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Strong Genetic Control of Emergence of Human Primary Incisors
1 School of Dentistry, The University of Adelaide, Frome Rd., Adelaide, Australia 5005; Correspondence: * corresponding author, toby.hughes{at}adelaide.edu.au
Our understanding of tooth eruption in humans remains incomplete. We hypothesized that genetic factors contribute significantly to phenotypic variation in the emergence of primary incisors. We applied model-fitting to data from Australian twins to quantify contributions of genetic and environmental factors to variation in timing of the emergence of human primary incisors. There were no significant differences in incisor emergence times between zygosity groups or sexes. Emergence times of maxillary central incisors and mandibular lateral incisors were less variable than those of maxillary lateral incisors and mandibular central incisors. Maxillary lateral incisors displayed significant directional asymmetry, the left side emerging earlier than the right. Variation in timing of the emergence of the primary incisors was under strong genetic control, with a small but significant contribution from the external environment. Estimates of narrow-sense heritability ranged from 82 to 94% in males and 71 to 96% in females.
Key Words: genetic • twins • teeth • eruption • asymmetry
Our understanding of the biological processes that cause teeth to erupt within the jaws and then emerge into the oral cavity remains incomplete, despite considerable research in humans and animals (Marks and Schroeder, 1996; Parner et al., 2002; Craddock and Youngson, 2004). Molecular studies indicate that a complex interplay of regulatory genes leads to a cascade of signaling molecules that determine eruption rates (Wise et al., 2002), but the nature of the links between the genome and phenotypic variation remains unknown. Apart from one pioneering study (Hatton, 1955), we are unaware of any recent studies that focus on the genetics of human tooth emergence in either the primary or permanent dentition. Pelsmaekers et al.(1997) applied genetic modeling to assess dental maturation in twins, and found that a model including additive genetic effects (43%) and common environmental effects (50%) provided the best data fit. However, their study did not address the timing of tooth emergence. Given the importance of the timing and sequence of tooth emergence in the development of dental occlusion, this missing information represents a major deficiency in our understanding of fundamental processes in oral biology and clinical dentistry. The classic twin design, which compares monozygotic and dizygotic twin pairs, has provided insights into contributions of genetic and environmental factors to many human features, including teeth (Osborne and DeGeorge, 1959; Garn et al., 1965). Most studies of the dentition, however, have not taken account of the role of common or family environment, maternal effects, interaction between/among genes (epistasis), or genotype-environment interaction. For these reasons, estimates of heritability have often represented the upper limits of true values. Modern methods for estimating the heritability of complex traits in studies of twins enable the testing of hypotheses on the relative contributions of genetic and environmental influences to variation within, and co-variation between, study variables (Martin and Eaves, 1977; Neale and Cardon, 1992; Martin et al., 1997). Furthermore, structural equation modeling can provide estimates of narrow-sense heritability, the proportion of the total phenotypic variation attributable to additive genetic effects, which was often not possible with earlier analyses of twin data. The aim of the present study was to use model-fitting methods applied to data from Australian twins to quantify the contributions of genetic and environmental factors to variations in timing of emergence of human primary incisors. We hypothesized that genetic factors would contribute significantly to phenotypic variation in these events.
Study Population The study sample was comprised of 98 pairs of twins aged between 1 and 3 yrs and enrolled in an ongoing study of dental development and oral health of Australian twins and their families. Parents provided informed consent for their twins. The twins are of European ancestry, and their zygosities were confirmed by analysis of highly polymorphic genetic loci (D3S1358, vWA, FGA, AMEL, D8S1179, D21S11, D18S51, D5S818, D13S317, D7S820) on 10 chromosomes. The probability of dizygosity, given concordance for all loci, was less than 0.1%. The present study included 25 pairs of monozygous males, 21 pairs of monozygous females, 21 pairs of dizygous males, 12 pairs of dizygous females, and 19 pairs of opposite-sexed dizygous twins for whom complete records of incisor emergence were available. The study was approved by the Human Research Ethics Committee, The University of Adelaide (H-78-2003).
