Epilepsy Research 51 (2002) 167
/177

www.elsevier.com/locate/epilepsyres

Genetic and environmental factors in febrile seizures: a Danish

population-based twin study
Marianne Juel Kjeldsen a,b,*, Kirsten Ohm Kyvik b, Mogens Laue Friis a,
Kaare Christensen b
b

a
Department of Neurology, Odense University Hospital, Odense, Denmark
The Danish Twin Registry, Epidemiology, Institute of Public Health, University of Southern Denmark, Odense University, Sdr.
Boulevard 23a, DK-5000 Odense C, Denmark

Received 20 January 2002; received in revised form 12 June 2002; accepted 14 June 2002

Abstract
The relative importance of genetic and environmental factors in the etiology of febrile seizures was estimated using a
large, unselected population-based twin sample. A total of 34 076 twins (aged 12
/41 years), recruited from the Danish
Twin Registry, were screened for febrile seizures by questionnaire. Information was obtained from 11 872 complete
pairs. Concordance rates, odds ratios and correlations were used to assess the degree of similarity in monozygotic (MZ)
and dizygotic (DZ) twins. Model fitting and estimation of heritability (proportion of the population variance
attributable to genetic variation) were performed using standard biometrical methods. Significantly higher probandwise
concordance rates were found for MZ compared with DZ twins (0.36 and 0.12, P B/0.01). Odds ratios and correlations
showed a similar pattern. An etiological model including additive genetic effects and individual-specific environmental
factors provided the best fit to the data with a heritability for febrile seizures of 70% (95% CI: 61
/77%). The remaining
30% of the variation could be attributed to individual-specific environmental factors. In conclusion, this study has
confirmed a major impact of genetic factors in the etiology of febrile seizures. Future studies aimed at identifying the
specific genetic factors and environmental exposures involved in determining febrile seizure risk are clearly warranted.
# 2002 Elsevier Science B.V. All rights reserved.
Keywords: Febrile seizures; Twin studies; Genetics; Heritability; Biometric modeling

1. Introduction
Febrile seizures are seizures usually occurring
between 3 months and 5 years of age, following
fever but without evidence of intracranial infec* Corresponding author. Tel.: /45-65-41-1884; fax: /45-6590-6938
E-mail address: mjkjeldsen@health.sdu.dk (M.J. Kjeldsen).

tions or other defined cause (Consensus Development Conference on Febrile Seizures, 1981).
Febrile seizures are the most common type of
seizures in children occurring in 2
/5% of all
children in Western Europe and the United States
and in 6
/9% of children in Japan (Hauser and
Kurland, 1975; Berg, 1992; MacDonald et al.,
1999; Tsuboi, 1984; Verity et al., 1985).

0920-1211/02/$ - see front matter # 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 9 2 0 - 1 2 1 1 ( 0 2 ) 0 0 1 2 1 - 3

168

M.J. Kjeldsen et al. / Epilepsy Research 51 (2002) 167
/177

Traditionally, febrile seizures were considered

mainly to be exogenously mediated seizures and
provoked by an intercurrent febrile disease. However, both twin and family studies have suggested
that genetic factors contribute to susceptibility for
febrile seizures. Family studies have shown that
relatives of probands with febrile seizures have a
higher risk of having a febrile seizure themselves
than that of the general population (Annegers et
al., 1990; Berg et al., 1997; Frantzen et al., 1970;
Fukuyama et al., 1979; Hauser et al., 1985). Twin
studies has shown higher concordance rates for
febrile seizures for monozygotic (MZ) than for
dizygotic (DZ) twins, although the concordance
rates vary greatly (Berkovic et al., 1998; Corey et
al., 1991; Lennox-Buchthal, 1973; Lennox, 1971;
Miller et al., 1999; Schittz-Christensen, 1972;
Tsuboi, 1987).
Several modes of inheritance for transmission of
the febrile seizure trait have been suggested
(Kugler and Johnson, 1998). There is growing
evidence that a polygenic or genetically complex
mode of inheritance underlines the common febrile
seizure trait and only a minor proportion of febrile
seizure cases are due to a monogenic disease. In
some multiplex families febrile seizures appear to
be an autosomal dominant trait with reduced
penetrance (Kugler et al., 1998; Rich et al., 1987).
The determinants of susceptibility for febrile
seizures are likely to be characterized by considerable genetic heterogeneity (Racacho et al., 2000).
Locus heterogeneity has already been documented
by the identification of several loci associated with
the febrile seizure phenotype. Putative autosomal
dominant loci for familial febrile seizures have
been localized to chromosomes 8q (Wallace et al.,
1996), 19p (Johnson et al., 1998), 2q (Peiffer et al.,
1999) and 5q (Kugler et al., 1998; Nakayama et al.,
2000). Further, a specific subgroup of the familial
febrile seizures, the generalized epilepsy and febrile
seizure plus syndrome (GEFS/) shows complex
inheritance in some families and evidence of a
major autosomal dominant gene in others. The
first GEFS/ susceptibility locus was identified on
chromosome 19q and a mutation was identified in
the SCN1B gene (Wallace et al., 1998, 2002). Other
loci have been found on chromosome 2q (Baulac
et al., 1999; Moulard et al., 1999; Lopes-Cendes et

