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Department of Endocrinology, Odense University Hospital (T.H.B., L.H.); and The Danish Twin Registry, Epidemiology, Institute of Public Health, University of Southern Denmark, Odense University (T.H.B., K.O.K., K.C.), DK-5000 Odense, Denmark
Address all correspondence and requests for reprints to: Dr. Thomas Heiberg Brix, The Danish Twin Register, Epidemiology, Institute of Public Health, University of Southern Denmark, Odense University, Sdr. Boulevard 23A, DK-5000 Odense C, Denmark. E-mail: tbrix{at}health.sdu.dk
Abstract
The etiology of Graves’ disease (GD), affecting up to 2% of a population in iodine-sufficient areas, is incompletely understood. According to current thinking, the development of GD depends on complex interactions among genetic, environmental, and endogenous factors. However, the relative contributions of the genetic and environmental factors remain to be clarified.
In this study we report probandwise concordance rates for GD in a new cohort of same sex twin pairs born between 1953 and 1976 (young cohort), ascertained from the nationwide population-based Danish Twin Register. To elucidate the magnitude of the genetic and environmental influence in the etiology of GD, these new twin data were pooled with our previously published twin data on GD (old cohort). The old cohort consisted of 2338 same sex twin pairs born between 1870 and 1920 who had participated in questionnaire surveys during the 1950s, 1960s, and 1970s. The young cohort included 6628 same sex twin pairs born between 1953 and 1976 who had participated in a questionnaire survey in 1994.
In the young cohort there were four monozygotic (MZ) pairs and one dizygotic (DZ) pair concordant for clinically overt GD, giving an overall probandwise concordance rate of 0.35 [95% confidence interval (CI), 0.16–0.57] for MZ pairs and 0.07 (95% CI, 0.01–0.24) for DZ pairs (P < 0.02). In the combined twin cohorts there were eight MZ pairs and one DZ pair concordant for clinically overt GD, giving a crude concordance rate of 0.35 (95% CI, 0.21–0.50) for MZ pairs and 0.03 (95% CI, 0.01–0.12) for DZ pairs (P < 0.02). Model-fitting analysis on the pooled twin data showed that 79% of the liability to the development of GD is attributable to genetic factors. Individual specific environmental factors not shared by the twins could explain the remaining 21%. In conclusion, our study strongly supports the idea that genetic factors play a major role in the etiology of GD and suggest that a further search for susceptibility genes is worthwhile.
GRAVES’ DISEASE (GD) is an organ-specific autoimmune thyroid disorder characterized by hyperthyroidism, various degrees of diffuse goiter, ophthalmopathy, and, less commonly, pretibial myxedema (1). The etiology of GD is incompletely understood, but seems to involve complex interactions among genetic, environmental, and endogenous factors (1, 2). The importance of genetic factors is evident from clustering of GD within families (3, 4), and the limited twin data available suggest a higher concordance rate for GD in monozygotic (MZ) than in dizygotic (DZ) twins (2, 5). In addition, recent studies indicate the presence of a number of genes or genetic markers with association and or linkage with GD (2, 6, 7, 8). However, the relative contributions of genetic and environmental influences on disease susceptibility remain to be defined. This can be investigated in twins (9).
There are only a few studies concerning the occurrence of GD or thyrotoxicosis in unselected twin populations (5, 10, 11). The two early studies (10, 11) dealt only with self-reported nonverified diagnoses of thyrotoxicosis, hampering any conclusions with respect to GD (2). In our recent population-based twin study (5) in which all of the probands had well defined phenotypes, the concordance rates for GD were much lower than those previously reported, but were still significantly higher for MZ than DZ pairs. This finding of a lower overall concordance rate for confirmed GD has led the authors of recent reviews to imply that the genetic contribution to disease etiology might not be as strong as previously believed (8, 12). However, such simple calculations of twin data give an erroneous assessment of the genetic contribution to disease development. In complex diseases, the concordance rates are a function of both the prevalence of the disease and the heritability (13). Thus, it follows that if the prevalence is low the concordance rate in twins will also be low even though there is a high degree of heritability. More sophisticated analyses of twin data give more precise estimates of the magnitude of the genetic component in disease susceptibility (14). In rheumatoid arthritis, for example, the heritability has been estimated to be approximately 60% despite a concordance rate of only 12% in MZ twins (15). Unfortunately, it requires a large population-based twin study within a genetically homogeneous population to obtain a reliable estimate of the heritability, which has not been available for GD.
