Genome-wide analysis of dental caries and periodontitis combining clinical and self-reported data

Dmitry Shungin, Simon Haworth, Kimon Divaris, Cary S Agler, Yoichiro Kamatani, Myoung Keun Lee, Kelsey Grinde, George Hindy, Viivi Alaraudanjoki, Paula Pesonen, Alexander Teumer, Birte Holtfreter, Saori Sakaue, Jun Hirata, Yau-Hua Yu, Paul M Ridker, Franco Giulianini, Daniel I Chasman, Patrik K E Magnusson, Takeaki Sudo, Yukinori Okada, Uwe Völker, Thomas Kocher, Vuokko Anttonen, Marja-Liisa Laitala, Marju Orho-Melander, Tamar Sofer, John R Shaffer, Alexandre Vieira, Mary L Marazita, Michiaki Kubo, Yasushi Furuichi, Kari E North, Steve Offenbacher, Erik Ingelsson, Paul W Franks, Nicholas J Timpson, Ingegerd Johansson, Dmitry Shungin, Simon Haworth, Kimon Divaris, Cary S Agler, Yoichiro Kamatani, Myoung Keun Lee, Kelsey Grinde, George Hindy, Viivi Alaraudanjoki, Paula Pesonen, Alexander Teumer, Birte Holtfreter, Saori Sakaue, Jun Hirata, Yau-Hua Yu, Paul M Ridker, Franco Giulianini, Daniel I Chasman, Patrik K E Magnusson, Takeaki Sudo, Yukinori Okada, Uwe Völker, Thomas Kocher, Vuokko Anttonen, Marja-Liisa Laitala, Marju Orho-Melander, Tamar Sofer, John R Shaffer, Alexandre Vieira, Mary L Marazita, Michiaki Kubo, Yasushi Furuichi, Kari E North, Steve Offenbacher, Erik Ingelsson, Paul W Franks, Nicholas J Timpson, Ingegerd Johansson

Abstract

Dental caries and periodontitis account for a vast burden of morbidity and healthcare spending, yet their genetic basis remains largely uncharacterized. Here, we identify self-reported dental disease proxies which have similar underlying genetic contributions to clinical disease measures and then combine these in a genome-wide association study meta-analysis, identifying 47 novel and conditionally-independent risk loci for dental caries. We show that the heritability of dental caries is enriched for conserved genomic regions and partially overlapping with a range of complex traits including smoking, education, personality traits and metabolic measures. Using cardio-metabolic traits as an example in Mendelian randomization analysis, we estimate causal relationships and provide evidence suggesting that the processes contributing to dental caries may have undesirable downstream effects on health.

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Estimated heritability of and genetic correlation between measures of dental disease. a estimated heritability (h2LDSR) for each trait in GLIDE (plotted in circles) and UKB (plotted in triangles). Error bars represent 95% confidence intervals. b Estimated genetic correlations (Rg) between traits in GLIDE and UKB. Cells are shaded according to the value of Rg
Fig. 2
Fig. 2
Single-variant results in combined analysis of GLIDE and UKB. a Manhattan plot of the DMFS/dentures combined analysis. The red line indicates the threshold for genome-wide significance at (P = 5 × 10−8), and the black line indicates a suggestive threshold for association at (P = 1 × 10−5). Loci achieving genome-wide significance in the combined analysis (Z-test) are coloured in magenta. P-values for the same loci are shown in blue for dentures in UKB and yellow for DMFS in GLIDE. b Concordance of genetic effects in the DMFS/dentures combined analysis. Each point represents a conditionally independent signal of association (P < 5 × 10−8). c Manhattan plot of the periodontitis/loose teeth combined analysis. The red line indicates the threshold for genome-wide significance at (P = 5 × 10−8), and the black line indicates a suggestive threshold for association at (P = 1 × 10−5). The single-locus meeting this threshold is coloured in magenta. P-values for the same locus are shown in yellow for periodontitis in GLIDE, and blue for loose teeth in UKB. d Concordance in genetic effects in the periodontitis/loose teeth combined analysis. The magenta point represents the single locus with P < 5 × 10−8, grey points represent conditionally independent suggestively associated loci with P < 1 × 10−5 in combined analysis
Fig. 3
Fig. 3
Estimated genetic correlations between DMFS/dentures and health traits or outcomes. Markers indicate the estimated magnitude of Rg, error bars represent 95% confidence intervals (1.96* LDSR standard errors on either side of the point estimate)
Fig. 4
Fig. 4
Estimated genetic correlations between periodontitis/loose teeth and health traits or outcomes. Markers indicate the estimated magnitude of Rg, error bars represent 95% confidence intervals (1.96* LDSR standard errors on either side of the point estimate)

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