudia P.. University of Pittsburgh; Estados UnidosFil: Long, Ross E.. University of Pittsburgh; Estados UnidosFil: Shaffer, John R.. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados UnidosFil: Reis, Steven E.. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados Unidos. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Weinberg, Seth M.. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados UnidosFil: Neiswanger, Katherine. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados UnidosFil: McNeil, Daniel W.. No especifíca;Fil: Marazita, Mary L.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados Unido