Background: Over 90% of adults aged 20 years or older with permanent teeth have suffered from dental caries\r\nleading to pain, infection, or even tooth loss. Although caries prevalence has decreased over the past decade, there\r\nare still about 23% of dentate adults who have untreated carious lesions in the US. Dental caries is a complex\r\ndisorder affected by both individual susceptibility and environmental factors. Approximately 35-55% of caries\r\nphenotypic variation in the permanent dentition is attributable to genes, though few specific caries genes have\r\nbeen identified. Therefore, we conducted the first genome-wide association study (GWAS) to identify genes\r\naffecting susceptibility to caries in adults.\r\nMethods: Five independent cohorts were included in this study, totaling more than 7000 participants. For each\r\nparticipant, dental caries was assessed and genetic markers (single nucleotide polymorphisms, SNPs) were\r\ngenotyped or imputed across the entire genome. Due to the heterogeneity among the five cohorts regarding age,\r\ngenotyping platform, quality of dental caries assessment, and study design, we first conducted genome-wide\r\nassociation (GWA) analyses on each of the five independent cohorts separately. We then performed three\r\nmeta-analyses to combine results for: (i) the comparatively younger, Appalachian cohorts (N = 1483) with\r\nwell-assessed caries phenotype, (ii) the comparatively older, non-Appalachian cohorts (N = 5960) with inferior caries\r\nphenotypes, and (iii) all five cohorts (N = 7443). Top ranking genetic loci within and across meta-analyses were\r\nscrutinized for biologically plausible roles on caries.\r\nResults: Different sets of genes were nominated across the three meta-analyses, especially between the younger\r\nand older age cohorts. In general, we identified several suggestive loci (P-value = 10E-05) within or near genes with\r\nplausible biological roles for dental caries, including RPS6KA2 and PTK2B, involved in p38-depenedent MAPK\r\nsignaling, and RHOU and FZD1, involved in the Wnt signaling cascade. Both of these pathways have been\r\nimplicated in dental caries. ADMTS3 and ISL1 are involved in tooth development, and TLR2 is involved in immune\r\nresponse to oral pathogens.\r\nConclusions: As the first GWAS for dental caries in adults, this study nominated several novel caries genes for\r\nfuture study, which may lead to better understanding of cariogenesis, and ultimately, to improved disease\r\npredictions, prevention, and/or treatment
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