al., 2000) where mutations have been identified in

the SCN1A gene (Escayg et al., 2000, 2001;
Wallace et al., 2001b) and in the SCN2A gene
(Sugawara et al., 2001). On chromosome 5 a
mutation has been found in the GABRG2 gene
in families with phenotypes closely related to
GEFS/ (Baulac et al., 2001; Wallace et al.,
2001a). The etiological relationship between the
GEFS/ disorders and uncomplicated febrile seizures is currently unclear.
Although family studies have shown an increased risk of febrile seizures in relatives of
probands, this is not necessarily proof of a genetic
etiology, as families may share predisposing environmental factors as well as genes. Twin studies
provide one of the most efficient methods of
investigating the relative importance of genetic
and environmental factors in explaining phenotypic variation. Population-based twin data are
especially valuable since selection biases are minimized. The classical twin study design is well
documented and has been used to examine the
role of genetic and environmental influences on a
number of complex disorders (Martin et al., 1997).
It is based on the fact that MZ twins share all of
their genes, while DZ twins share on average half
of their genes, as ordinary siblings. By examining
the similarity of MZ and DZ twins, as is usually
done through a comparison of concordance rates,
information about the genetic or environmental
basis of an observed pattern of familial similarity
can be obtained (Neale and Cardon, 1992).
Assuming that the intrapairwise environment is
equal among MZ and DZ twins, a higher concordance for febrile seizures among MZ twins as
compared with DZ twins would indicate that
genetic factors are important. A similar concordance for the two groups of twins would suggest
an environmental cause. Statistical models can be
applied to data from large samples of twins to fit
etiological models and thus determine the magnitude of the contributions of genetic and environmental effects to susceptibility for febrile seizures.
Previous twin studies of febrile seizures have
demonstrated higher concordance rates in MZ
than in DZ twins, however, the results obtained
have varied and the use of different types of
concordance rates (pairwise, casewise and pro-

M.J. Kjeldsen et al. / Epilepsy Research 51 (2002) 167
/177

bandwise) have made the results difficult to

compare across studies (Table 1). The aim of the
present study was to estimate the relative importance of genetic and environmental factors in the
etiology of febrile seizures using a large, unselected, population-based twin data set and to
estimate the heritability of febrile seizures in this
population.

2. Methods
2.1. Subjects

169

responded, giving an individual response rate of

86% and a pairwise response rate of 79%. Of these,
186 pairs were excluded due to incomplete or
missing data and 298 pairs were excluded due to
unknown zygosity. Statistical analyses and biometric modeling were conducted on the remaining
sample of 11 872 twin pairs.
Informed consent was obtained from all participants, and the study was approved by all
regional Danish Ethics Committees (93/300/MC)
and by the Danish Data Protection Agency (19941200-114).
2.2. Zygosity diagnosis

The twin pairs were recruited from the younger

cohort of the nation-wide, population-based Danish Twin Registry. Ascertainment procedures and
characteristics of this cohort have been previously
described in detail elsewhere (Kjeldsen et al.,
present data, Kyvik et al., 1995). This cohort
comprises 34 076 twin individuals (included in
15 558 complete pairs) born in Denmark between
1953 and 1982 who were willing to participate in
twin studies. In 1994 a health related questionnaire
was sent to these twins and detailed information
on physical health issues were obtained. The
question used to identify those with a history of
febrile seizures was: Have you ever had a febrile
seizure? For twins below the age of 18 years the
questionnaire was sent to the parents of the twins
for completion. All together 29 179 twin individuals included in 12 356 complete twin pairs

