Multi-Ancestry Genome-Wide Association Study of Early Childhood Caries and Developmental Defects of Enamel in a Community-Based Sample of Preschool-Age Children

ABSTRACTPoojan Shrestha: Multi-Ancestry Genome-Wide Association Study of Early Childhood Caries and Developmental Defects of Enamel in a Community-Based Sample of Preschool-Age Children (Under the direction of Kari E. North) Early childhood caries (ECC) is the most common non-communicable disease of childhood and it confers a substantial public health burden. Developmental defects of enamel (DDE) are a heterogeneous group of conditions resulting from qualitative or quantitative defects of dental enamel. Both are complex traits and their genetic underpinning has been well established. However, evidence on specific genetic risk loci underlying these conditions is lacking. To address this knowledge gap, we carried out a genome-wide association study (GWAS) in a multi-ethnic population of preschool-age children with the overarching goal of identifying genetic risk loci for ECC and DDE. Specifically, we employed 3 genetic association analysis approaches that, while seeking to identify genetic 'main effects’, leveraged heterogeneity and interactions with important environmental factors for ECC, including sugar and fluoride exposure, as well as sex. We estimated 24% and 20% of the phenotypic variance of the primary ECC and the combined DDE traits were explained by common SNPs. We identified multiple risk loci associated with ECC and DDE, with most showing heterogeneous associations across strata of the 3 examined environmental factors. We identified 21 novel loci for ECC, with 18 of those emerging after accounting for sex, fluoride exposure, and sugar exposure. For DDE, we identified 38 genetic risk loci associated with DDE, with 18 of those emerging from analyses accounting for sex heterogeneity. Multiple identified loci were near genes with biologically plausible roles in the pathogenesis of ECC and DDE. Two loci, namely, RP11-856F16.2 (rs74606067), and SLC41A3 (rs71327750) generalized in external pediatric and adult cohorts. The gene-based tests identified TAAR6 and CDH10 as genome-wide significant genes for ECC and DDE traits, respectively. These results add to the genomics knowledge base for these common complex dental conditions. The findings of substantial heterogeneity of genetic effects across different levels of environmental factors including sex emphasize further investigation into these pertinent environmental exposures and their inclusion in future genetic studies of oral health. Upon further replication and mechanistic validation, these results can inform caries risk assessment, the development of polygenic risk scores to guide preventive and treatment modalities, and eventually in precision dentistry applications.Doctor of Philosoph