Supplementary Material for: Genetic Analyses of Enamel Hypoplasia in Multiethnic Cohorts

Enamel hypoplasia causes 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 7-82 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 &lt; 510-8), and many suggestive association signals (510-8 &lt; P &lt; 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.釉质发育不全（Enamel hypoplasia）会导致受累牙釉质厚度降低，是最为常见的牙齿发育异常病症之一。该缺陷由干扰牙齿形成的环境因素及/或遗传因素引发，凸显了从流行病学与遗传层面开展釉质发育不全研究的重要性。研究团队针对釉质发育不全开展了多队列全基因组关联分析（Genome-wide association），整体纳入7159名年龄介于7至82岁的受试者。研究采用混合模型进行遗传关联检验，同时对亲缘关系与遗传群体结构进行校正。随后开展了荟萃分析（Meta-analysis）。在单个队列中，研究人员对超过500万个单核苷酸多态性（single-nucleotide polymorphisms，SNP）位点进行了关联检验。对单个队列及荟萃分析的结果解析显示，存在接近全基因组显著性水平（P < 5×10^-8）的关联信号，同时还发现大量提示性关联信号（5×10^-8 < P < 5×10^-6），这些信号均位于与牙齿/牙釉质发育具有合理关联的基因附近。在某一单个队列中，研究人员于BMP2K基因附近观测到最强的关联信号（P = 1.57×10^-9）。荟萃分析中，研究人员还在诸多与牙齿发育具有合理关联的基因附近观测到提示性关联信号，例如可影响釉质发育不全的SLC4A4基因。后续仍需开展人类遗传学研究以重复本研究所得结果，并通过模式生物系统的功能实验验证本次发现。