<b><i>Introduction:</i></b> 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. <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> Analyses of the individual cohorts and meta-analysis identified association signals close to genome-wide significance (<i>p</i> < 5 × 10<sup>–8</sup>), and many suggestive association signals (5 × 10<sup>–8</sup> < <i>p <</i> 5 × 10<sup>–6</sup>) near genes with plausible roles in tooth/enamel development. <b><i>Conclusion:</i></b> The strongest association signal (<i>p</i> = 1.57 × 10<sup>–9</sup>) was observed near <i>BMP2K</i> 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 <i>SLC4A4</i> 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.