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*Twins, Triplets, Multiple Births
The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 5 2071-2077
Copyright © 2004 by The Endocrine Society

Genetic and Environmental Causes of Individual Differences in Thyroid Size: A Study of Healthy Danish Twins

Pia Skov Hansen, Thomas Heiberg Brix, Finn Noe Bennedbæk, Steen Joop Bonnema, Kirsten Ohm Kyvik and Laszlo Hegedüs

Department of Endocrinology M, Odense University Hospital (P.S.H., T.H.B., F.N.B., S.J.B., L.H.), DK-5000 Odense C, Denmark; and Danish Twin Registry, Department of Epidemiology, Institute of Public Health, University of Southern Denmark (P.S.H., K.O.K.), Odense, Denmark

Address all correspondence and requests for reprints to: Dr. Pia Skov Hansen, Danish Twin Registry, Epidemiology, Institute of Public Health, University of Southern Denmark, Odense, Sdr. Boulevard 23A, DK-5000 Odense C, Denmark. E-mail: piaskovhansen{at}dadlnet.dk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Factors such as iodine intake, serum TSH concentration, gender, age, body mass index, parity, and cigarette smoking are thought to influence thyroid size. The purpose of our study was to determine the relative roles of these environmental and physiological factors compared with genetic factors in euthyroid subjects with a clinically normal thyroid gland. A representative sample of self-reported healthy twin pairs was identified through the Danish Twin Registry.

A total of 520 individuals divided into 104 monozygotic (MZ), 107 dizygotic same sex (DZ), and 49 opposite sex twin pairs were investigated. After adjustment for age, gender, and other covariates, intraclass correlations were calculated. To elucidate the relative importance of genetic and environmental factors to the variation of ultrasonically determined thyroid volume, quantitative genetic modeling was used.

Regression analysis suggested that serum TSH, serum free T4, gender, age, smoking, and body mass index each played a small, but significant, role for variation in thyroid volume. The intraclass correlations for thyroid volume were consistently higher for MZ than for DZ twin pairs (rMZ = 0.71; rDZ = 0.18; P < 0.001). Using quantitative genetic modeling, it was calculated that genetic factors (with 95% confidence intervals) accounted for 71% (61–78%) of the individual differences in thyroid volume.

Genetic influences are important in the regulation of normal thyroid size. This fits the observation that goiter may be seen also in the absence of evident environmental goitrogens such as iodine deficiency and that not all individuals develop goiter even in iodine-deficient areas.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE FACTORS INFLUENCING the size of the thyroid gland are many, and these factors, some of which may be unknown, seem to interact in a complex way (1). A profound negative relationship between increasing iodine intake and goiter prevalence is incontestable (1, 2). In a recent Danish study, even relatively small differences in iodine intake in a population led to notable differences in median thyroid volume estimated by ultrasound (3). The effect of age on thyroid volume seems to be dependent on iodine status. In Denmark, which is a borderline iodine-deficient area (4), thyroid volume increases up to around age 40–45 yr, whereupon it is, on the whole, unchanged thereafter (2, 3). In contrast, thyroid volume seems to decline after the age of 40 yr in areas with sufficient iodine supply (5). Furthermore, thyroid volume is related to gender, with males generally having higher thyroid volumes than females (1, 2, 3, 5). However, to some extent this might reflect the fact that thyroid volume is correlated to lean body mass (5, 6) and body mass index (BMI) (7). Presumably, a more direct gender-specific effect is related to pregnancy (8) and/or sex hormones (2, 3). In previous studies, smoking has also been associated with increased thyroid volume (9, 10), and it seems that the association is stronger in areas with iodine deficiency (10, 11), although some controversy does exist (5).

We have previously established that genetic factors play a substantial role in the etiology of simple goiter (12). Although a distinction between the clinically normal and abnormal sized thyroid gland is not always straightforward, we have tried to separate the two phenotypes by means of ultrasound, which is considered a precise method for determination of thyroid size (1, 13). The purpose of our study was to examine the individual differences in thyroid volume and gain insight into the etiology of these differences, in particular to establish whether there is a genetic component.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The present study is part of a nationwide project (GEMINAKAR) investigating the relative influence of genetic and environmental factors on a variety of different traits among Danish twins.

A representative sample of complete twin pairs was recruited from the population-based Danish Twin Registry (14). The majority of these twins participated in a questionnaire survey regarding physical health and health-related behavior. The twins included in the GEMINAKAR study were self-reported healthy. However, individuals with chronic diseases, such as low back pain, asthma, migraine, etc., were included in the study population, but no twins were taking medicine known to affect the pituitary-thyroid axis or thyroid size. To obtain an equal distribution of twin pairs, sampling was stratified according to age, sex, and zygosity.

