Genome-wide association study reveals multiple loci associated with primary tooth development during infancy

Abstract

Tooth development is a highly heritable process which relates to other growth and developmental processes, and which interacts with the development of the entire craniofacial complex. Abnormalities of tooth development are common, with tooth agenesis being the most common developmental anomaly in humans. We performed a genome-wide association study of time to first tooth eruption and number of teeth at one year in 4,564 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966) and 1,518 individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC). We identified 5 loci at P<5x10(-8), and 5 with suggestive association (P<5x10(-6)). The loci included several genes with links to tooth and other organ development (KCNJ2, EDA, HOXB2, RAD51L1, IGF2BP1, HMGA2, MSRB3). Genes at four of the identified loci are implicated in the development of cancer. A variant within the HOXB gene cluster associated with occlusion defects requiring orthodontic treatment by age 31 years.

Figure 1. Linkage disequilibrium and association at loci reaching genome-wide significance for primary tooth development in meta-analysis of NFBC1966 and ALSPAC.

(A) KCNJ2 gene region for time to first tooth eruption. (B) EDA gene region for time to first tooth. (C) MSRB3 gene region for time to first tooth. (D) IGF2BP1 gene region for number of teeth at 12 months (SNP with high P at 44000 kb is that near HOXB2, rs6504340). Note: This is a gene-rich region, so most genes are omitted to simplify the plot. (E) RAD51L1 gene region for number of teeth at 12 months. -log₁₀ p-value is plotted against genomic position (NCBI build 36). Most significant SNP in each region is plotted in blue, r² with top SNP is colour coded red (0.8 – 1.0), orange (0.5 – 0.8), yellow (0.2 – 0.5), and white <0.2. Gene annotations are based on Genome Browser (RefSeq Genes) and arrows represent direction of transcription. Recombination rate is estimated by LDhat using HapMap CEU sample. All r² values are calculated in NFBC1966.

Figure 2. Meta-analysis for primary tooth development by genotype for the five SNPs attaining genome-wide significance.

Estimates and 95% confidence intervals for regression coefficients are given for the effect of delayed teething allele in Gaussian regression on time to first tooth and an ordinal regression on number of teeth.

Figure 3. The combined impact of the delayed tooth eruption alleles in 5 identified loci at P<5×10⁻⁸ in the NFBC1966.

Subjects are classified by the number of delayed tooth eruption alleles. SNPs are chosen so that they had the strongest signal for number of teeth at each locus. Mean time of first tooth eruption is plotted in red and number of teeth by the age of one year in black. The bars represent the number of individuals for each count of ‘delayed tooth eruption’ alleles. The line through points is a linear regression fit.