Early childhood caries (ECC) is the most common non-communicable childhood disease. It is an important health problem with known environmental and social/behavioral influences that lacks evidence for specific associated genetic risk loci. To address this knowledge gap, we conducted a genome-wide association study of ECC in a multi-ancestry population of U.S. preschool-age children (n=6,103) participating in a community-based epidemiologic study of early childhood oral health. Calibrated examiners used ICDAS criteria to measure ECC with the primary trait using the dmfs index with decay classified as macroscopic enamel loss (ICDAS ≥3). We estimated heritability, concordance rates, and conducted genome-wide association analyses to estimate overall genetic effects; the effects stratified by sex, household water fluoride, and dietary sugar; and leveraged the combined gene/gene-environment effects using the 2-degree-of-freedom (2df) joint test. The common genetic variants explained 24% of the phenotypic variance (heritability) of the primary ECC trait and the concordance rate was higher with a higher degree of relatedness. We identified 21 novel non-overlapping genome-wide significant loci for ECC. Two loci, namely RP11-856F16.2 (rs74606067) and SLC41A3 (rs71327750) showed evidence of association with dental caries in external cohorts, namely the GLIDE consortium adult cohort (n=~487,000) and the GLIDE pediatric cohort (n=19,000), respectively. The gene-based tests identified TAAR6 as a genome-wide significant gene. Implicated genes have relevant biological functions including roles in tooth development and taste. These novel associations expand the genomics knowledge base for this common childhood disease and underscore the importance of accounting for sex and pertinent environmental exposures in genetic investigations of oral health.

During the preparation of this manuscript, John Preisser served on a data safety and monitoring board of a study funded by NIDCR. The remaining authors declare no competing interests.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642073/

This work was supported by research grants from the National Institutes of Health: National Institute for Dental and Craniofacial Research U01DE025046 (K.D., A.G.F.Z, D.Y.L, J.S.P, G.D.S., K.E.N) and National Human Genome Research Institute X01HG010871 (K.D.).

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The study was reviewed and approved by the University of North Carolina - Chapel Hill Office of Human Research Ethics Institutional Review Board on 18th September 2014 (IRB# 14-1992).

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