title: Genome-wide association scan of dental caries in the permanent dentition.
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.
authors.affiliation: Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, 15219, USA. marazita@pitt.edu.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Wang
authors.forename: John R
authors.initials: JR
authors.lastname: Shaffer
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zeng
authors.forename: Ferdouse
authors.initials: F
authors.lastname: Begum
authors.forename: Alexandre R
authors.initials: AR
authors.lastname: Vieira
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Noel
authors.forename: Ida
authors.initials: I
authors.lastname: Anjomshoaa
authors.forename: Karen T
authors.initials: KT
authors.lastname: Cuenco
authors.forename: Myoung-Keun
authors.initials: MK
authors.lastname: Lee
authors.forename: James
authors.initials: J
authors.lastname: Beck
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: Marilyn C
authors.initials: MC
authors.lastname: Cornelis
authors.forename: Frank B
authors.initials: FB
authors.lastname: Hu
authors.forename: David R
authors.initials: DR
authors.lastname: Crosslin
authors.forename: Cathy C
authors.initials: CC
authors.lastname: Laurie
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Nelson
authors.forename: Kimberly F
authors.initials: KF
authors.lastname: Doheny
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: Pugh
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Polk
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Weyant
authors.forename: Richard
authors.initials: R
authors.lastname: Crout
authors.forename: Daniel W
authors.initials: DW
authors.lastname: McNeil
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Weeks
authors.forename: Eleanor
authors.initials: E
authors.lastname: Feingold
authors.forename: Mary L
authors.initials: ML
authors.lastname: Marazita
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002877:Chromosomes, Human / Q000235:genetics; D004245:DMF Index; D003731:Dental Caries / Q000235:genetics*; D003733:Dental Caries Susceptibility / Q000235:genetics*; D019229:Dentition, Permanent; D055106:Genome-Wide Association Study; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics*; D008875:Middle Aged; D060449:Wnt Signaling Pathway / Q000235:genetics*; D055815:Young Adult