In this study we report concordance rates for GD in a new cohort of Danish twins born between 1953 and 1976, ascertained from the nationwide population-based Danish Twin Register. To estimate the magnitude of the genetic and environmental contributions to the etiology of GD, these new twin data on GD were pooled with our previously published twin data on GD (5).
Subjects and Methods
The twins were recruited from the Danish twin register. The ascertainment procedure, completeness, and validity of this nation-wide population-based register was described in detail previously (16). The present study population was restricted to same sex twin pairs born between 1870 and 1920 and between 1953 and 1976, named the old and young cohorts, respectively. In both cohorts information on self-reported hyperthyroidism was obtained from nation-wide questionnaire surveys, and a diagnosis of GD was confirmed by information from hospitals, out-patient clinics, specialists in endocrinology, and general practitioners. All respondents were living in Denmark, which during the last century has been regarded as a nonendemic goiter area. When investigated, the median urinary iodine excretion has been between 70 and 100 µg/24 h (17).
Data for the old cohort have been published in detail previously (5). The young cohort included 6628 same sex pairs (3556 female and 3072 male) who participated in a nation-wide questionnaire survey in 1994. Three hundred and twelve subjects (201 females and 111 males) indicated present or previous hyperthyroidism. In 265 (85%) of these subjects it was possible to obtain further information with respect to thyroid disease from hospitals, out-patient clinics, specialists, or general practitioners. In 210 subjects the presence of previous or current hyperthyroidism was excluded; the main reasons were weight problems interpreted by the individual as hyperthyroidism (137 subjects), error when filling out the questionnaire (36 subjects), or nontoxic thyroid disease (37 subjects). Thus, it follows that a total of 55 subjects with verified hyperthyroidism were identified in the young cohort. Of these, 5 subjects had toxic nodular goiter and were therefore excluded from further consideration. In the remaining 50 subjects (45 females and 5 males) the hyperthyroidism was due to GD.
Overall, a total of 105 subjects with verified GD were identified from the 2 cohorts. Fourteen of these 105 subjects were males (13%). Informed consent was obtained from all of the participants, and the study was approved by all regional scientific-ethical committees in Denmark (case file 96/150 PMC).
Classification of the hyperthyroidism
All information from hospitals, out-patient clinics, specialists, and general practitioners was reviewed by two of us (L.H. and T.H.B.), both blinded to the zygosity of the twins. In the old cohort a diagnosis of GD was assigned on the basis of clinical and histopathological evidence (5). In the young cohort a diagnosis of GD was based on biochemical hyperthyroidism and a diffuse symmetrical goiter in combination with either positive thyroid antibodies (thyroglobulin, thyroid peroxidase, or TSH receptor) and/or thyroid ophthalmopathy and/or diffuse hyperplasia on an isotope scan or ultrasonography demonstrating homogenous echotexture.
Zygosity
In both cohorts determination of zygosity was primarily based on self-reported answers to specific questions about similarity and mistaken identity, which is a well established and valid method (18). In addition, the zygosity of the four concordant pairs from the young cohort was verified by means of DNA typing of nine short tandem repeat systems with the PE Applied Biosystems AmpFISTR Profiler Plus Kit (19).
Analysis of data
We defined a proband as a subject with verified GD who was ascertained through one of the questionnaire surveys independently of disease status in the cotwin. The similarity in MZ and DZ twins was assessed by probandwise concordance rates, which is defined as the proportion of affected cotwins of probands. It gives the risk that a twin is affected given that the cotwin is affected and is, thus, directly comparable to risk estimates reported for other relatives or in the background population (20). Estimation of the 95% confidence intervals (CI) for the concordance rates were based on the binomial distribution.
