Abstract
Dental occlusion requires harmonious development of teeth, jaws, and other elements of the craniofacial complex, which are regulated by environmental and genetic factors. We performed the first genome-wide association study (GWAS) on dental development (DD) using the Demirjian radiographic method. Radiographic assessments from participants of the Generation R Study (primary study population, N1 = 2,793; mean age of 9.8 y) were correlated with ~30 million genetic variants while adjusting for age, sex, and genomic principal components (proxy for population stratification). Variants associated with DD at genome-wide significant level (P < 5 × 10−8) mapped to 16q12.2 (IRX5) (lead variant rs3922616, B = 0.16; P = 2.2 × 10−8). We used Fisher’s combined probability tests weighted by sample size to perform a meta-analysis (N = 14,805) combining radiographic DD at a mean age of 9.8 y from Generation R with data from a previous GWAS (N2 = 12,012) on number of teeth (NT) in infants used as proxy of DD at a mean age of 9.8 y (including the ALSPAC and NFBC1966). This GWAS meta-analysis revealed 3 novel loci mapping to 7p15.3 (IGF2BP3: P = 3.2 × 10−8), 14q13.3 (PAX9: P = 1.9 × 10−8), and 16q12.2 (IRX5: P = 1.2 × 10−9) and validated 8 previously reported NT loci. A polygenic allele score constructed from these 11 loci was associated with radiographic DD in an independent Generation R set of children (N = 703; B = 0.05, P = 0.004). Furthermore, profiling of the identified genes across an atlas of murine and human stem cells observed expression in the cells involved in the formation of bone and/or dental tissues (>0.3 frequency per kilobase of transcript per million mapped reads), likely reflecting functional specialization. Our findings provide biological insight into the polygenic architecture of the pediatric dental maturation process.
| Original language | English |
|---|---|
| Pages (from-to) | 349-356 |
| Number of pages | 8 |
| Journal | Journal of Dental Research |
| Volume | 102 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Mar 2023 |
Bibliographical note
Funding Information:The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The general design of the Generation R Study is made possible by financial support from the Erasmus Medical Center, Rotterdam; the Erasmus University Rotterdam; the Netherlands Organization for Health Research and Development (ZonMw); the Netherlands Organisation for Scientific Research (NWO); the Ministry of Health, Welfare and Sport; and the Ministry of Youth and Families. In addition, the Netherlands Organization for Health Research and Development supported C.M.-G. and F.R. of this article (ZonMw VIDI 016.136.367 to F.R. and C. M.-G.), while the National Institutes of Health provided support for A.J.v.W (R01 AR075803). ALSPAC is extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. The UK Medical Research Council and Wellcome (217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. Lastly, N.J.T. of this manuscript is a Wellcome Trust Investigator (202802/Z/16/Z), is the principal investigator of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215-2001) and the MRC Integrative Epidemiology Unit (MC_UU_00011/1), and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019). This publication is the work of the authors and the authors will serve as guarantors for the contents of this article.
Publisher Copyright:
© International Association for Dental Research and American Association for Dental, Oral, and Craniofacial Research 2022.