Meta-Analysis

. 2019 Jun 24;10(1):2773.

doi: 10.1038/s41467-019-10630-1.

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

Dmitry Shungin^{1

2}, Simon Haworth^{3

4}, Kimon Divaris^{5

6}, Cary S Agler⁷, Yoichiro Kamatani⁸, Myoung Keun Lee⁹, Kelsey Grinde¹⁰, George Hindy¹¹, Viivi Alaraudanjoki¹², Paula Pesonen¹³, Alexander Teumer¹⁴, Birte Holtfreter¹⁵, Saori Sakaue¹⁶, Jun Hirata¹⁶, Yau-Hua Yu^{17

18}, Paul M Ridker^{17

19}, Franco Giulianini¹⁷, Daniel I Chasman^{17

19}, Patrik K E Magnusson²⁰, Takeaki Sudo²¹, Yukinori Okada¹⁶, Uwe Völker²², Thomas Kocher¹⁵, Vuokko Anttonen^{12

23}, Marja-Liisa Laitala¹², Marju Orho-Melander¹¹, Tamar Sofer^{19

24}, John R Shaffer^{9

25

26}, Alexandre Vieira²⁶, Mary L Marazita^{9

25

26}, Michiaki Kubo⁸, Yasushi Furuichi²⁷, Kari E North²⁸, Steve Offenbacher²⁹, Erik Ingelsson^{30

31

32}, Paul W Franks^{33

34

35}, Nicholas J Timpson³⁶, Ingegerd Johansson¹

Affiliations

¹ Department of Odontology, Umeå University, Umeå, SE-901 85, Sweden.
² Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
³ Medical Research Council Integrative Epidemiology Unit, Bristol Medical School, Bristol, BS8 2BN, UK. simon.haworth@bristol.ac.uk.
⁴ Bristol Dental School, Bristol, BS1 2LY, UK. simon.haworth@bristol.ac.uk.
⁵ Department of Pediatric Dentistry, School of Dentistry, University of North Carolina, Chapel Hill, NC, 27599, USA.
⁶ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, 27599, USA.
⁷ Department of Oral and Craniofacial Health Sciences, University of North Carolina, Chapel Hill, NC, 27599, USA.
⁸ RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, Japan.
⁹ Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, 15219, USA.
¹⁰ Department of Biostatistics, University of Washington, Seattle, WA, 98195, USA.
¹¹ Lund University, Lund, SE-223 62, Sweden.
¹² Research Unit of Oral Health Sciences University of Oulu, Oulu, FI-90014, Finland.
¹³ Infrastructure for Population Studies, Faculty of Medicine, University of Oulu, Oulu, FI-90014, Finland.
¹⁴ Institute for Community Medicine, University Medicine Greifswald, Greifswald, 17475, Germany.
¹⁵ Department of Restorative Dentistry, Periodontology, Endodontology, and Preventive and Pediatric Dentistry University Medicine Greifswald, Greifswald, 17475, Germany.
¹⁶ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan.
¹⁷ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, 02215, USA.
¹⁸ Department of Periodontology, Tufts University School of Dental Medicine, Boston, MA, 02111, USA.
¹⁹ Harvard Medical School, Boston, MA, 02115, USA.
²⁰ Department of Medical Epidemiology and Biostatistics, Karolinska Instituet, Stockholm, SE-171 77, Sweden.
²¹ Department of Periodontology, Graduate School of Medical and Dental Science of Tokyo Medical and Dental University, Tokyo, 113-8510, Japan.
²² Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, 17475, Germany.
²³ MRC, Oulu University Hospital and University of Oulu, Oulu, FI-90014, Finland.
²⁴ Department of Sleep Medicine, Brigham and Women's Hospital, Boston, MA, 02130, USA.
²⁵ Department of Human Genetics, University of Pittburgh, Pittsburgh, PA, 15261, USA.
²⁶ Department of Oral Biology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
²⁷ Department of Oral Rehabilitation, Division of Periodontology and Endodontology, School of Dentistry, Health Sciences University of Hokkaido, Tobetsu, Hokkaido, 061-0293, Japan.
²⁸ Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27516, USA.
²⁹ Department of Periodontology, University of North Carolina, Chapel Hill, NC, 27599, USA.
³⁰ Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
³¹ Stanford Cardiovascular Institute, Stanford University, Stanford, CA, 94305, USA.
³² Stanford Diabetes Research Center, Stanford University, Stanford, CA, 94305, USA.
³³ Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, SE-214 28, Sweden.
³⁴ Department of Public Health and Clinical Medicine, Umeå University, Umeå, SE-901 87, Sweden.
³⁵ Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA.
³⁶ Medical Research Council Integrative Epidemiology Unit, Bristol Medical School, Bristol, BS8 2BN, UK.

