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The Journal of Clinical Endocrinology & Metabolism 89(5):2071–2077
Copyright © 2004 by The Endocrine Society
doi: 10.1210/jc.2003-031999
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
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.
T
HE 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 iodinedeficient 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 (1–3, 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
Abbreviations: BMI, Body mass index; CV, coefficient(s) of variation;
DZ, dizygotic; MZ, monozygotic; OS, opposite sex; Tgab, thyroglobulin
antibody; TPOab, thyroid peroxidase antibody.
JCEM is published monthly by The Endocrine Society (http://www.
endo-society.org), the foremost professional society serving the endocrine community.
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 ⴝ 0.71; rDZ ⴝ
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. (J Clin Endocrinol Metab
89: 2071–2077, 2004)
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
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,
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J Clin Endocrinol Metab, May 2004, 89(5):2071–2077
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 intraand 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, twostep, 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
Hansen et al. • Heredity of Thyroid Size
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 –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 ␹2 statistics. A small ␹2 value
and a high P value indicate a good agreement between the model and
the observed data, whereas a significant ␹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
Hansen et al. • Heredity of Thyroid Size
J Clin Endocrinol Metab, May 2004, 89(5):2071–2077
in ␹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
Descriptive statistics
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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 2. 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.
Intraclass correlations
Table 1 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.
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
Figure 1 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. 1.
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).
TABLE 1. Basic descriptives for thyroid volume according to sex, smoking habits, supplementary iodine intake, thyroid antibody status,
zygosity, hormone replacement therapy, and pregnancy
All
Gender
Female
Male
Smoking
No
Yes
Suppl. iodine intake
No
Yes
Antibody status
No
Yes
Zygosity
MZ
DZb
HRTc
No
Yes
Pregnancy
No
Yes
Males
Females
n
Mean
SD
P value
(Wilcoxona)
n
Mean
SD
P value
(Wilcoxona)
0.0021
157
124
16.07
17.97
6.04
6.04
0.0306
137
102
13.77
15.61
4.02
6.10
0.0853
5.89
5.64
0.8767
169
112
16.66
17.29
6.17
6.01
0.4538
114
125
14.96
14.19
5.31
4.86
0.7089
15.87
15.11
5.87
3.99
0.8412
272
9
16.92
16.56
6.18
3.25
0.8126
218
21
14.56
14.49
5.17
4.20
0.4994
15.74
16.12
5.71
5.85
0.3553
116
116
17.22
16.91
6.33
6.24
0.8505
92
96
13.87
15.18
4.14
5.22
0.0944
139
100
14.88
14.11
4.98
5.22
0.2255
93
146
12.97
15.57
3.96
5.47
0.0011
n
Mean
SD
P value
(Wilcoxona)
239
281
14.56
16.91
5.09
6.11
0.0002
294
226
15.00
16.90
5.32
6.17
283
237
15.97
15.65
490
30
208
214
Suppl., Supplemental.
a
A modified Wilcoxon test was used to test the difference between the groups, taking the dependence of the twins into account.
b
DZ same sex twin pairs.
c
Hormone replacement therapy. Users compared to nonusers of oral contraceptives or postmenopausal estrogen therapy.
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Hansen et al. • Heredity of Thyroid Size
TABLE 2. Results of the regression analyses regarding thyroid
volume in the twins as a single group and for each gender
Study
population
All
Males
Females
Explanatory variables
TSH
Free T4
Gender
Age
Smoking
BMI
Free T3
Antibody status
Family history
Iodine supplementation
TSH
Age
BMI
Free T4
Free T3
Antibody status
Smoking
Family history
Iodine supplementation
TSH
Free T4
BMI
Free T3
Age
Antibody status
Smoking
Pregnancy
HRT
Iodine supplementation
Regression
coefficients
⫺0.10
0.02
0.09
0.01
0.07
0.02
⫺0.09
0.01
0.03
⫺0.11
0.06
0.02
P value
⬍0.001
0.011
0.005
0.016
0.044
⬍0.001
Ns
Ns
Ns
Ns
0.002
0.008
0.003
Ns
Ns
Ns
Ns
Ns
Ns
⬍0.001
⬍0.001
⬍0.001
Ns
Ns
Ns
Ns
Ns
Ns
Ns
HRT, Hormone replacement therapy; Ns, not significant.
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. 2, 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.
