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Bone Abstracts (2017) 6 P118 | DOI: 10.1530/boneabs.6.P118

1The Generation R Study Group, Rotterdam, The Netherlands; 2Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands; 3Department of Oral & Maxillofacial Surgery, Special Dental Care and Orthodontics, Erasmus MC, Rotterdam, The Netherlands; 4NFBC1966/Lifecourse Epidemiology, Imperial College, London, UK; 5ALSPAC/MRC Integrative Epidemiology Unit, Bristol University, Bristol, UK; 6Diamantina Institute, University of Queensland/AU, Queensland, Australia.

Objectives: Advanced or delayed physiological age may influence significantly health and disease processes. Physiological age can be estimated using several parameters including dental age (DA). Previous meta-analyses studying “Number of Teeth at 15 Months” (NT15M) and “Age at First Teeth Eruption” (AFTE) have identified 15 loci. We performed a genome-wide association study (GWAS) meta-analysis to identify genetic determinants of in children of school age.

Methods: Discovery GWAS of DA was performed in the Generation R study, a multiethnic pregnancy cohort in Rotterdam, The Netherlands. We included 2,793 children with mean age 9.82 (S.D.=0.34) years. DA was determined from dental panoramic radiographs using the Demirjian method. Participants were genotyped with the HumanHap 610K platform, imputed to the 1000GP reference panel. Analysis was adjusted for age, sex, height, BMI and 20 genomic principal components; genome-wide significance (GWS) was set at P<5×10−8. Replication of signals associated with DA was pursued using summary level results from the published GWAS meta-analysis of the ALSPAC and NFBC1966 studies (n=12,012) studying NT15M and AFTE. Fisher’s combined probability test weighted by sample size, implemented in METAL, was used for the combined meta-analysis.

Results: Top signals mapped to 16q12.2(IRX5; P=1.1×10−7) and 17p11.2(SREBF1; P=9.1×10−8) loci associated with advanced DA. Significant evidence for replication of both GWAS signals was observed in the previous NT15M meta-analysis (IRX5: P=2.7×10−5 and SREBF1: P=0.001). In the combined meta-analysis, the top-associated marker in the IRX5-region reached GWS (P=2.1×10−9). Also, alleles of these markers associated with higher DA were nominally associated with earlier teeth eruption in the AFTE meta-analysis (IRX5: P=1.5×10−5 and SREBF1: P=0.002). Furthermore, after genome-wide meta-analysis we identified variants in three novel loci: 1q32.1(ASCL5; P=3.2×10−8), 7p15.3 (IGF2BP3; P=2.87×10−8) and 14q13.3 (PAX9; P=3×10−8); on top of replicating seven previously reported loci: 2q13 (EDAR), 10q22.2 (ADK), 12q14.3 (HMGA2), 14q22.2 (BMP4), 14q24.1 (RAD51B), 17q21.32 (IGF2BP1), 17q22 (TEX5) and 17q25.3 (intergenic).

Conclusion: We describe here five novel loci associated with dental development. These findings provide further understanding into the process of dental maturation in children from early infancy to late school age. Further, these novel loci implicate diverse pathways related to BMI, lipid metabolism, growth hormone/insulin-like growth factors and craniofacial development.

Disclosure: The authors declared no competing interests.

Volume 6

8th International Conference on Children's Bone Health


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