Genome-wide association study of dental caries in the Hispanic Communities Health Study/Study of Latinos (HCHS/SOL)

Abstract

Dental caries is the most common chronic disease worldwide, and exhibits profound disparities in the USA with racial and ethnic minorities experiencing disproportionate disease burden. Though heritable, the specific genes influencing risk of dental caries remain largely unknown. Therefore, we performed genome-wide association scans (GWASs) for dental caries in a population-based cohort of 12 000 Hispanic/Latino participants aged 18-74 years from the HCHS/SOL. Intra-oral examinations were used to generate two common indices of dental caries experience which were tested for association with 27.7 M genotyped or imputed single-nucleotide polymorphisms separately in the six ancestry groups. A mixed-models approach was used, which adjusted for age, sex, recruitment site, five principal components of ancestry and additional features of the sampling design. Meta-analyses were used to combine GWAS results across ancestry groups. Heritability estimates ranged from 20-53% in the six ancestry groups. The most significant association observed via meta-analysis for both phenotypes was in the region of the NAMPT gene (rs190395159; P-value = 6 × 10(-10)), which is involved in many biological processes including periodontal healing. Another significant association was observed for rs72626594 (P-value = 3 × 10(-8)) downstream of BMP7, a tooth development gene. Other associations were observed in genes lacking known or plausible roles in dental caries. In conclusion, this was the largest GWAS of dental caries, to date and was the first to target Hispanic/Latino populations. Understanding the factors influencing dental caries susceptibility may lead to improvements in prediction, prevention and disease management, which may ultimately reduce the disparities in oral health across racial, ethnic and socioeconomic strata.

Figure 1.

Manhattan (left) and Q–Q (right) plots showing meta-analysis results (log₁₀-transformed P-values) for DMFT (top) and DMFS (bottom). Genomic inflation (λ) was 1.006 and 1.017, respectively, for DMFT and DMFS, indicating minimal evidence of model misspecification.

Figure 2.

Genetic association for NAMPT and (A) DMFS, (B) DFS and (C) MS. LocusZoom plots show the association (left y-axis; log₁₀-transformed P-values) with dental caries-related phenotypes of SNPs in the region around NAMPT. The purple triangle represents the top SNP, rs190395159, from the genome-wide scans (which was imputed with information quality score = 0.918 and R² = 0.947). Genotyped SNPs are indicated by circles and imputed SNPs are indicated by Xs. The blue overlay represents recombination rate (right y-axis) from reference data. Positions of genes are indicated below the plot. Linkage disequilibrium (r²) values were calculated from the HCHS/SOL sample.

Figure 3.

Forest plot for rs190395159. β-Values for DMFS models are shown for each ancestry group as squares proportional to the sample size. Error bars indicate the 99.999995% (i.e. genome-wide significant) confidence intervals. Meta-analyses effect sizes and confidence intervals are conveyed by the position and width of diamonds.

Figure 4.

Three SNPs, rs6947923, rs73409446 and rs73411544, in high-linkage disequilibrium (r² ≥ 0.7) with the lead SNP (rs190395159) overlap with putative enhancers. The rug plot shows positions relative to NAMPT of SNPs in linkage disequilibrium (indicated by color) with the lead SNP: red (r² = 1), blue (r² = 0.8), gold (r² = 0.7), light blue (r² = 0.6) and gray (r² = 0.5–0.4). Signal tracks are shown for biochemical signatures typical of upstream enhancer elements: DNase I hypersensitivity (22,23) (an indicator of chromatin accessibility; blue), transcription factor CTCF binding (red), Histone mark H3k4me1 (yellow) and Histone mark H3K27ac (magenta). The ENCODE (19) Txn factor ChIP track shows transcription factor-binding sites as gray boxes where the darkness of the shading is proportional to the maximum value seen in any ENCODE cell line in that region. A green highlighted region indicates the highest scoring site of a Factorbook-identified (24) canonical motif for the corresponding factor. The black boxes shown in the FANTOM5 enhancers track represent in vivo-transcribed enhancers identified using cap analysis gene expression in the FANTOM5 (21) project. HGF: human gingival fibroblasts; HPdLF: normal human periodontal ligament fibroblasts; AG09319: gum tissue fibroblasts from apparently healthy 24-year old; PKFPC: penis foreskin fibroblast primary cells; CfMdMS: chondrocytes from bone marrow-derived mesenchymal stem cell cultured cells.