Association of Early Childhood Caries with Bitter Taste Receptors: A Meta-Analysis of Genome-Wide Association Studies and Transcriptome-Wide Association Study

Ekaterina Orlova; Tom Dudding; Jonathan M. Chernus; Rasha N. Alotaibi; Simon Haworth; Richard J. Crout; Myoung Keun Lee; Nandita Mukhopadhyay; Eleanor Feingold; Steven M. Levy; Daniel W. McNeil; Betsy Foxman; Robert J. Weyant; Nicholas J. Timpson; Mary L. Marazita; John R. Shaffer

doi:10.3390/genes14010059

Association of Early Childhood Caries with Bitter Taste Receptors: A Meta-Analysis of Genome-Wide Association Studies and Transcriptome-Wide Association Study

Ekaterina Orlova
, Tom Dudding
, Jonathan M. Chernus
, Rasha N. Alotaibi
, Simon Haworth
, Richard J. Crout
, Myoung Keun Lee
, Nandita Mukhopadhyay
, Eleanor Feingold
, Steven M. Levy
, Daniel W. McNeil
, Betsy Foxman
, Robert J. Weyant
, Nicholas J. Timpson
, Mary L. Marazita
, John R. Shaffer^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

17 Citations (Scopus)

Abstract

Although genetics affects early childhood caries (ECC) risk, few studies have focused on finding its specific genetic determinants. Here, we performed genome-wide association studies (GWAS) in five cohorts of children (aged up to 5 years, total N = 2974, cohorts: Center for Oral Health Research in Appalachia cohorts one and two [COHRA1, COHRA2], Iowa Fluoride Study, Iowa Head Start, Avon Longitudinal Study of Parents and Children [ALSPAC]) aiming to identify genes with potential roles in ECC biology. We meta-analyzed the GWASs testing ~3.9 million genetic variants and found suggestive evidence for association at genetic regions previously associated with caries in primary and permanent dentition, including the β-defensin anti-microbial proteins. We then integrated the meta-analysis results with gene expression data in a transcriptome-wide association study (TWAS). This approach identified four genes whose genetically predicted expression was associated with ECC (p-values < 3.09 × 10⁻⁶; CDH17, TAS2R43, SMIM10L1, TAS2R14). Some of the strongest associations were with genes encoding members of the bitter taste receptor family (TAS2R); other members of this family have previously been associated with caries. Of note, we identified the receptor encoded by TAS2R14, which stimulates innate immunity and anti-microbial defense in response to molecules released by the cariogenic bacteria, Streptococcus mutans and Staphylococcus aureus. These findings provide insight into ECC genetic architecture, underscore the importance of host-microbial interaction in caries risk, and identify novel risk genes.

Original language	English
Article number	59
Number of pages	17
Journal	Genes
Volume	14
Issue number	1
Early online date	24 Dec 2022
DOIs	https://doi.org/10.3390/genes14010059
Publication status	Published - 1 Jan 2023

Bibliographical note

Funding Information:
This research was funded by the UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z); the University of Bristol provides core support for ALSPAC; a comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf); ALSPAC GWAS data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe; the research on data from the COHRA1 and COHRA2 cohorts was supported by U.S. National Institutes of Health (NIH) grants R01-DE014899, 1-U01-DE018903, and X01-HG009878; the IFS and IHS cohorts were supported by NIH grants R01-DE09551, 1-U01-DE018903, X01-HG009878, R01-DE014899, and P30-DE10126. The authors declare no financial relationships with any organizations that might have an interest in the submitted work in the previous three years and no other relationships or activities that could appear to have influenced the submitted work.

Publisher Copyright:
© 2022 by the authors.

Keywords

child
genetics
molecular epidemiology
oral health

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Orlova, E., Dudding, T., Chernus, J. M., Alotaibi, R. N., Haworth, S., Crout, R. J., Lee, M. K., Mukhopadhyay, N., Feingold, E., Levy, S. M., McNeil, D. W., Foxman, B., Weyant, R. J., Timpson, N. J., Marazita, M. L., & Shaffer, J. R. (2023). Association of Early Childhood Caries with Bitter Taste Receptors: A Meta-Analysis of Genome-Wide Association Studies and Transcriptome-Wide Association Study. Genes, 14(1), Article 59. https://doi.org/10.3390/genes14010059