The examinations, including ultrasonography of the thyroid gland, took place throughout the year at the Danish Twin Registry in Odense from March 1998 to November 2000. The twins in a pair were examined on the same day. With the exception of 29 twin pairs, both twins in a pair lived in the western part of Denmark. Blood samples were drawn between 0800 and 0900 h after a 12-h fast; this was followed by a clinical examination. During the day the twins completed additional questionnaires regarding their general health and lifestyle, including questions regarding thyroid disease, smoking habits, and medicine intake.

In all, 610 individuals (305 twin pairs) were examined with ultrasonography of the thyroid gland. However, due to missing blood samples (30 individuals in 15 twin pairs) and self-reported thyroid disease (16 individuals in 14 twin pairs), 29 pairs (58 individuals) were excluded.

Moreover, four individuals in three twin pairs were excluded as a consequence of overt biochemical thyroid disease (hypothyroidism was defined as serum TSH > 4.0 mU/liter and serum free T4 < 9.9 pmol/liter, whereas hyperthyroidism was defined as serum TSH < 0.3 mU/liter and serum free T4 > 17.7 pmol/liter and/or serum free T3 > 7.4 pmol/liter). At the clinical investigation, 14 individuals in 13 twin pairs were identified as having a visible and/or palpable thyroid gland (corresponding to WHO grade Ib or larger) (15), and these twin pairs were also excluded. Thus, the final study group consisted of 520 individuals or 260 twin pairs [104 monozygotic (MZ), 107 dizygotic same sex (DZ), and 49 opposite sex (OS) twin pairs] who were all biochemically euthyroid and without clinically detectable goiter. The mean ages of the MZ, DZ same sex, and OS twins were 33.7 yr (SD, 11.7), 36.4 yr (SD, 11.5), and 33.7 yr (SD, 11.0), respectively.

As the WHO definition of thyroid enlargement (15) carries a considerable observer variation (13), we also defined goiter as a thyroid volume (measured by ultrasound) exceeding 18 ml for women and 25 ml for men (which corresponds to the mean ± 3 SD in iodine-sufficient populations) (16). Simultaneously, we performed the analyses using the latter definition. This population comprised 404 individuals or 202 twin pairs distributed in 87 MZ, 78 DZ, and 37 OS twin pairs.

Written informed consent was obtained from all participants, and the study was approved by all regional Danish scientific-ethical committees (case file 97/25 PMC).

Methods

Thyroid volume was calculated on the basis of an ultrasonic scanning procedure using a 5.5-MHz compound scanner (type 1846, Brüel and Kjær, Naerum, Denmark) (17). The calculation of thyroid volume was based on recordings of cross-sectional areas through the gland at 0.5-cm intervals, followed by computerized calculation of the volume. Intraobserver variation was assessed previously and was approximately 5% (1, 13, 17). For each twin pair, the volume measurement was performed by the same operator (L.H., F.N.B., or S.B.) with blinding toward zygosity status and volume data of the co-twin.

Serum TSH was measured using a time-resolved fluoroimmunometric assay (AutoDELFIA hTSH Ultra Kit, PerkinElmer/Wallac, Turku, Finland). The reference range is 0.30–4.00 mU/liter. The intra- and interassay coefficients of variation (CV) at serum TSH concentrations between 0.046 and 17.6 mU/liter range from 1.3–4.7% and 1.7–3.7%, respectively. Serum free T4 and serum free T3 were determined using the AutoDELFIA FT4 and FT3 kits (PerkinElmer/Wallac), respectively. For free T4 the reference range was 9.9–17.7 pmol/liter, and for free T3 it was 4.3–7.4 pmol/liter. The intra- and interassay CV for free T4 at serum free T4 concentrations between 9.2 and 19.2 pmol/liter ranged from 1.3–2.0% and 3.9–5.4%, respectively. For free T3 the intra- and interassay CV at serum free T3 concentrations between 4.7 and 9.7 pmol/liter ranged from 3.9–5.0% and 2.9–4.2%, respectively. Thyroid peroxidase antibodies (TPOab) and thyroglobulin antibodies (Tgab) were measured by solid phase, two-step, time-resolved fluoroimmunoassays (AutoDELFIA TPOab kit and human Tgab kit, respectively, PerkinElmer/Wallac). Intra- and interassay CV for TPOab and Tgab were 3.2–8.4% and 3.8–10.1%, respectively, in the range of 50–155 U/ml. Values above 60 U/ml were regarded as positive for both TPOab and Tgab. Subjects were considered antibody positive if either of the tests was positive. Twin pairs were analyzed within the same run. All serum samples were analyzed at the same laboratory in Odense. Zygosity was established by analysis of nine highly polymorphic restriction fragment length polymorphisms and microsatellite markers widely scattered through the genome with an AmpFISTR Profiles Plus kit (PE Applied Biosystems, Foster City, CA) (18).