Twin zygosity (classified as monozygotic, dizygotic, or unknown) was assigned on the basis of
the responses given to a series of questions about
physical similarity and mistaken identity. This
method of zygosity determination has been found
to be reliable in large twin populations and has
been shown to correctly assign zygosity in more
than 95% of twin pairs (Cederlof et al., 1982;
Hauge, 1981; Magnus et al., 1983).
2.3. Statistical analysis
The similarity in MZ and DZ twins was assessed
using probandwise concordance rates, odds ratios
and correlations for febrile seizures. The twin pairs
were stratified by sex and zygosity into two age
categories. The old age category comprised twins

Table 1
Published concordance rates for febrile seizures in population-based and register twin studies
Author

Schittz-Christensen (1972)
Tsuboi (1987)
Corey et al. (1991)
Miller et al. (1999)
Berkovic et al. (1998)
Kjeldsen et al. (present data)
a
b

Number of pairs

64
16
252
203
82
608

Concordance rates for twins 16
/35 years of age.

Concordance rates for twins above 35 years of age.

Concordance rates separated on type

Pairwise

Casewise

Probandwise

MZ

DZ

MZ

DZ

MZ

DZ

0.28
0.44
0.19

/
0.42

0.11
0.14
0.06

/
0.07

/

/

/

/
0.58

/

/

/

/
0.14

0.46

/
0.33
0.39a, 0.42b

/
0.36

0.20

/
0.11
0.12a, 0.14b

/
0.12

170

M.J. Kjeldsen et al. / Epilepsy Research 51 (2002) 167
/177

born 1953
/1967 and the younger, twins born

1968
/1982. Differences due to sex and zygosity
within age groups were evaluated using x2, The
heritability (proportion of the population variance
attributable to genetic variation) was estimated
using standard biometrical methods.
A proband was defined as a twin reporting a
history of febrile seizures who was ascertained
independently of the disease status of the cotwin.
In this study, all affected twins were probands.
Twins were said to be concordant if both pair
members reported a history of febrile seizures and
discordant if only one pair member reported being
affected. Probandwise concordance rates were
used to assess the similarity of MZ and DZ twins
since they are the most informative measure of
concordance and estimate the risk that a twin is
affected given an affected cotwin. This statistic is,
therefore, directly comparable to disease risk rates
in the background population and to estimates of
recurrence risks in relatives (McGue, 1992). The
probandwise concordance rates were estimated as
2C2  C1
2C2  C1  D
where C1, the number of singly ascertained concordant pairs; C2, the number of independently
ascertained concordant pairs, and D , the number
of discordant pairs.
The relative risk of febrile seizures was estimated
as an odds ratio and calculated separately by sex,
age group and zygosity. The odds ratio utilizes the
additional information available from concordant
nondiseased twin pairs and expresses the increased
risk of febrile seizures for one twin due to the
presence or absence of febrile seizures in the
cotwin (Ramakrishnan et al., 1992).
The correlations for febrile seizures, expressed
as tetrachoric correlations due to a dichotomous
outcome, were estimated under the assumption of
the multifactorial threshold model (Falconer,
1965). This assumes that there is an underlying
normally distributed liability (susceptibility) to a
disease due to genetic and environmental factors.
The disease becomes manifest when an individual
exceeds the threshold of affection on the liability
distribution, and the impact of genetic and envir-