@article{43f2b71b92104896bac9c8d496bad272,

title = "Association of Early Childhood Caries with Bitter Taste Receptors: A Meta-Analysis of Genome-Wide Association Studies and Transcriptome-Wide Association Study",

abstract = "Although genetics affects early childhood caries (ECC) risk, few studies have focused on finding its specific genetic determinants. Here, we performed genome-wide association studies (GWAS) in five cohorts of children (aged up to 5 years, total N = 2974, cohorts: Center for Oral Health Research in Appalachia cohorts one and two [COHRA1, COHRA2], Iowa Fluoride Study, Iowa Head Start, Avon Longitudinal Study of Parents and Children [ALSPAC]) aiming to identify genes with potential roles in ECC biology. We meta-analyzed the GWASs testing \textasciitilde{}3.9 million genetic variants and found suggestive evidence for association at genetic regions previously associated with caries in primary and permanent dentition, including the β-defensin anti-microbial proteins. We then integrated the meta-analysis results with gene expression data in a transcriptome-wide association study (TWAS). This approach identified four genes whose genetically predicted expression was associated with ECC (p-values < 3.09 × 10−6; CDH17, TAS2R43, SMIM10L1, TAS2R14). Some of the strongest associations were with genes encoding members of the bitter taste receptor family (TAS2R); other members of this family have previously been associated with caries. Of note, we identified the receptor encoded by TAS2R14, which stimulates innate immunity and anti-microbial defense in response to molecules released by the cariogenic bacteria, Streptococcus mutans and Staphylococcus aureus. These findings provide insight into ECC genetic architecture, underscore the importance of host-microbial interaction in caries risk, and identify novel risk genes.",

keywords = "child, genetics, molecular epidemiology, oral health",

author = "Ekaterina Orlova and Tom Dudding and Chernus, \{Jonathan M.\} and Alotaibi, \{Rasha N.\} and Simon Haworth and Crout, \{Richard J.\} and Lee, \{Myoung Keun\} and Nandita Mukhopadhyay and Eleanor Feingold and Levy, \{Steven M.\} and McNeil, \{Daniel W.\} and Betsy Foxman and Weyant, \{Robert J.\} and Timpson, \{Nicholas J.\} and Marazita, \{Mary L.\} and Shaffer, \{John R.\}",

note = "Funding Information: This research was funded by the UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z); the University of Bristol provides core support for ALSPAC; a comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf); ALSPAC GWAS data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe; the research on data from the COHRA1 and COHRA2 cohorts was supported by U.S. National Institutes of Health (NIH) grants R01-DE014899, 1-U01-DE018903, and X01-HG009878; the IFS and IHS cohorts were supported by NIH grants R01-DE09551, 1-U01-DE018903, X01-HG009878, R01-DE014899, and P30-DE10126. The authors declare no financial relationships with any organizations that might have an interest in the submitted work in the previous three years and no other relationships or activities that could appear to have influenced the submitted work. Publisher Copyright: {\textcopyright} 2022 by the authors.",

year = "2023",

month = jan,

day = "1",

doi = "10.3390/genes14010059",

language = "English",

volume = "14",

journal = "Genes",

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Orlova, E, Dudding, T, Chernus, JM, Alotaibi, RN, Haworth, S, Crout, RJ, Lee, MK, Mukhopadhyay, N, Feingold, E, Levy, SM, McNeil, DW, Foxman, B, Weyant, RJ, Timpson, NJ, Marazita, ML & Shaffer, JR 2023, 'Association of Early Childhood Caries with Bitter Taste Receptors: A Meta-Analysis of Genome-Wide Association Studies and Transcriptome-Wide Association Study', Genes, vol. 14, no. 1, 59. https://doi.org/10.3390/genes14010059

TY - JOUR

T1 - Association of Early Childhood Caries with Bitter Taste Receptors

T2 - A Meta-Analysis of Genome-Wide Association Studies and Transcriptome-Wide Association Study

AU - Orlova, Ekaterina

AU - Dudding, Tom

AU - Chernus, Jonathan M.

AU - Alotaibi, Rasha N.

AU - Haworth, Simon

AU - Crout, Richard J.

AU - Lee, Myoung Keun

AU - Mukhopadhyay, Nandita

AU - Feingold, Eleanor

AU - Levy, Steven M.

AU - McNeil, Daniel W.