Statistical analyses

The distribution of thyroid volume was skewed. Therefore, after descriptive analysis, but before twin analysis, the data were transformed by the natural logarithm to normalize distributions. In the descriptive analyses a modified Wilcoxon test was used testing the differences between the groups (19). The equality of variances between the MZ and DZ same sex groups was tested using an F test as well as maximum likelihood analyses (20).

The potential effects of gender, age, BMI (defined as weight in kilograms divided by the square of height in meters), family history regarding thyroid diseases, pregnancy (nulliparous compared with parous women), use of hormone replacement therapy (current oral contraceptives or postmenopausal estrogen therapy), supplementary iodine intake (defined as intake or use of vitamin tablets or herbal medicine), cigarette smoking (smokers were defined as former or current smokers, whereas nonsmokers were subjects who had never smoked), serum TSH, serum free T4, serum free T3, and thyroid antibody status on thyroid volume were analyzed using backward stepwise multiple regression analysis (with a limit for entry into the model of 0.05) and with cluster option (taking the dependence of the twin data into account). All of the twin pairs were used in the descriptive and regression analyses. The intraclass correlation coefficients and the impact of genetic and environmental factors on thyroid volume were calculated using the adjusted residuals resulting from the regression. All MZ and DZ same sex pairs, with the exception of two outliers, were used in these calculations.

Quantitative genetic model fitting of twin data

The classical twin study compares phenotypic resemblances of MZ and DZ twins (20). This is based on the assumption that MZ twins are genetically identical, and therefore differences between them are solely due to the environment. DZ twins share, on the average, 50% of their genes, and therefore differences between them are due to a combination of environmental and genetic factors (20, 21, 22).

Structural equation modeling was used to estimate the magnitude of the genetic and environmental effects. This technique quantifies sources of individual differences by decomposing the observed phenotypic variance into genetic and environmental contributions (20). The genetic contribution is further subdivided into an additive (A) component (represents the influence of alleles at several gene loci acting in an additive manner) and a dominance (D) component (represents intralocus interaction). The environmental contribution is divided into a shared/common environmental (C) component (refers to environmental factors that are affecting both twins in a pair in the same way and are a source of their similarity) and a unique (E) environmental component (the environmental factors that are not shared by twins in a pair and are a source of their dissimilarity). The latter component (E) also includes measurement error. The heritability is defined as the proportion of the total variance attributable to total genetic variance (i.e. additive and dominance components) (20, 22).

C and D are confounded and cannot be estimated simultaneously in a twin study of MZ and DZ twins reared together (20, 22, 23). In the univariate model fitting procedure, the full models ACE and ADE were examined and compared with their specific submodels AE, CE, and E, and AE, DE, and E, respectively, as described in detail previously (20). The selection of the best-fitting model was based on a balance between goodness of fit and parsimony (20). The fit of the models was assessed by likelihood ratio {chi}2 statistics. A small {chi}2 value and a high P value indicate a good agreement between the model and the observed data, whereas a significant {chi}2 value means that the model provides a poor fit with the data. The statistical significance between a full model and a submodel can be tested by the difference in {chi}2 and the difference in degrees of freedom between the two models (20, 23). In practice we are testing whether the components A, D, C, and E are significantly greater than zero.

The difference in heritability between males and females was tested using a Z test (24).

Statistical software

The statistical analyses were carried out using STATA (25). The level of significance was set at 0.05. Univariate quantitative genetic modeling was carried out using Mx (26).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Descriptive statistics

Table 1Go shows the basic descriptive statistics for thyroid volume with respect to gender, smoking habits, supplementary iodine intake, thyroid antibody status, and zygosity. Males had significantly higher thyroid volume than females. Smokers had a significantly increased thyroid volume compared with nonsmokers; however, after stratifying for gender, this difference was only significant for males. Neither supplementary iodine intake nor the presence of thyroid antibodies influenced thyroid volume. Females who had been pregnant had higher thyroid volume than those who had not. Hormone replacement therapy did not significantly influence thyroid volume.