For a complex trait such as GD there is no simple method by which to
assess heritability (proportion of variance of a disease attributable
to additive genetic effects) (21). We analyzed the data by
structural equation modeling for twin data as described in detail by
Neale and Cardon (22). In this approach, the phenotypic
variance of the liability to GD is partitioned into genetic and
environmental components. The genetic variance may be due to additive
(A) or dominant (D) genetic influence. The environmental variance can
be divided into variance due to common environmental factors (C) shared
by twins reared in the same family and variance due to individual
nonshared environmental factors (E). Five different etiological models,
ACE, ADE, AE, CE, and E, were fitted to the data using the computer
software Mx, programmed for analysis of categorical twin data
(23). The DE model is not taken into account, because it
is biologically rare to have genetic dominance in the absence of
additive genetic factors. The fit of each model was assessed by a
2 goodness of fit test that tested the
agreement between the observed and the predicted statistics (a small
2 value and a high P value indicate
a good agreement between the model and the observed data). The goal in
model fitting is to explain the observed data as well as possible with
as few parameters as possible (parsimony). We used Akaike’s
Information Criterion, which equals the 2
value minus twice the degrees of freedom (24). The model
with the lowest value of Akaike’s Information Criterion reflects the
best balance of goodness of fit and parsimony.
Results
Concordance rates
Results regarding concordance rates are summarized in Table 1
. For comparison, the number of cases
and the concordance rate for GD in the old cohort is also shown. In the
young cohort there were 4 MZ pairs (3 female) and 1 DZ pair (female)
concordant for clinically overt GD, giving a crude probandwise
concordance rate of 0.35 (95% CI, 0.16–0.57) for MZ pairs and 0.07
(95% CI, 0.01–0.24) for DZ pairs (P = 0.015). When
the twins from the young cohort were stratified according to gender
(females, 45 twin individuals; males, 5 twin individuals), the
difference in the probandwise concordance rate between MZ and DZ pairs
did not reach statistical significance. However, among females there
was a tendency toward a higher concordance rate in MZ than in DZ pairs,
although this was not, strictly speaking, statistically significant (MZ
vs. DZ, 0.29 vs. 0.08; P = 0.08).
Due to the low number of affected male subjects, no tests of the
difference between male MZ and DZ pairs has been performed. Concordance
rates for the combined twin cohort are shown in Table 1.
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Among the 4 concordant MZ pairs in the young cohort, the time from the diagnosis of GD in the first affected twin until diagnosis in the cotwin was less than 4 yr (1, 1, 2, and 4 yr, respectively). The discordance time in the concordant DZ pair was 1 yr. Regardless of zygosity and gender, the overall mean follow-up time of the healthy cotwins was 10.3 yr (range, 3–24 yr). The mean follow-up time of the proband’s cotwin (time span between disease onset in the proband and last contact with the cotwin) was similar in MZ and DZ cotwins (MZ vs. DZ, 10.8 vs. 10.1 yr; P = 0.78). In 4 of the 40 discordant pairs (2 MZ and 2 DZ pairs), the cotwin of the twin with GD had a history of goiter. In all 4 cases the subject was, according to their general practitioner, biochemically and clinically euthyroid. Data for the old cohort have been published previously (5).
Model fitting and heritability
The outcome of the etiological modeling for the pooled twin data
(old plus young cohorts) is summarized in Table 2. Models that only included
environmental factors (CE and E models) provided a poor fit to the data
(P < 0.05) and could be excluded. The three models
including both genetic and environmental effects (ACE, ADE, and AE) all
explained the observed data statistically well. However, according to
the AIC (24), the AE model provided the best overall fit
for the data. In this model 79% of the liability to clinically overt
GD is attributable to genetic factors, whereas individual-specific
environmental factors not shared by cotwins explain the remaining 21%
of the phenotypic variance. No cohort effect was observed, as biometric
modeling, allowing the variance components (a2,
d2, c2, and
e2) to vary across the two cohorts, did not
change the overall results (data not shown).