onmental effects is reflected in the similarity of the

other twins liability to the disease (Neale and
Cardon, 1992).
Twin data were analyzed under standard biometric assumptions assuming no epistasis (genetic
interlocus interaction), no gene-environment interaction or correlation and no assortative mating.
The specific genetic and environmental effects
examined include additive genetic effects (A),
dominant genetic effects (D), the effects of shared
environments (C) and the effects of non-shared
environment (E). The E-component also includes
measurement errors. In the classical twin study the
effect of genetic dominance (D) and shared
environment (C) are completely confounded (in
twins reared together) and it is not possible to
estimate all of the parameters simultaneously in a
single model. The following etiological models
were fitted to the twin data: ACE, ADE, AE,
CE, and E using MX. The genetic and environmental variance components of liability to febrile
seizures and their confidence intervals were calculated using MX and based on the data from samesex pairs only. The method is described in detail
elsewhere (Neale et al., 1999; Neale and Cardon,
1992).
Standard methods, which reflected the best
balance between goodness of fit and parsimony,
were used in model selection, x2 tests were used to
assess the fit of each model and to select the best
fitting model (a small x2 value and a high P value
indicates 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). The
Akaikes Information Criterion (AIC) (Akaike,
1987) calculated for each model as the x2 value
minus twice the degrees of freedom, was used to
test for parsimony.
Based on the best fitting model, estimates of the
proportion of variance in febrile seizures attributable to A, D, C and E were calculated. Analyses
were first performed using full models, allowing
the variance components to vary across sex and
age. Then, submodels of the best fitting model in
which the variance components were constrained
to be equal across sex and age groups, were
analyzed to test the effect of sex and age on the

M.J. Kjeldsen et al. / Epilepsy Research 51 (2002) 167
/177

parameters. Finally, the heritability of the liability

to febrile seizures (the proportion of the total
phenotypic variance due to genetic variance) was
derived from the best fitting model.

3. Results
Of the 29 179 twin individuals who returned the
1994-health related questionnaire, 805 reported a
history of febrile seizures, resulting in a lifetime
prevalence of 2.8%. When the full data set is
restricted to the 11 872 complete twin pairs of
known zygosity the total number of affected twins
is 678 individuals (2.9%) (345 female subjects and
333 male subjects) included in 608 pairs. Male and
female subjects reported febrile seizures equally
frequent (2.9% for both sexes). Significantly more
MZ than DZ twins reported febrile seizures (3.2%
of MZ vs. 2.7% of DZ, P /0.03) and significantly
more cases were found among younger as compared with older twins (3.7 vs. 2.1%, P B/0.001).
Of the 678 individuals with febrile seizures, 51 also
reported a history of epilepsy (7.5%).
3.1. Concordance rates, odds ratios and tetrachoric
correlations
The distribution of febrile seizures among MZ
and DZ twin pairs is shown in Table 2. This table
also details the probandwise concordance rates,
odds ratios and tetrachoric correlations estimated
for MZ and DZ twins, stratified by sex and
partitioned into two age groups. No sex differences were found in febrile seizures concordance
rates, however, concordance rates for febrile
seizures were consistently significantly higher for
MZ than for DZ twins. The concordance rate for
MZ overall was 36% and drops significantly to
12% for DZ twins (P B/0.01). Higher concordance
rates were also found in the younger cohort than
in the older cohort, but only significant in the DZ
twins (P /0.02). The concordance rates were
virtually unchanged when further restricting the
young cohort to include only the twins under the
age of 18 (data not shown). Excluding pairs with a
history of both febrile seizures and epilepsy did not
change the concordance rates.

171

MZ twins were characterized by significantly

higher odds ratios and tetrachoric correlations for
febrile seizures than were DZ twins. The cotwin of
an affected MZ twin had a risk of febrile seizures
that was 26.6 times that of a cotwin of an
unaffected MZ twin while a cotwin of an affected
DZ twin had a risk that was 5.4 times that of a
cotwin of an unaffected DZ twin. The odds ratios
showed no difference according to sex. Although
the odds ratios were generally higher in the young
versus the old cohort, this difference was not
significant. Tetrachoric correlations showed the
same pattern as the concordance rates and the
odds ratios with significantly higher values observed for MZ compared with DZ twins. No
significant changes were seen in odds ratios or
tetrachoric correlations when data were analyzed
excluding the pairs with both febrile seizures and
epilepsy.
3.2. Biometrical modeling and heritability
The results of the biometrical analyses using full
models where variance components were not
constrained to be equal across sex and age are
shown in Table 3. All models that included both
genetic and environmental factors fit the data well
(P ]/0.2), however, a model that included additive
genetic factors and non-shared environment (AEmodel) gave the best overall fit to the data (lowest
AIC). Models that included environmental factors
alone (CE and E models) provided a very poor fit
to the data (P B/0.001) and could be excluded. In
the submodel analysis, the model that constrained
the parameter estimated to be equal for men and
women and for the two age groups provided the
best fit to the data. The heritability was estimated
to 70% (95% CI: 61
/77%) (i.e. 70% of the liability
to develop febrile seizures is attributable to genetic
factors), whereas individual-specific environmental
factors account for the remaining 30% (95% CI:
23
/39%).