Recording Methods
Statistical Analysis Descriptive statistics were calculated for each tooth (PROC UNIVARIATE; SAS 9.1, 2003). We used the coefficient of variation (CV = Standard Deviation/Mean) to compare variations in timing of emergence between teeth. We used unpaired t tests to compare mean values between sexes and zygosity groups, and assessed directional asymmetry in emergence timing using paired t tests between antimeres, with statistical significance set at p < 0.05 (PROC TTEST; SAS 9.1, 2003).
Genetic Modeling Initially, we undertook a Cholesky decomposition of the data to produce a ’super-model’ against which to test goodness-of-fit of nested sub-models. A model incorporating decompositions of additive genetic, unique environmental and common environmental variances was then fitted. We assessed sexual heterogeneity for sources of variation by fitting models to male and female same-sex twins separately, and subtracting the sum of their likelihood estimates from the likelihood estimate of a model incorporating both sexes. This value, distributed asymptotically as a chi-squared statistic with one degree of freedom (Neale and Cardon, 1992), is suggestive of heterogeneity if significant. Individual variance components (A and C) were then assessed for model validity, and the resulting models further refined to include different genetic and environmental factors, as follows:
As part of the model-fitting approach, path coefficients (a, c, and e) were estimated, and chi-squared statistics for goodness-of-fit of the models were calculated. Akaike’s Information Criterion (AIC = chi-squared value minus twice the degrees of freedom) was also used to indicate the parsimony of each model. The general approach adopted was to accept a more complex model only if a simpler one had failed. Narrow-sense heritability estimates (h2), ranging from 0 to 100%, were calculated as the ratio of additive genetic variance to total phenotypic variance in the best-fitting model. Values of heritability estimates near 100% indicated that most of the phenotypic variation could be explained by additive genetic effects, whereas values near zero indicated that environmental effects accounted for most of the variation in the phenotype.
The breakdown of individuals examined clinically by total number of incisors present was: 0–2, 7; 3–4, 7; 5–6, 16; and 7–8, 45. Concordance of parental report with clinical examination for the presence and type of individual incisors was high. At the individual tooth level (489 emerged, 111 unemerged), 9 were misreported as unemerged, and 1 was misreported as emerged. Of the 10 misreported teeth, 9 were lateral incisors. There was no evidence of incisor misclassification at the clinical examination. Tooth emergence times were approximately normally distributed within tooth type, and analytical approaches used were robust to deviations from normality. No large outliers were observed within tooth type.
Comparisons of means and variances found no significant differences between zygosity groups or between sexes (Table 1
The ranges of emergence times were as follows: mandibular central incisors (116–513 days/4–17 mos); maxillary central incisors (216–505 days/7–17 mos); maxillary lateral incisors (204–612 days/7–20.5 mos); and mandibular lateral incisors (213–701 days/7–23 mos). Emergence times of maxillary central incisors and mandibular lateral incisors (CV 18% and 19%, respectively) were less variable than those of the maxillary lateral incisors and mandibular central incisors (CV 23% and 25%, respectively). In 43 cases out of 311 comparisons (14%), antimeric teeth emerged on the same day, whereas in 59 cases (19%) antimeric teeth differed in their timing of emergence by at least 30 days. The only antimeric pair to display significant directional asymmetry was the maxillary lateral incisors (mean difference = 8.7 ± 3.2 days), with the left tooth emerging earlier (average 352 days) than the right (average 364 days).
There was no significant effect of common environment on the timing of incisor emergence in the decomposition model, and it was subsequently excluded from less-saturated sub-models (Table 2
The most parsimonious model for males incorporated a general genetic factor and a general environmental factor acting on all 8 teeth, and 3 specific genetic factors associated with lateral incisors, mandibular central incisors, and mandibular lateral incisors, respectively. Each tooth was subject to a unique environmental effect whose parameter estimates subsumed residual phenotypic variance (experimental error). The most parsimonious model for females incorporated a general genetic factor and a general environmental factor acting on all 8 teeth, and 2 specific genetic factors associated with maxillary lateral and mandibular lateral incisors, respectively. As with males, each tooth was subject to a unique environmental effect (Fig.  ). Narrow-sense heritability estimates were high for all incisors, ranging from 82 to 94% in males and 71 to 96% in females (Table 3).