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The goal of this population-based twin study was to confirm our previous results on GD and, if possible to investigate the magnitude of genetic and environmental factors in the etiology of GD. Clearly, the concordance rates for clinically overt GD found in the present study in a new cohort of Danish twins with well defined phenotypes are fully comparable with our previous results. Our findings (significantly higher concordance rates in MZ than in DZ twins) are supported by preliminary results from a very recent population-based twin study from California (25). In the latter study the pairwise concordance rate for GD was estimated to approximately 0.17 in MZ and 0.02 in DZ twins. Thus, in all three population-based twin studies using well defined phenotypes the concordance rate for GD was significantly higher in MZ than in DZ twins, confirming the presence of genetic factors in the etiology of GD.
Accepting, therefore, that there is a genetic component in the etiology of GD, how large is its effect? In the model-fitting analyses we found that a model that comprised only additive genetic effects and nonshared unique environmental effects had the best overall fit to the observed data. In this model (AE model), approximately 80% of the liability to develop clinically overt GD is attributable to genetic factors, whereas individual-specific environmental factors not shared by the twins explain the remaining 20%. The AE model is a simple one, and it does not include shared environmental effects (C), suggesting that all familial resemblance for GD is due solely to genetic factors. These findings, which were consistent across two twin cohorts, not only confirm the presence of a genetic component in the etiology of GD, but also suggest that the magnitude of the genetic contribution in GD may be at the same level as that seen in other common autoimmune diseases, such as rheumatoid arthritis and insulin-dependent diabetes mellitus (15, 26).
The results of this study should be interpreted in the context of potential limitations. The data in this study were obtained from Caucasians living in Denmark, among whom cultural background and living conditions are generally homogeneous. Thus, the results of this study cannot uncritically be extrapolated to other groups or populations. Heritability estimates are specific to the population in which they were estimated. Other populations may differ in genetic or environmental variance, or both, and hence the ratio of genetic to total phenotypic variance will differ too. It is also important to point out that due to inadequacy of power, the heritability estimates based on the genetic modeling used here do not take a possible gene-environment interaction into account. Clearly, the prevalence of GD changes with variations in environmental factors such as iodine intake (27) and smoking (28, 29). Thus, gene-environment interactions may be important in GD, making the results of heritability difficult to interpret.
In addition, one of the basic assumptions of the classical twin study, that MZ twins carry identical genes, may not be fulfilled in twin studies of immune-mediated diseases, such as GD (2, 30). The generation of Igs and T cell receptors by somatic mutations of germline genes and rearrangements that take place during the differentiation of the immune system are a potential source of difference between the two twin individuals in a given MZ pair (2, 15). Indeed, there is now evidence for a bias in the use of T cell receptor V genes by T cells involved in autoimmune diseases, including autoimmune thyroid disease (30). Therefore, the classic twin study will tend to underestimate the magnitude of the genetic component in GD as well as in other autoimmune diseases.
Although the Danish Twin Register is population based, our final study sample is unlikely to be completely representative of the entire twin population. Twins who did not answer/return the questionnaires were not included. However, as we used the probandwise concordance rate, it is not crucial that all twins should be studied as long as there is no systematic bias in the ascertainment procedure (20). The information on the presence or absence of GD was based on self-reports. This may induce a bias, because of problems in recall or validity of the questionnaire. However, the diagnosis was confirmed by review of medical records. Additionally, in the young cohort, a record linkage between the Twin Register and the National Discharge Register did not suggest systematic under reporting of thyroid disease.
In the young cohort, the follow-up period of the healthy cotwins was rather short. That is, not much time was allowed for the cotwin to develop GD, and hence the concordance rates may increase with increasing follow-up time. This is, however, a very complex process, because new discordant pairs may also appear with increasing observation time. Moreover, it seems unlikely that such a potential increase in concordance should be restricted to DZ compared with MZ twins. This is supported by the fact that the concordance rates found in the young cohort were nearly identical to those found in our previously study, in which there was 25-yr follow-up of the cotwins (5).
