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Meta-Analysis
, 12, 57

Genome-wide Association Scan of Dental Caries in the Permanent Dentition

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Meta-Analysis

Genome-wide Association Scan of Dental Caries in the Permanent Dentition

Xiaojing Wang et al. BMC Oral Health.

Abstract

Background: Over 90% of adults aged 20 years or older with permanent teeth have suffered from dental caries leading to pain, infection, or even tooth loss. Although caries prevalence has decreased over the past decade, there are still about 23% of dentate adults who have untreated carious lesions in the US. Dental caries is a complex disorder affected by both individual susceptibility and environmental factors. Approximately 35-55% of caries phenotypic variation in the permanent dentition is attributable to genes, though few specific caries genes have been identified. Therefore, we conducted the first genome-wide association study (GWAS) to identify genes affecting susceptibility to caries in adults.

Methods: Five independent cohorts were included in this study, totaling more than 7000 participants. For each participant, dental caries was assessed and genetic markers (single nucleotide polymorphisms, SNPs) were genotyped or imputed across the entire genome. Due to the heterogeneity among the five cohorts regarding age, genotyping platform, quality of dental caries assessment, and study design, we first conducted genome-wide association (GWA) analyses on each of the five independent cohorts separately. We then performed three meta-analyses to combine results for: (i) the comparatively younger, Appalachian cohorts (N = 1483) with well-assessed caries phenotype, (ii) the comparatively older, non-Appalachian cohorts (N = 5960) with inferior caries phenotypes, and (iii) all five cohorts (N = 7443). Top ranking genetic loci within and across meta-analyses were scrutinized for biologically plausible roles on caries.

Results: Different sets of genes were nominated across the three meta-analyses, especially between the younger and older age cohorts. In general, we identified several suggestive loci (P-value ≤ 10E-05) within or near genes with plausible biological roles for dental caries, including RPS6KA2 and PTK2B, involved in p38-depenedent MAPK signaling, and RHOU and FZD1, involved in the Wnt signaling cascade. Both of these pathways have been implicated in dental caries. ADMTS3 and ISL1 are involved in tooth development, and TLR2 is involved in immune response to oral pathogens.

Conclusions: As the first GWAS for dental caries in adults, this study nominated several novel caries genes for future study, which may lead to better understanding of cariogenesis, and ultimately, to improved disease predictions, prevention, and/or treatment.

Figures

Figure 1
Figure 1
GWAS results in three Meta-Analyses: Manhattan and Q-Q plots. All P-values are negative log10 transformed. Each point represents a genotyped or imputed (whenever available) SNP marker.
Figure 2
Figure 2
Regional plots of P-values at top loci in meta-analyses. Negative log10 transformed P-values and physical positions for SNPs in the region are shown. Colors indicate linkage disequilibrium between the index SNP (colored in purple) and other SNPs based on HapMap CEU data. The rug plot indicates regional SNP density. The recombination rate overlay is based on HapMap CEU data. Gene positions and directions of transcription are annotated based on hg19/1000 Genomes Nov 2010 release.
Figure 3
Figure 3
Venn diagram summarizing common Genes (on or near SNPs with P-value ≤ 10E-5) cross meta-analyses.

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