TY - JOUR
T1 - Genome-wide association Scan of dental caries in the permanent dentition
AU - Wang, Xiaojing
AU - Shaffer, John R.
AU - Zeng, Zhen
AU - Begum, Ferdouse
AU - Vieira, Alexandre R.
AU - Noel, Jacqueline
AU - Anjomshoaa, Ida
AU - Cuenco, Karen T.
AU - Lee, Myoung Keun
AU - Beck, James
AU - Boerwinkle, Eric
AU - Cornelis, Marilyn C.
AU - Hu, Frank B.
AU - Crosslin, David R.
AU - Laurie, Cathy C.
AU - Nelson, Sarah C.
AU - Doheny, Kimberly F.
AU - Pugh, Elizabeth W.
AU - Polk, Deborah E.
AU - Weyant, Robert J.
AU - Crout, Richard
AU - McNeil, Daniel W.
AU - Weeks, Daniel E.
AU - Feingold, Eleanor
AU - Marazita, Mary L.
N1 - Funding Information:
(1) Funding support for the study entitled “Dental Caries: Whole Genome Association and Gene x Environment Studies” was provided by the National Institutes of Dental and Craniofacial Research (NIDCR) as part of the trans-NIH Genes, Environment and Health Initiative [GEI] (U01-DE018903). This study is one of the genome-wide association studies funded as part of the Gene Environment Association Studies (GENEVA) program of the GEI. Genotyping was done by the Johns Hopkins University (JHU) Center for Inherited Disease Research (CIDR), with funding from the National Institute of Dental and Craniofacial Research (NIDCR), through the National Institutes of Health (NIH) contract to JHU, contract number HHSN268200782096C. Funds for this project’s genotyping were provided by the NIDCR through CIDR’s NIH contract. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01-HG004446) and by NCBI. Data and samples were provided by the Center for Oral Health Research in Appalachia (a collaboration of the University of Pittsburgh and West Virginia University funded by NIDCR R01-DE 014899); (2) the University of Pittsburgh School of Dental Medicine Dental Registry and DNA Repository (DRDR). The DRDR is supported by the School of Dental Medicine and NIH Grant 5TL1RR024155. I. Anjomshoaa was supported by the CTSI START UP program, the short-term pre-doctoral award through the Clinical and Translational Science Institute and the Institute for Clinical Research Education at the University of Pittsburgh (NIH Grant 5TL1RR024155-02). Financial support for A.R. Vieira was provided by NIH Grant R01-DE018914. (3) Additional support was provided by R03-DE021425, and UL1RR024153 . Dental data from two other GENEVA projects ARIC and HPFS were also included. ARIC dental data collection was funded by R01-DE11551 from NIDCR. Data collection for HPFS T2D cohort included in this project was funded by U01-HG004399 from NIH. The datasets used for the analyses described in this manuscript are available from dbGaP [http://www.ncbi.nlm.nih.gov/gap]; specifically dbGaP accession number phs000095.v1.p1 for the GENEVA dental caries data, accession number phs000090.v1.p1 for ARIC and phs000091.v2.p1 for HPFS.
PY - 2012/12/21
Y1 - 2012/12/21
N2 - 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.
AB - 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.
KW - Dental caries
KW - Genetics
KW - Genome wide association
KW - Genomics
KW - Permanent dentition
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U2 - 10.1186/1472-6831-12-57
DO - 10.1186/1472-6831-12-57
M3 - Article
C2 - 22748001
AN - SCOPUS:84871397749
VL - 12
JO - BMC Oral Health
JF - BMC Oral Health
SN - 1472-6831
IS - 1
M1 - 57
ER -