AU - Foxman, Betsy

AU - Weyant, Robert J.

AU - Timpson, Nicholas J.

AU - Marazita, Mary L.

AU - Shaffer, John R.

N1 - Funding Information: This research was funded by the UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z); the University of Bristol provides core support for ALSPAC; a comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf); ALSPAC GWAS data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe; the research on data from the COHRA1 and COHRA2 cohorts was supported by U.S. National Institutes of Health (NIH) grants R01-DE014899, 1-U01-DE018903, and X01-HG009878; the IFS and IHS cohorts were supported by NIH grants R01-DE09551, 1-U01-DE018903, X01-HG009878, R01-DE014899, and P30-DE10126. The authors declare no financial relationships with any organizations that might have an interest in the submitted work in the previous three years and no other relationships or activities that could appear to have influenced the submitted work. Publisher Copyright: © 2022 by the authors.

PY - 2023/1/1

Y1 - 2023/1/1

N2 - Although genetics affects early childhood caries (ECC) risk, few studies have focused on finding its specific genetic determinants. Here, we performed genome-wide association studies (GWAS) in five cohorts of children (aged up to 5 years, total N = 2974, cohorts: Center for Oral Health Research in Appalachia cohorts one and two [COHRA1, COHRA2], Iowa Fluoride Study, Iowa Head Start, Avon Longitudinal Study of Parents and Children [ALSPAC]) aiming to identify genes with potential roles in ECC biology. We meta-analyzed the GWASs testing ~3.9 million genetic variants and found suggestive evidence for association at genetic regions previously associated with caries in primary and permanent dentition, including the β-defensin anti-microbial proteins. We then integrated the meta-analysis results with gene expression data in a transcriptome-wide association study (TWAS). This approach identified four genes whose genetically predicted expression was associated with ECC (p-values < 3.09 × 10−6; CDH17, TAS2R43, SMIM10L1, TAS2R14). Some of the strongest associations were with genes encoding members of the bitter taste receptor family (TAS2R); other members of this family have previously been associated with caries. Of note, we identified the receptor encoded by TAS2R14, which stimulates innate immunity and anti-microbial defense in response to molecules released by the cariogenic bacteria, Streptococcus mutans and Staphylococcus aureus. These findings provide insight into ECC genetic architecture, underscore the importance of host-microbial interaction in caries risk, and identify novel risk genes.

AB - Although genetics affects early childhood caries (ECC) risk, few studies have focused on finding its specific genetic determinants. Here, we performed genome-wide association studies (GWAS) in five cohorts of children (aged up to 5 years, total N = 2974, cohorts: Center for Oral Health Research in Appalachia cohorts one and two [COHRA1, COHRA2], Iowa Fluoride Study, Iowa Head Start, Avon Longitudinal Study of Parents and Children [ALSPAC]) aiming to identify genes with potential roles in ECC biology. We meta-analyzed the GWASs testing ~3.9 million genetic variants and found suggestive evidence for association at genetic regions previously associated with caries in primary and permanent dentition, including the β-defensin anti-microbial proteins. We then integrated the meta-analysis results with gene expression data in a transcriptome-wide association study (TWAS). This approach identified four genes whose genetically predicted expression was associated with ECC (p-values < 3.09 × 10−6; CDH17, TAS2R43, SMIM10L1, TAS2R14). Some of the strongest associations were with genes encoding members of the bitter taste receptor family (TAS2R); other members of this family have previously been associated with caries. Of note, we identified the receptor encoded by TAS2R14, which stimulates innate immunity and anti-microbial defense in response to molecules released by the cariogenic bacteria, Streptococcus mutans and Staphylococcus aureus. These findings provide insight into ECC genetic architecture, underscore the importance of host-microbial interaction in caries risk, and identify novel risk genes.

KW - child

KW - genetics

KW - molecular epidemiology

KW - oral health

U2 - 10.3390/genes14010059

DO - 10.3390/genes14010059

M3 - Article (Academic Journal)

C2 - 36672800

AN - SCOPUS:85146764314

SN - 2073-4425

VL - 14

JO - Genes

JF - Genes

IS - 1

M1 - 59

ER -

Association of Early Childhood Caries with Bitter Taste Receptors: A Meta-Analysis of Genome-Wide Association Studies and Transcriptome-Wide Association Study

Abstract

Bibliographical note

Keywords

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