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. 2016 May 15;25(10):2113-2129.
doi: 10.1093/hmg/ddw069. Epub 2016 Mar 8.

Genome-wide association study of biologically informed periodontal complex traits offers novel insights into the genetic basis of periodontal disease

Steven Offenbacher  1 , Kimon Divaris  2 , Silvana P Barros  3 , Kevin L Moss  4 , Julie T Marchesan  3 , Thiago Morelli  3 , Shaoping Zhang  3 , Steven Kim  3 , Lu Sun  3 , James D Beck  4 , Matthias Laudes  5 , Matthias Munz  6 , Arne S Schaefer  7 , Kari E North  8
Affiliations

Genome-wide association study of biologically informed periodontal complex traits offers novel insights into the genetic basis of periodontal disease

Steven Offenbacher et al. Hum Mol Genet. .

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.

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Figures

Figure 1.
Figure 1.
Principal component trait (PCT) pattern profiles.
Figure 2.
Figure 2.
(A) Periodontal Complex Trait 1 (Socransky Trait) Manhattan plot. (B) Periodontal Complex Trait 4 Manhattan plot. (C) Periodontal Complex Trait 5 (Pg Trait) Manhattan plot.
Figure 3.
Figure 3.
(A) PCT1 locus CLEC19A. (B) PCT1 locus IFI16. (C) PCT1 locus PKP2.
Figure 4.
Figure 4.
Model of genetic and microbial patterns of periodontal disease.
See this image and copyright information in PMC

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