Rare and Common Variants Conferring Risk of Tooth Agenesis

Abstract

We present association results from a large genome-wide association study of tooth agenesis (TA) as well as selective TA, including 1,944 subjects with congenitally missing teeth, excluding third molars, and 338,554 controls, all of European ancestry. We also tested the association of previously identified risk variants, for timing of tooth eruption and orofacial clefts, with TA. We report associations between TA and 9 novel risk variants. Five of these variants associate with selective TA, including a variant conferring risk of orofacial clefts. These results contribute to a deeper understanding of the genetic architecture of tooth development and disease. The few variants previously associated with TA were uncovered through candidate gene studies guided by mouse knockouts. Knowing the etiology and clinical features of TA is important for planning oral rehabilitation that often involves an interdisciplinary approach.

Keywords: genetics; hypodontia; molecular genetics; odontogenesis; oligodontia; orofacial cleft(s).

Figure 1.

Study design flowchart. GWAS, genome-wide association study; TA, tooth agenesis.

Figure 2.

The Icelandic tooth agenesis sample. (a) The number of absent teeth at the specific dental positions, excluding the third molars, in an Icelandic sample of 1,944 subjects in which 5,423 teeth were missing. In total, 1,196 subjects were missing 1,987 mandibular second premolars; 600 subjects, 1,034 maxillary second premolars; and 600 subjects, 998 maxillary lateral incisors. (b) Illustration of the teeth in the mandible and the maxilla, as well as the cleft lip region. The 3 most commonly missing teeth analyzed in the 3 genome-wide association studies of selective tooth agenesis are indicated as red (maxillary lateral incisors), blue (maxillary second premolars), and green (mandibular second premolars).

Figure 3.

Manhattan plots for tooth agenesis (TA). (a) Genome-wide association study (GWAS) for TA in the Icelandic discovery sample. (b) GWAS for selective TA in the Icelandic discovery sample. The new signals (FOXP1 and EDA) from the GWAS of maxillary lateral incisors are indicated in red. (c) The new signal (LEF1) from the GWAS of the mandibular second premolars is indicated in green. (d) The new signal (NOL11) from the GWAS of maxillary second premolars is indicated in blue. P_threshold = 2.30 × 10^-9 for other variants within DNase I hypersensitivity sites (DHSs). Genome-wide significance thresholds after correction for multiple testing are based on type of variant as described in the study by Sveinbjornsson et al. (2016) per the following thresholds: P_threshold = 2.60 × 10^-7 for high-impact variants (stop-gain and stop-loss, frameshift indel, donor and acceptor splice-site, and initiator codon variants), P_threshold = 5.10 × 10^-8 for moderate-impact variants (missense, in-frame indel, and splice-region variants), P_threshold = 4.60 × 10^-9 for low-impact variants (synonymous, 3′ and 5′ UTR, and upstream and downstream variants), P_threshold = 2.30 × 10^-9 for other variants within DHSs, and P_threshold = 7.90 × 10^-10 for other variants not within DHSs.