4. Discussion
In a large, unselected, population-based twin
data set we studied the relative importance of

172

Age
years

Zygosity
group

Number of concordant pairs with FS

Number of discordant pairs with FS

Number of concordant
non-affected pairs

Probandwise concordance
rates (95% CI)

OR (95% CI)

Tetrachoric correlation
(95% CI)

12
/26

MZ
DZ
MZ
DZ

33
20
11
6

96
224
58
160

1982
3375
1589
4318

0.41
0.15
0.28
0.07

28.4(16.7
/48.1)
5.4 (3.2
/9.0)
20.8 (9.5
/45.6)
4.1 (1.7
/9.6)

0.74
0.38
0.64
0.26

MZ
DZ

44
26

154
384

3571
7693

0.36 (0.30
/0.43)

0.12 (0.09
/0.15)

27
/41

12
/41

MZ, monozygotic; DZ, dizygotic; CI, confidence intervals; FS, febrile seizures.

(0.33
/0.49)
(0.11
/0.20)
(0.18
/0.39)
(0.04
/0.12)

(0.64
/0.82)
(0.25
/0.50)
(0.46
/0.77)
(0.07
/0.43)

26.6 (17.2
/40.9) 0.71 (0.63
/0.78)

5.4 (3.5
/8.4)
0.35 (0.25
/0.45)

M.J. Kjeldsen et al. / Epilepsy Research 51 (2002) 167
/177

Table 2
Probandwise concordance rates, odds ratios (OR) and tetrachoric correlations for febrile seizures by zygosity and age

M.J. Kjeldsen et al. / Epilepsy Research 51 (2002) 167
/177

173

Table 3
Biometrical models analyses for febrile seizures: variance components and model fit statistics
Model

ACE
ADE
AE*
CE
E

Variance components (95% Cl interval)

Goodness of fit tests

a2

d2

c2

e2

0.70 (0.48
/0.78)

0.52 (0.00
/0.76)
0.70 (0.61
/0.77)

/

/

/
0.18 (0.00
/0.75)

/

/

/

0.00 (0.00
/0.22)

/

/
0.56 (0.48
/0.63)

/

0.30
0.29
0.30
0.44
1.00

(0.22
/0.38)
(0.23
/0.38)
(0.23
/0.39)
(0.37
/0.52)

x2 (df)

AIC

4.7
4.4
4.7
28.4
184.3

0.20
0.22
0.32
B/0.001
B/0.001

/1.3
/1.6
/3.3
20.4
174.3

(3)
(3)
(4)
(4)
(5)

The variables are additive genetic (A); genetic dominance (D); shared environment (C); and nonshared environment (E). The
proportions of variance in liability to febrile seizures due to A, D, C and E are a2, d2, c2 and e2, respectively, df: degrees of freedom;
AIC: Akaiki information Criterion; *: best fitting model by AIC. CI: confidence interval.

genetic and environmental factors in the etiology

of febrile seizures. The twins were recruited
independently of zygosity and disease status,
thereby avoiding the ascertainment biases usually
associated with volunteer populations and clinic
based twin samples. By using the Danish Central
Personal Registration System, we were able to
recruit twins from the whole country (population
approximately 5.2 /106 inhabitants), thereby
making our sample as genuine population-based
as possible (Kyvik et al., 1995).
Comparisons of the similarity of MZ and DZ
twins for history of febrile seizures showed substantially higher concordance rates, odds ratios
and tetrachoric correlations in MZ compared with
DZ twins. This emphasizes the importance of the
genetic contribution to susceptibility for febrile
seizures. This conclusion is strengthened by the
results of biometrical modeling. In biometrical
modeling, a model that included additive genetic
and non-shared environmental effects (AE-model)
had the best overall fit to the observed data. Since
this model does not include shared environmental
effects, it suggests that the familial resemblance for
febrile seizures observed in this sample is due
solely to genetic factors.
Previous twin studies have provided evidence
for a genetic etiology of febrile seizures, however,
the concordance rates observed have varied (Table
1). Population-based and register-based twin studies have reported concordance rates ranging from
0.28 to 0.58 for MZ and 0.06 to 0.20 for DZ twins
(Berkovic et al., 1998; Corey et al., 1991; Miller et
al., 1999; Schittz-Christensen, 1972; Tsuboi,