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  		TABLE 1. Basic descriptives for thyroid volume according to sex, smoking habits, supplementary iodine intake, thyroid antibody status, zygosity, hormone replacement therapy, and pregnancy

 
A significant increase in thyroid volume was observed in the youngest age groups, from 17–35 yr. However, after that age, thyroid volume was not significantly altered (data not shown).

No difference in variance between MZ and DZ same sex groups was found, whether looking at the total study population or at males and females separately.

We demonstrated a highly significant negative correlation between ln thyroid volume and ln TSH (r = –0.26; P < 0.00001), whereas ln thyroid volume and BMI were positively correlated (r = 0.31; P < 0.00001).

The results regarding adjustment using multiple regression analyses are presented in Table 2Go. Serum TSH, serum free T4, gender, age, smoking, and BMI played a small, but significant, role in the differences in thyroid volume. In males, serum TSH, age, and BMI were significant variables, whereas in females this adjustment included serum TSH, free T4, and BMI.


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  		TABLE 2. Results of the regression analyses regarding thyroid volume in the twins as a single group and for each gender

 
Intraclass correlations

Figure 1Go is a scatterplot of the transformed and adjusted thyroid volume values for the 104 MZ twin pairs and the 107 DZ same sex twin pairs. Furthermore, the intraclass correlations of the logarithmically transformed and adjusted thyroid volume values are presented in Fig. 1Go.



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  		FIG. 1. Scatterplots and intraclass correlations of the logarithmically transformed and adjusted thyroid volume values according to zygosity and gender. Ninety-five percent confidence intervals and number of twin pairs are given in parentheses. a and b, These two twin pairs were secondarily excluded because they were clearly outliers, and they had an immense influence on the calculation of correlations. The presented intraclass correlations do not include these two outliers.

 
Analyzing all twins together, the correlation coefficients were substantially higher for MZ pairs than for DZ pairs (rMZ = 0.71; rDZ = 0.18; P < 0.001). Subdividing according to gender revealed the same highly significant difference in males (rMZ = 0.80; rDZ = 0.10; P < 0.001), whereas the difference was less pronounced in females (rMZ = 0.48; rDZ = 0.13; P = 0.035). Looking at individuals with a thyroid volume less than 18 and 25 ml for females and males, respectively, did not significantly change these results (data not shown). Excluding females who had been pregnant within 1 yr or were lactating, leaving 38 MZ and 46 DZ female twin pairs, did not alter the correlations in females (data not shown).

Biometric analyses

Comparing the full models (ACE and ADE), the ADE model provided the best fit to the data. In this model, A was estimated to be close to zero, however with a large confidence interval. Reductions to nested submodels indicated that the DE model was the best fitting model in the total study population as well as in females and males separately.

As evident from Fig. 2Go, considering males and females together, the univariate model fitting procedure showed that genetic effects (i.e. the heritability) explained 71% (95% confidence interval, 61–78%) of the total variance in thyroid volume, whereas the estimate for the unique environmental (E) effects was 29% (95% confidence interval, 22–39%). Subdividing according to gender, genetic influences explained 79% (95% confidence interval, 68%–86%) and 50% (95% confidence interval, 25%–68%) of the variance in thyroid volume for males and females, respectively. These estimates were not significantly different (P = 0.23). Defining normal thyroid size as a thyroid volume less than 18 ml for women and 25 ml for men had no influence on these estimates. Likewise, excluding pregnant and lactating individuals did not change the results.



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  		FIG. 2. Estimates of genetic and unique environmental influences (percentages) to variation in thyroid volume. Confidence intervals are given.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We have demonstrated that genetic factors play a significant role in the individual differences in thyroid volume in clinically healthy individuals. The precise definition of normal thyroid size is still a matter of discussion (1, 5, 13, 27, 28, 29). In the present study we focused on individuals without a palpable and/or visibly enlarged thyroid. However, defining normal thyroid size as a thyroid volume less than 18 ml for women and 25 ml for men did not influence the overall results. Using less sophisticated methods and lacking information on environmental factors, a recent small twin study by Langer et al. (30) demonstrated a higher similarity in thyroid volume between MZ than between DZ twin pairs, suggesting that our findings may be valid in other populations.

The sources of individual differences in thyroid volume are many. Ultimately, all those sources can be divided into genetic and environmental influences. We have demonstrated a clear correlation between thyroid volume and serum TSH. As we have previously shown that genetic factors also influence the variation in serum TSH (31), a part of the variation in thyroid volume may well be shared with the variation in TSH. As an example, the specific genetic set-up may influence individual differences in the number, affinity, and efficiency of signaling cascades of TSH receptors (32) affecting the function of the cells (the secretion) as well as thyroid cell proliferation and growth (32, 33, 34).