In twin studies it is assumed that the intrapair difference in environment is the same for MZ and DZ twins. It has, however, been argued that twins in MZ pairs are more likely to share more similar environments than twins in DZ pairs (31). This could result in an overestimation of the genetic influence in disease etiology. In our study the ADE and AE models fitted the observed data better than the model that included shared environmental effects (ACE model). On the other hand, this may be due to inadequacy of power to detect a small to modest effect of shared environment in this study. Therefore, we can only conclude that we were unable to identify major shared environmental influences on the risk for GD.
In conclusion, our study suggests a multifactorial etiology of GD among Caucasians living in areas with borderline iodine deficiency. It supports a major etiological role for genetic factors in the development of GD, but also indicates that environmental factors are of importance. It is likely that genetic predisposition (susceptibility) is necessary for the development of GD, and that environmental factors possibly have a predominant role in controlling whether a genetically predisposed subject progresses to clinically overt GD.
Footnotes
1 This work was supported by grants from the Agnes and Knut Mørks
Foundation, the Dagmar Marshalls Foundation, the Novo Nordisk
Foundation Committee, the A. P. Møller and Hustru Chastine
McKinney Møllers Foundation, and the Clinical Research Institute,
Odense University. 
Received April 19, 2000.
Revised September 15, 2000.
Accepted October 9, 2000.
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Y. Ban, E. S. Concepcion, R. Villanueva, D. A. Greenberg, T. F. Davies, and Y. Tomer Analysis of Immune Regulatory Genes in Familial and Sporadic Graves' Disease J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4562 - 4568. [Abstract] [Full Text] [PDF]
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 G Birrell and T Cheetham Juvenile thyrotoxicosis; can we do better? Arch. Dis. Child., August 1, 2004; 89(8): 745 - 750. [Abstract] [Full Text] [PDF]
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 Y. Ban, D. A. Greenberg, E. Concepcion, L. Skrabanek, R. Villanueva, and Y. Tomer Amino acid substitutions in the thyroglobulin gene are associated with susceptibility to human and murine autoimmune thyroid disease PNAS, December 9, 2003; 100(25): 15119 - 15124. [Abstract] [Full Text] [PDF]
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B. S. Prabhakar, R. S. Bahn, and T. J. Smith Current Perspective on the Pathogenesis of Graves' Disease and Ophthalmopathy Endocr. Rev., December 1, 2003; 24(6): 802 - 835. [Abstract] [Full Text] [PDF]
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Y. Tomer and T. F. Davies Searching for the Autoimmune Thyroid Disease Susceptibility Genes: From Gene Mapping to Gene Function Endocr. Rev., October 1, 2003; 24(5): 694 - 717. [Abstract] [Full Text] [PDF]
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A. Kretowski, N. Wawrusiewicz, K. Mironczuk, J. Mysliwiec, M. Kretowska, and I. Kinalska Intercellular Adhesion Molecule 1 Gene Polymorphisms in Graves' Disease J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4945 - 4949. [Abstract] [Full Text] [PDF]
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J. E. Collins, J. M. Heward, J. Carr-Smith, J. Daykin, J. A. Franklyn, and S. C. L. Gough Association of a Rare Thyroglobulin Gene Microsatellite Variant with Autoimmune Thyroid Disease J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 5039 - 5042. [Abstract] [Full Text] [PDF]
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Y. Jin, W. Teng, S. Ben, X. Xiong, J. Zhang, S. Xu, Y. Y. Shugart, L. Jin, J. Chen, and W. Huang Genome-Wide Scan of Graves' Disease: Evidence for Linkage on Chromosome 5q31 in Chinese Han Pedigrees J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1798 - 1803. [Abstract] [Full Text] [PDF]
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L. Hegedus, S. J. Bonnema, and F. N. Bennedbaek Management of Simple Nodular Goiter: Current Status and Future Perspectives Endocr. Rev., February 1, 2003; 24(1): 102 - 132. [Abstract] [Full Text] [PDF]
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B. Vaidya, P. Kendall-Taylor, and S. H. S. Pearce The Genetics of Autoimmune Thyroid Disease J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5385 - 5397. [Full Text] [PDF]
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