1987). The varying concordance rates obtained

are most likely due to the calculation of different
types of concordance rates and different ascertainment procedures. Three types of concordance rates
exists: the pairwise, the casewise and the probandwise. The pairwise concordance rate applies to
twin pairs and estimates the probability that both
members of a twin pair are affected given that at
least one member of the pairs is affected. The
casewise concordance rate applies to twin individuals and estimates the probability that a twin is
affected given that his/her cotwin is affected. The
probandwise concordance rates take into account
the ascertainment method and differentiates between concordant pairs where both probands are
independently ascertained and concordant pairs
that are singly ascertained. This concordance rate
is, therefore, more robost to incomplete ascertainment (McGue, 1992).
In a Danish population-based sample, SchittzChristensen (1972) investigated 64 same-sex twin
pairs with febrile seizures in one or both twins and
found higher concordance rates in MZ compared
with DZ twin pairs, however, this difference was
only significant when analyses were restricted to
female-female pairs. This result, together with the
finding of a high prevalence of febrile seizures in
siblings, led to the conclusion that febrile seizures
are caused by factors that are shared by siblings
and are largely non-genetic in nature. The sample
size of the study is relatively small and could
account for the insignificant difference observed in
concordance rates in the total material. Our
analysis of a much larger twin sample demon-

174

M.J. Kjeldsen et al. / Epilepsy Research 51 (2002) 167
/177

strated both by concordance rates and model

fitting that the factor that are shared by twins
and which is responsible for febrile seizures
susceptibility is indeed genetic and is not due to
shared environments. Our findings are in agreement with those of Corey et al. (1991) who also
found significantly higher concordance rates for
febrile seizures in a population-based study of
Virginian and Norwegian twins. This group, in
another study in Virginian twins, also demonstrated higher concordance rates for Caucasians
for febrile seizures (0.39 for MZ and 0.12 for DZ
for twins 16
/35 years of age, and 0.42 for MZ and
0.14 for DZ for twins above 35 years of age)
(Miller et al., 1999).
Only one previous study has used model fitting
to assess the determinants of risk for febrile
seizures using twin data. Miller et al. (1998) found,
in agreement with our results, that an AE model
displayed the best fit to the observed data.
Although the calculation method used was the
same, the heritability estimate obtained was
slightly higher that ours (81 vs. 70%). Other studies
that have estimated the heritability of febrile
seizures predisposition using non-twin material
have obtained results similar to ours (68
/76%)
(Fukuyama et al., 1979; Rich et al., 1987; Tsuboi
and Endo, 1991).
Twin studies are not without weaknesses. In
order to derive a valid assessment of the magnitude of genetic and environmental effects using
twin data, important assumptions are made. The
assumption that MZ and DZ twins have similar
pre- and postnatal environments (equal environment assumption), and therefore, that the greater
phenotypic similarity observed between MZ twins
is due to their greater genetic similarity is particularly critical (Guo, 2001; Pam et al., 1996; Phillips,
1993). If this assumption is correct, the observation of an increased concordance rate (i.e. a
greater phenotypic similarity) in MZ twins as
compared with DZ twins is likely to be due to
the greater genetic similarity of MZs. If, however,
this assumption is not correct and environmental
similarity is greater among MZ twins than among
DZ twins, genetic effects are likely to be overestimated.

Furthermore, the results from twin studies may

not necessarily be applicable to singletons. In
order for the results obtained in this study to be
applied to the general population, it is necessary
that the cause of febrile seizures in twins does not
differ from that in singletons. One previous
Australian study, however, has shown that twin
birth is not a major risk factor for seizures
(Berkovic et al., 1993), suggesting that the results
obtained in this study can be applied to the general
population. However, despite the populationbased nature of the Danish registry and high
response rates obtained in the questionnaire survey, potential biases exist that decrease the likelihood that our sample is completely representative
of the Danish twin population. Twins with unknown zygosity, discordant participating twin
pairs and twin pairs with missing or incomplete
information of febrile seizures in one of the twins
were excluded from this study, leaving 11 872 pairs
(76% of all represented pairs) accessible for
analysis of similarity. Underreporting of febrile
seizures and misclassification of zygosity may also
induce bias. While the method used to assign
zygosity is valid and has a misclassification rate of
less than 5%, a history of febrile seizures may be
underreported due to recall bias or the lack of
knowledge of ever having had the disorder. Since
febrile seizures occur before age 5 years it is likely
that some of the participating twins were unaware
of their own febrile seizure history. The higher
prevalence of febrile seizures in younger than older
twins is an indication of such underreporting by
older individuals. Since the 2.9% prevalence of
febrile seizures observed in the total sample
population is within the expected range, a fair
ascertainment of cases is indicated. For twins
below the age of 18 years questionnaires were
sent to the parents of the twins. Although recall
bias may be present also in parents, more valid
report about febrile seizures is likely to come from
the parents. The concordance rates, however, were
virtually unchanged for the twins under 18 years of
age, compared with the complete younger cohort.
The prevalence of a febrile seizure history was
higher in MZ than DZ twins suggesting that MZ
twins carry a higher risk of having febrile seizures
than DZ twins. There is no support for this in the

M.J. Kjeldsen et al. / Epilepsy Research 51 (2002) 167
/177

literature. Another more likely explanation is

information bias. It is possible that MZ pairs
differ from DZ twins in the likelihood of finding
out their febrile seizure histories from their parents
leading to a higher probability of reporting febrile
seizures in MZ than in DZ twins. This would
increase the estimates of the genetic effect.
Although model fitting can be used to estimate
the magnitude of the heritable component in
susceptibility to febrile seizures, this method does
not provide any information about how this
component acts or interacts with other factors,
for example with environmental factors. A modifying effect of the environment on the genetic
component cannot be excluded, and in fact is
likely to be present to a certain extent since at least
one environmental factor needs to be present to
elicit a febrile seizure, i.e. fever. In principle any
illness or environmental factor that raises body
temperature could precipitate febrile seizures. This
does not introduce any biases with regard to our
sample since episodes of fever are widespread
among children and the chance of going through
the vulnerable period for febrile seizures without
ever experiencing fever is very low.
The impact of genetic factors may vary depending on fever seizure type (simple or complex) and
presence of later afebrile seizures. By allowing the
relatively small number of pairs with both febrile
seizures and afebrile seizures in the material, bias
could have been introduced. However, excluding
pairs with both self-reported epilepsy and febrile
seizures did not change the concordance rates,
odds ratios or tetrachoric correlations. In order to
evaluate whether the role of genetic factors varies
with seizure type, a complete validation of the
material, including classification of seizures and
identification of possible GEFS/ cases, would be
necessary. By validating all twin pairs with selfreported febrile seizures, cases misdiagnosed as
febrile seizures, i.e. night terrors and shuttering
attacks during fever episodes, can also be identified. Thereby the reliability of self-reported febrile
seizures based on a questionnaire can be determined.
In conclusion, the significantly higher degree of
resemblance observed among MZ twins compared
with DZ twins for the occurrence of febrile

175

seizures and the high heritability of febrile seizures

demonstrated in this large, unselected, populationbased twin sample, confirm that genetic factors
play a major role in the etiology of this disorder.
Future studies aimed at identifying the specific
genetic factors and environmental exposures involved in determining febrile seizure risk are
clearly warranted.

Acknowledgements
This study was supported in parts by the
following grants: The grant committee of Consultancy Counsel, Odense University Hospital;
The K.A. Rohdes Foundation; The Danish Epilepsy Society Research Foundation; The Novo
Nordic Foundation; The Hede Nielsen Foundation, The Clinical Research Institute, University of
Southern Denmark, Odense University and a
NINDS grant (NS-31564). We especially would
like to thank all the participating twins, without
whom this study would not have been possible.