Discussion
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, 27–29).
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 (32–34).
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 (1–3, 37–39). 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
Hansen et al. • Heredity of Thyroid Size
J Clin Endocrinol Metab, May 2004, 89(5):2071–2077
2075
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.
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 genotypeenvironment 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 geneenvironment interactions in our study is not clear; however,
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Hansen et al. • Heredity of Thyroid Size
4.
5.
6.
7.
8.
9.
FIG. 2. Estimates of genetic and unique environmental influences
(percentages) to variation in thyroid volume. Confidence intervals are
given.
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.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
Received November 17, 2003. Accepted February 18, 2004.
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: [email protected].
This work was supported by grants from the Foundation of 17-121981, 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.
32.
References
33.
1. Hegedüs L 1990 Thyroid size determined by ultrasound. Influence of physiological factors and non-thyroidal disease. Dan Med Bull 37:249 –263
2. Knudsen N, Laurberg P, Perrild H, Bülow I, Ovesen L, Jørgensen T 2002 Risk
factors for goiter and thyroid nodules. Thyroid 12:879 – 888
3. Knudsen N, Bülow I, Jørgensen T, Laurberg P, Ovesen L, Perrild H 2000
Goitre prevalence and thyroid abnormalities at ultrasonography: a compar-
34.
28.
29.
30.
31.
35.
36.
ative epidemiological study in two regions with slightly different iodine status.
Clin Endocrinol (Oxf) 53:479 – 485
Pedersen KM, Laurberg P, Nøhr S, Jørgensen A, Andersen S 1999 Iodine in
drinking water varies by more than 100-fold in Denmark. Importance for
iodine content of infant formulas. Eur J Endocrinol 140:400 – 403
Gomez JM, Maravall FJ, Gomez N, Guma A, Soler J 2000 Determinants of
thyroid volume as measured by ultrasonography in healthy adults randomly
selected. Clin Endocrinol (Oxf) 53:629 – 634
Wesche MF, Wiersinga WM, Smits NJ 1998 Lean body mass as a determinant
of thyroid size. Clin Endocrinol (Oxf) 48:701–706
Barrere X, Valeix P, Preziosi P, Bensimon M, Pelletier B, Galan P, Hercberg
S 2000 Determinants of thyroid volume in healthy French adults participating
in the SU.VI.MAX cohort. Clin Endocrinol (Oxf) 52:273–278
Rasmussen NG, Hornnes PJ, Hegedüs L 1989 Ultrasonographically determined thyroid size in pregnancy and post partum: the goitrogenic effect of
pregnancy. Am J Obstet Gynecol 160:1216 –1220
Hegedüs L, Karstrup S, Veiergang D, Jacobsen B, Skovsted L, FeldtRasmussen U 1985 High frequency of goitre in cigarette smokers. Clin Endocrinol (Oxf) 22:287–292
Knudsen N, Bülow I, Laurberg P, Ovesen L, Perrild H, Jørgensen T 2002
Association of tobacco smoking with goiter in a low-iodine-intake area. Arch
Intern Med 162:439 – 443
Berghout A, Wiersinga WM, Smits NJ, Touber JL 1987 Determinants of
thyroid volume as measured by ultrasonography in healthy adults in a noniodine deficient area. Clin Endocrinol (Oxf) 26:273–280
Brix TH, Kyvik KO, Hegedüs L 1999 Major role of genes in the etiology of
simple goiter in females: a population-based twin study. J Clin Endocrinol
Metab 84:3071–3075
Hegedüs L 2001 Thyroid ultrasound. Endocrinol Metab Clin North Am 30:
339 –360
Skytthe A, Kyvik K, Holm NV, Vaupel JW, Christensen K 2002 The Danish
Twin Registry: 127 birth cohorts of twins. Twin Res 5:352–357
Delange F 1994 The disorders induced by iodine deficiency. Thyroid 4:107–128
Gutekunst R, Becker W, Hehrmann R, Olbricht T, Pfannenstiel P 1988
Ultrasonic diagnosis of the thyroid gland. Dtsch Med Wochenschr 113:1109 –
1112
Hegedüs L, Perrild H, Poulsen LR, Andersen JR, Holm B, Schnohr P, Jensen
G, Hansen JM 1983 The determination of thyroid volume by ultrasound and
its relationship to body weight, age, and sex in normal subjects. J Clin Endocrinol Metab 56:260 –263
PerkinElmer 1997 User’s manual. Foster City, CA: PerkinElmer
Brunner E 1991 A nonparametric estimator of the shift effect for repeated
observations. Biometrics 47:1149 –1153
Neale MC, Maes HH 2002 Methodology for genetic studies of twins and
families. Dordrecht: Kluwer
Boomsma D, Busjahn A, Peltonen L 2002 Classical twin studies and beyond.