PMID: 31235808
PMCID: PMC6591304
DOI: 10.1038/s41467-019-10630-1

Meta-Analysis

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

Dmitry Shungin et al. Nat Commun. 2019.

. 2019 Jun 24;10(1):2773.

doi: 10.1038/s41467-019-10630-1.

Authors

Affiliations

¹ Department of Odontology, Umeå University, Umeå, SE-901 85, Sweden.
² Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
³ Medical Research Council Integrative Epidemiology Unit, Bristol Medical School, Bristol, BS8 2BN, UK. simon.haworth@bristol.ac.uk.
⁴ Bristol Dental School, Bristol, BS1 2LY, UK. simon.haworth@bristol.ac.uk.
⁵ Department of Pediatric Dentistry, School of Dentistry, University of North Carolina, Chapel Hill, NC, 27599, USA.
⁶ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, 27599, USA.
⁷ Department of Oral and Craniofacial Health Sciences, University of North Carolina, Chapel Hill, NC, 27599, USA.
⁸ RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, Japan.
⁹ Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, 15219, USA.
¹⁰ Department of Biostatistics, University of Washington, Seattle, WA, 98195, USA.
¹¹ Lund University, Lund, SE-223 62, Sweden.
¹² Research Unit of Oral Health Sciences University of Oulu, Oulu, FI-90014, Finland.
¹³ Infrastructure for Population Studies, Faculty of Medicine, University of Oulu, Oulu, FI-90014, Finland.
¹⁴ Institute for Community Medicine, University Medicine Greifswald, Greifswald, 17475, Germany.
¹⁵ Department of Restorative Dentistry, Periodontology, Endodontology, and Preventive and Pediatric Dentistry University Medicine Greifswald, Greifswald, 17475, Germany.
¹⁶ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan.
¹⁷ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, 02215, USA.
¹⁸ Department of Periodontology, Tufts University School of Dental Medicine, Boston, MA, 02111, USA.
¹⁹ Harvard Medical School, Boston, MA, 02115, USA.
²⁰ Department of Medical Epidemiology and Biostatistics, Karolinska Instituet, Stockholm, SE-171 77, Sweden.
²¹ Department of Periodontology, Graduate School of Medical and Dental Science of Tokyo Medical and Dental University, Tokyo, 113-8510, Japan.
²² Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, 17475, Germany.
²³ MRC, Oulu University Hospital and University of Oulu, Oulu, FI-90014, Finland.
²⁴ Department of Sleep Medicine, Brigham and Women's Hospital, Boston, MA, 02130, USA.
²⁵ Department of Human Genetics, University of Pittburgh, Pittsburgh, PA, 15261, USA.
²⁶ Department of Oral Biology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
²⁷ Department of Oral Rehabilitation, Division of Periodontology and Endodontology, School of Dentistry, Health Sciences University of Hokkaido, Tobetsu, Hokkaido, 061-0293, Japan.
²⁸ Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27516, USA.
²⁹ Department of Periodontology, University of North Carolina, Chapel Hill, NC, 27599, USA.
³⁰ Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
³¹ Stanford Cardiovascular Institute, Stanford University, Stanford, CA, 94305, USA.
³² Stanford Diabetes Research Center, Stanford University, Stanford, CA, 94305, USA.
³³ Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, SE-214 28, Sweden.
³⁴ Department of Public Health and Clinical Medicine, Umeå University, Umeå, SE-901 87, Sweden.
³⁵ Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA.
³⁶ Medical Research Council Integrative Epidemiology Unit, Bristol Medical School, Bristol, BS8 2BN, UK.

PMID: 31235808
PMCID: PMC6591304
DOI: 10.1038/s41467-019-10630-1

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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1**
Estimated heritability of and genetic correlation between measures of dental disease. a estimated heritability (h²_LDSR) for each trait in GLIDE (plotted in circles) and UKB (plotted in triangles). Error bars represent 95% confidence intervals. b Estimated genetic correlations (R_g) between traits in GLIDE and UKB. Cells are shaded according to the value of R_g

**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**
Estimated genetic correlations between DMFS/dentures and health traits or outcomes. Markers indicate the estimated magnitude of R_g, error bars represent 95% confidence intervals (1.96* LDSR standard errors on either side of the point estimate)

**Fig. 4**
Estimated genetic correlations between periodontitis/loose teeth and health traits or outcomes. Markers indicate the estimated magnitude of R_g, error bars represent 95% confidence intervals (1.96* LDSR standard errors on either side of the point estimate)

See this image and copyright information in PMC

References

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical