title: Chronic periodontitis genome-wide association studies: gene-centric and gene set enrichment analyses.
abstract: Recent genome-wide association studies (GWAS) of chronic periodontitis (CP) offer rich data sources for the investigation of candidate genes, functional elements, and pathways. We used GWAS data of CP (n = 4,504) and periodontal pathogen colonization (n = 1,020) from a cohort of adult Americans of European descent participating in the Atherosclerosis Risk in Communities study and employed a MAGENTA approach (i.e., meta-analysis gene set enrichment of variant associations) to obtain gene-centric and gene set association results corrected for gene size, number of single-nucleotide polymorphisms, and local linkage disequilibrium characteristics based on the human genome build 18 (National Center for Biotechnology Information build 36). We used the Gene Ontology, Ingenuity, KEGG, Panther, Reactome, and Biocarta databases for gene set enrichment analyses. Six genes showed evidence of statistically significant association: 4 with severe CP (NIN, p = 1.6 × 10(-7); ABHD12B, p = 3.6 × 10(-7); WHAMM, p = 1.7 × 10(-6); AP3B2, p = 2.2 × 10(-6)) and 2 with high periodontal pathogen colonization (red complex-KCNK1, p = 3.4 × 10(-7); Porphyromonas gingivalis-DAB2IP, p = 1.0 × 10(-6)). Top-ranked genes for moderate CP were HGD (p = 1.4 × 10(-5)), ZNF675 (p = 1.5 × 10(-5)), TNFRSF10C (p = 2.0 × 10(-5)), and EMR1 (p = 2.0 × 10(-5)). Loci containing NIN, EMR1, KCNK1, and DAB2IP had showed suggestive evidence of association in the earlier single-nucleotide polymorphism-based analyses, whereas WHAMM and AP2B2 emerged as novel candidates. The top gene sets included severe CP ("endoplasmic reticulum membrane," "cytochrome P450," "microsome," and "oxidation reduction") and moderate CP ("regulation of gene expression," "zinc ion binding," "BMP signaling pathway," and "ruffle"). Gene-centric analyses offer a promising avenue for efficient interrogation of large-scale GWAS data. These results highlight genes in previously identified loci and new candidate genes and pathways possibly associated with CP, which will need to be validated via replication and mechanistic studies.
authors: Department of Pediatric Dentistry, School of Dentistry, University of North Carolina, Chapel Hill, NC, USA.
authors: K
authors: K
authors: Rhodin
authors: Department of Pediatric Dentistry, School of Dentistry, University of North Carolina, Chapel Hill, NC, USA Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
authors: K
authors: K
authors: Divaris
authors: Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA Carolina Center for Genome Sciences, Chapel Hill, NC, USA.
authors: K E
authors: KE
authors: North
authors: Department of Periodontology, School of Dentistry, University of North Carolina, Chapel Hill, NC, USA.
authors: S P
authors: SP
authors: Barros
authors: Department of Dental Ecology, School of Dentistry, University of North Carolina, Chapel Hill, NC, USA.
authors: K
authors: K
authors: Moss
authors: Department of Dental Ecology, School of Dentistry, University of North Carolina, Chapel Hill, NC, USA.
authors: J D
authors: JD
authors: Beck
authors: Department of Periodontology, School of Dentistry, University of North Carolina, Chapel Hill, NC, USA Steven_Offenbacher@unc.edu.
authors: S
authors: S
authors: Offenbacher
mesh_terms: D033963:Adaptor Protein Complex 3 / Q000235:genetics; D033966:Adaptor Protein Complex beta Subunits / Q000235:genetics; D000328:Adult; D000368:Aged; D016976:Aggregatibacter actinomycetemcomitans / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000382:microbiology; D002135:Calcium-Binding Proteins; D002874:Chromosome Mapping; D055113:Chronic Periodontitis / Q000235:genetics* / Q000382:microbiology; D015331:Cohort Studies; D003598:Cytoskeletal Proteins / Q000235:genetics; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics; D056726:Genetic Association Studies; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008875:Middle Aged; D008994:Monoacylglycerol Lipases / Q000235:genetics; D009077:Mucins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D016966:Porphyromonas gingivalis / Q000235:genetics; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics; D011446:Prospective Studies; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D018000:Receptors, Peptide / Q000235:genetics; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D012307:Risk Factors; D053319:Tumor Necrosis Factor Decoy Receptors / Q000235:genetics; D020703:ras GTPase-Activating Proteins / Q000235:genetics
chemical_list: C094471:ADGRE1 protein, human; C095597:AP3B2 protein, human; D033963:Adaptor Protein Complex 3; D033966:Adaptor Protein Complex beta Subunits; D002135:Calcium-Binding Proteins; D003598:Cytoskeletal Proteins; C462952:DAB2IP protein, human; D058851:GPI-Linked Proteins; C109137:KCNK1 protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009077:Mucins; C512806:NIN protein, human; D009687:Nuclear Proteins; D024683:Potassium Channels, Tandem Pore Domain; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D053320:Receptors, Tumor Necrosis Factor, Member 10c; C108661:TNFRSF10C protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; C578123:WHAMM protein, human; D020703:ras GTPase-Activating Proteins; C552558:ABHD12 protein, human; D008994:Monoacylglycerol Lipases
keywords: bacteria; genetics; genomics; inflammation; pathway analysis; periodontal disease