Nat Rev Genet 3:872– 882
Evans DM, Gillespie NA, Martin NG 2002 Biometrical genetics. Biol Psychol
61:33–51
Rijsdijk FV, Sham PC 2002 Analytic approaches to twin data using structural
equation models. Brief Bioinform 3:119 –133
Devore JL 1987 Probability and statistics for engineering and the sciences.
Monterey: Brooks/Cole; 322–367
Stata Corp. 2001 Stata statistical software: release 7.0. College Station: Stata
Corp.
Neale MC, Boker SM, Xie G, Maes HH 2002 Mx: statistical modeling, 6th Ed.
Richmond: Virginia Commonwealth University
Gutekunst R, Smolarek H, Hasenpusch U, Stubbe P, Friedrich HJ, Wood
WG, Scriba PC 1986 Goitre epidemiology: thyroid volume, iodine excretion,
thyroglobulin and thyrotropin in Germany and Sweden. Acta Endocrinol
(Copenh) 112:494 –501
Jarløv AE, Hegedüs L, Gjorup T, Hansen JM 1991 Observer variation in the
clinical assessment of the thyroid gland. J Intern Med 229:159 –161
Langer P 1999 Minireview: discussion about the limit between normal thyroid
goiter. Endocr Regul 33:39 – 45
Langer P, Tajtakova M, Bohov P, Klimes I 1999 Possible role of genetic factors
in thyroid growth rate and in the assessment of upper limit of normal thyroid
volume in iodine-replete adolescents. Thyroid 9:557–562
Hansen PS, Brix TH, Sørensen TIA, Kyvik KO, Hegedüs L 2004 Major genetic
influence on the regulation of the pituitary-thyroid axis. A study of healthy
Danish twins. J Clin Endocrinol Metab 89:1181–1187
Vassart G, Dumont JE 1992 The thyrotropin receptor and the regulation of
thyrocyte function and growth. Endocr Rev 13:596 – 611
Dumont JE, Jauniaux JC, Roger PP 1989 The cyclic AMP-mediated stimulation
of cell proliferation. Trends Biochem Sci 14:67–71
Dumont JE, Maenhaut C, Lamy F, Pirson I, Clement S, Roger PP 2003 Growth
and proliferation of the thyroid cell in normal physiology and in disease. Ann
Endocrinol (Paris) 64:10 –11
Maes HH, Neale MC, Eaves LJ 1997 Genetic and environmental factors in
relative body weight and human adiposity. Behav Genet 27:325–351
Arden NK, Spector TD 1997 Genetic influences on muscle strength, lean
Hansen et al. • Heredity of Thyroid Size
body mass, and bone mineral density: a twin study. J Bone Miner Res
12:2076 –2081
37. Hegedüs L, Rasmussen N, Knudsen N 1987 Seasonal variation in thyroid size
in healthy males. Horm Metab Res 19:391–392
38. Bertelsen JB, Hegedüs L 1994 Cigarette smoking and the thyroid. Thyroid
4:327–331
39. Knudsen N, Bülow I, Laurberg P, Ovesen L, Perrild H, Jørgensen T 2002
Parity is associated with increased thyroid volume solely among smokers in
an area with moderate to mild iodine deficiency. Eur J Endocrinol 146:39 – 43
J Clin Endocrinol Metab, May 2004, 89(5):2071–2077
2077
40. Hegedüs L, Karstrup S, Rasmussen N 1986 Evidence of cyclic alterations of
thyroid size during the menstrual cycle in healthy women. Am J Obstet
Gynecol 155:142–145
41. Hopper JL 1993 Variance components for statistical genetics: applications in
medical research to characteristics related to human diseases and health. Stat
Methods Med Res 2:199 –223
42. Rietveld MJ, Posthuma D, Dolan CV, Boomsma DL 2003 ADHD: sibling
interaction or dominance: an evaluation of statistical power. Behav Genet
33:247–255
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