Although parental reports of tooth emergence timing provide researchers with challenges in relation to accuracy and reliability, these can be managed with careful experimental design. Parental reports offer advantages over clinical examinations for large cohort studies, since they provide better resolution (days rather than months) and are easier to manage logistically. For genetic studies, errors in reporting are most likely to reduce the additive genetic variance, leading to conservative heritability estimates. The results of our error study showed that parental report of incisor tooth emergence provided accurate data for subsequent analysis. It has been shown that dental development, dental eruption, and tooth size may be delayed or reduced in low-birthweight, prematurely born children (Seow et al., 1988; Harris et al., 1993; Fearne and Brook, 1993; Seow and Wan, 2000), features common to many twin births. Mean emergence times in our twin cohort were 2 mos later, on average, than those reported by Hitchcock et al.(1984) for healthy Australian singletons, but the order of mean emergence times for the different incisors was as expected. The field model of dental development (Butler, 1939; Dahlberg, 1945), which has been applied mainly to the permanent dentition, suggests that the most mesial tooth in each tooth class, apart from the mandibular incisors, is the most stable in terms of size, morphology, and timing of emergence. The pattern of variation in timing of emergence that we observed among primary incisors supports this model. Variation in timing of emergence of the primary incisors was under strong genetic control, with a small but significant contribution from the external environment. The primary source of phenotypic variation was attributed to a genetic factor acting generally on all 8 incisors. There was also evidence of separate genetic factors influencing antimeric pairs, especially the lateral incisors in both arches. Males displayed a more complex genetic pattern than did females, particularly for lateral incisors, but this may be due to a sampling effect. Analyses based on larger samples are planned. Although significant directional asymmetry was noted in timing of emergence of the maxillary lateral incisors, there was no evidence of a genetic contribution to this variation. Previous studies of asymmetry in dental crown size and tooth emergence have shown that directional asymmetry occurs more often than expected, due to chance (Harris, 1992; Heikkinen et al., 1998; Townsend et al., 1999). Future studies that include all the primary teeth should enable us to determine whether directional asymmetry in tooth emergence has a patterned expression within or between arches, as suggested previously (Garn and Smith, 1980). The findings of our genetic modeling approach are consistent with previous results reported for other dental phenotypes (Hughes et al., 2000; Dempsey and Townsend, 2001). In these earlier investigations, models incorporating additive genetic and unique environmental variance (AE model) or common environmental and unique environmental variance (CE model) accounted for observed variation in crown size for all primary teeth, with narrow-sense heritability estimates ranging from 62 to 91%. A model including additive genetic and unique environmental variance (AE model) also provided a good fit for most permanent tooth dimensions, although there was evidence of a common environmental influence (22–27%) on maxillary first molar dimensions. Our studies indicate, therefore, that most of the variation in human dental development and crown size can be attributed to genetic factors. Over the past decade, there have been major advances in our understanding of the molecular basis of dental development, with over 200 genes thought to be involved (Sperber, 2004). Our application of model-fitting approaches to primary incisor emergence data in twins has provided the first estimates of narrow-sense heritability for this important developmental event. Having confirmed strong genetic influence on variation in the timing of the first human teeth to emerge into the oral cavity, the next challenge will be to identify the genes involved.
This study is part of an ongoing investigation of dental development and oral health of Australian twins and their families supported by the National Health and Medical Research Council of Australia (Project Grant 349448). We thank the twins and their families who agreed to participate, and the Australian Twin Registry. The assistance of Sandy Pinkerton is gratefully acknowledged. Received for publication December 15, 2006. Revision received July 21, 2007. Accepted for publication September 13, 2007.
Journal of Dental Research, Vol. 86, No. 12,
1160-1165 (2007)
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INTRODUCTION