The complexity is further illustrated by thyroid volume being positively correlated with lean body mass (5, 6) and, as in the present study, BMI (7), which are both under strong genetic control (35, 36). The genetic component in thyroid volume regulation may thus partly reflect a genetic component in the regulation of BMI and lean body mass. We adjusted for BMI, serum TSH, and other factors using linear relationships. The results imply an independent genetic component controlling the size of the thyroid gland. However, if these relations are nonlinear, the genetic effect estimated in our study may cover genetic contributions from different levels or sources. These integrated physiological systems illustrate that dissecting a complex trait, such as the size of the thyroid gland, is complicated because the effect of one factor may be obscured by those of others.

The environmental influences on thyroid volume have been studied extensively (1, 2, 3, 37, 38, 39). These may affect several thyroid-related variables at the same time. We assumed that the twins had the same iodine intake, because the majority of the twin pairs lived in the same part of Denmark. However, iodine intake was not de facto quantified, nor was the possible effect of menstrual cycle-related variations in thyroid size taken into account (1, 40). The potential influences of diurnal (1, 13) and seasonal (37) alterations in serum TSH and thyroid volume were, however, ruled out by the study design. Finally, it is important to point out that at the individual level, genotype and environment are inseparable. Thus, despite the strong genetic influence on thyroid volume, the identification of potentially modifiable environmental influences remains important.

We regard this sample of twins as being representative, because basic thyroid-related characteristics, such as sex and age differences in thyroid volume as well as serum TSH level, were similar to those in comparable studies of thyroid function in Denmark (2, 3). It is assumed that environmental similarity is roughly the same for MZ and DZ twin pairs (20, 22). This may, however, not be the case, leading to an overestimation of the genetic effect. Moreover, the possibilities of a genotype-environment correlation (genetic control of exposure to the environment), epistasis (the effects of one gene being modulated by genes at another locus), as well as epigenetic modifications (for example, DNA methylation) are all neglected in twin studies. The degree to which the above assumptions are not fulfilled and the possible effects on the results in our study are unknown.

We have previously demonstrated that genetic factors play a substantial role in the etiology of simple goiter (12). The normal thyroid gland and goiter could be regarded as a continuum of the same phenotype with the same genetic basis. Certain strong environmental factors, such as iodine deficiency, may trigger the development of goiter in the case of a certain genetic set-up. This is an example of genotype-environment interaction. The analysis of genotype-environment interaction is extremely difficult (20), and twin methods are not able to take this into account. The effect of gene-environment interactions in our study is not clear; however, it may form part of the unique environmental component (E) (35).

In twin studies, it is generally difficult to detect and disentangle dominance effects (D) from additive (A) genetic influence, especially when the sample size is modest (23, 41, 42). In accordance with this, we estimated the effect of A as being close to zero; however, A as well as D were estimated with large 95% confidence intervals, reflecting low statistical power to distinguish between these two theoretically different genetic components. Nevertheless, our results clearly indicate a substantial genetic component in individual differences in thyroid volume.

In conclusion, genetic effects are important in the regulation of thyroid size. However, the magnitude may vary between various populations. This corresponds to the observation that there is no clear-cut relationship between the presence or absence of environmental goitrogens and goiter at the individual level.


   Acknowledgments
 
PerkinElmer/Wallac (Turku, Finland) kindly provided the kits for determination of serum TSH, free T4, free T3, Tgab, and TPOab. We thank Ole Blaabjerg and Esther Jensen for performing the Clinical Biochemical analyses, and Ivan Iachine for excellent statistical assistance.


   Footnotes
 
This work was supported by grants from the Foundation of 17-12-1981, the Agnes and Knut Mørk Foundation, the Novo Nordisk Foundation, the Foundation of Medical Research in the County of Funen, Else Poulsens Mindelegat, the Foundation of Direktør Jacob Madsen and Hustru Olga Madsen, the Foundation of Johan Boserup and Lise Boserup, the A. P. Møller and Hustru Chastine McKinney Møllers Foundation, the A. P. Møller Relief Foundation, and the Clinical Research Institute, Odense University.

Abbreviations: BMI, Body mass index; CV, coefficient(s) of variation; DZ, dizygotic; MZ, monozygotic; OS, opposite sex; Tgab, thyroglobulin antibody; TPOab, thyroid peroxidase antibody.

Received November 17, 2003.

Accepted February 18, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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