title: Genome-wide association study of biologically informed periodontal complex traits offers novel insights into the genetic basis of periodontal disease.
abstract: Genome-wide association studies (GWAS) of chronic periodontitis (CP) defined by clinical criteria alone have had modest success to-date. Here, we refine the CP phenotype by supplementing clinical data with biological intermediates of microbial burden (levels of eight periodontal pathogens) and local inflammatory response (gingival crevicular fluid IL-1β) and derive periodontal complex traits (PCTs) via principal component analysis. PCTs were carried forward to GWAS (∼2.5 million markers) to identify PCT-associated loci among 975 European American adult participants of the Dental ARIC study. We sought to validate these findings for CP in the larger ARIC cohort (n = 821 participants with severe CP, 2031-moderate CP, 1914-healthy/mild disease) and an independent German sample including 717 aggressive periodontitis cases and 4210 controls. We identified six PCTs with distinct microbial community/IL-1β structures, although with overlapping clinical presentations. PCT1 was characterized by a uniformly high pathogen load, whereas PCT3 and PCT5 were dominated by Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis, respectively. We detected genome-wide significant signals for PCT1 (CLEC19A, TRA, GGTA2P, TM9SF2, IFI16, RBMS3), PCT4 (HPVC1) and PCT5 (SLC15A4, PKP2, SNRPN). Overall, the highlighted loci included genes associated with immune response and epithelial barrier function. With the exception of associations of BEGAIN with severe and UBE3D with moderate CP, no other loci were associated with CP in ARIC or aggressive periodontitis in the German sample. Although not associated with current clinically determined periodontal disease taxonomies, upon replication and mechanistic validation these candidate loci may highlight dysbiotic microbial community structures and altered inflammatory/immune responses underlying biological sub-types of CP.
authors.affiliation: Department of Periodontology, UNC School of Dentistry, Chapel Hill, NC, USA steven_offenbacher@unc.edu.
authors.forename: Steven
authors.initials: S
authors.lastname: Offenbacher
authors.affiliation: Department of Pediatric Dentistry, UNC School of Dentistry, Chapel Hill, NC, USA Department of Epidemiology, UNC Gillings School of Global Public Health, Chapel Hill, NC, USA.
authors.forename: Kimon
authors.initials: K
authors.lastname: Divaris
authors.affiliation: Department of Periodontology, UNC School of Dentistry, Chapel Hill, NC, USA.
authors.forename: Silvana P
authors.initials: SP
authors.lastname: Barros
authors.affiliation: Department of Dental Ecology, UNC School of Dentistry, Chapel Hill, NC, USA.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Moss
authors.affiliation: Department of Periodontology, UNC School of Dentistry, Chapel Hill, NC, USA.
authors.forename: Julie T
authors.initials: JT
authors.lastname: Marchesan
authors.affiliation: Department of Periodontology, UNC School of Dentistry, Chapel Hill, NC, USA.
authors.forename: Thiago
authors.initials: T
authors.lastname: Morelli
authors.affiliation: Department of Periodontology, UNC School of Dentistry, Chapel Hill, NC, USA.
authors.forename: Shaoping
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Periodontology, UNC School of Dentistry, Chapel Hill, NC, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Periodontology, UNC School of Dentistry, Chapel Hill, NC, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Dental Ecology, UNC School of Dentistry, Chapel Hill, NC, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Beck
authors.affiliation: Clinic of Internal Medicine I, University Clinic Schleswig-Holstein, Kiel, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Laudes
authors.affiliation: Department of Periodontology, Institute of Dental, Oral and Maxillary Medicine, Charité-University Medicine Berlin, Berlin, Germany Institute of Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Munz
authors.affiliation: Department of Periodontology, Institute of Dental, Oral and Maxillary Medicine, Charité-University Medicine Berlin, Berlin, Germany.
authors.forename: Arne S
authors.initials: AS
authors.lastname: Schaefer
authors.affiliation: Department of Epidemiology, UNC Gillings School of Global Public Health, Chapel Hill, NC, USA.
authors.forename: Kari E
authors.initials: KE
authors.lastname: North
mesh_terms: D055113:Chronic Periodontitis / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D005260:Female; D055106:Genome-Wide Association Study; D005858:Germany; D005883:Gingival Crevicular Fluid / Q000382:microbiology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000382:microbiology / Q000473:pathology; D053583:Interleukin-1beta / Q000235:genetics; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010510:Periodontal Diseases / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D010641:Phenotype; D016966:Porphyromonas gingivalis / Q000472:pathogenicity; D025341:Principal Component Analysis; D000074407:SAP90-PSD95 Associated Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D053583:Interleukin-1beta; D009419:Nerve Tissue Proteins; D000074407:SAP90-PSD95 Associated Proteins; C502845:UBE3D protein, human; D044767:Ubiquitin-Protein Ligases