References
Akaike, H., 1987. Factor analysis and AIC. Psychometrika 52,
317
/332.
Annegers, J.F., Blakley, S.A., Hauser, W.A., Kurland, L.T.,
1990. Recurrence of febrile convulsions in a populationbased cohort. Epilepsy Res. 5, 209
/216.
Baulac, S., Gourfinkel-An, I., Picard, F., Rosenberg-Bourgin,
M., Prudhomme, J.F., Baulac, M., Brice, A., LeGuern, E.,
1999. A second locus for familial generalized epilepsy with
febrile seizures plus maps to chromosome 2q21
/q33. Am. J.
Hum. Genet. 65, 1078
/1085.
Baulac, S., Huberfeld, G., Gourfinkel-An, I., Mitropoulou, G.,
Beranger, A., Prudhomme, J.F., Baulac, M., Brice, A.,
Bruzzone, R., LeGuern, E., 2001. First genetic evidence of
GABA(A) receptor dysfunction in epilepsy: a mutation in
the gamma2-subunit gene. Nat. Genet. 28, 46
/48.
Berg, A.T., 1992. Febrile seizures and epilepsy: the contributions of epidemiology. Paediatr. Perinat. Epidemiol. 6, 145
/
152.
Berg, A.T., Shinnar, S., Darefsky, A.S., Holford, T.R., Shapiro,
E.D., Salomon, M.E., Crain, E.F., Hauser, A.W., 1997.
Predictors of recurrent febrile seizures. A prospective cohort
study. Arch. Pediatr. Adolesc. Med. 151, 371
/378.
Berkovic, S.F., Howell, R.A., Hay, D.A., Hopper, J.L., 1993.
Twin birth is not a risk factor for seizures. Neurology 43,
2515
/2519.

176

M.J. Kjeldsen et al. / Epilepsy Research 51 (2002) 167
/177

Berkovic, S.F., Howell, R.A., Hay, D.A., Hopper, J.L., 1998.

Epilepsies in twins: genetics of the major epilepsy syndromes. Ann. Neurol. 43, 435
/445.
Cederlof, R., Rantasalo, I., Floderus-Myrhed, B., Hammar, N.,
Kaprio, J., Koskenvuo, M., Langinvainio, H., Sarna, S.,
1982. Across-national epidemiological resource: the Swedish
and Finnish cohort studies of like-sexed twins. Int. J.
Epidemiol. 11, 387
/390.
Corey, L.A., Berg, K., Pellock, J.M., Solaas, M.H., Nance,
W.E., DeLorenzo, R.J., 1991. The occurrence of epilepsy
and febrile seizures in Virginian and Norwegian twins.
Neurology 41, 1433
/1436.
Escayg, A., MacDonald, B.T., Meisler, M.H., Baulac, S.,
Huberfeld, G., An-Gourfinkel, I., Brice, A., LeGuern, E.,
Moulard, B., Chaigne, D., Buresi, C., Malafosse, A., 2000.
Mutations of SCN1A, encoding a neuronal sodium channel,
in two families with GEFS/2. Nat. Genet. 24, 343
/345.
Escayg, A., Heils, A., MacDonald, B.T., Haug, K., Sander, T.,
Meisler, M.H., 2001. A novel SCN1A mutation associated
with generalized epilepsy with febrile seizures plus */and
prevalence of variants in patients with epilepsy. Am. J.
Hum. Genet. 68, 866
/873.
Falconer, D.S., 1965. The inheritance of liability to certain
diseases, estimated from the incidence among relatives. Ann.
Hum. Genet. 29, 51
/76.
Frantzen, E., Lennox-Buchtal, M., Nygaard, A., Stene, J.,
1970. A genetic study of febrile convulsions. Neurology 20,
909
/917.
Fukuyama, Y., Kagawa, K., Tanaka, K., 1979. A genetic study
of febrile convulsions. Eur. Neurol. 18, 166
/182.
Guo, S.W., 2001. Does higher concordance in monozygotic
twins than in dizygotic twins suggest a genetic component.
Hum. Hered. 51, 121
/132.
Hauge, M., 1981. The danish twin register. In: Mednick, S.,
Baert, A., Bachmann, B. (Eds.), Prospective Longitudinal
Research. An Empirical Basis for the Primary Prevention of
Psychological Disorders. Oxford University Press, Oxford,
pp. 217
/221.
Hauser, W.A., Kurland, L.T., 1975. The epidemiology of
epilepsy in Rochester, MN, 1935
/1967. Epilepsia 16, 1
/66.
Hauser, W.A., Annegers, J.F., Anderson, V.E., Kurland, L.T.,
1985. The risk of seizure disorders among relatives of
children with febrile convulsions. Neurology 35, 1268
/1273.
Johnson, E.W., Dubovsky, J., Rich, S.S., ODonovan, C.A.,
Orr, H.T., Anderson, V.E., Gil, N.A., Ahmann, P.,
Dokken, C.G., Schneider, D.T., Weber, J.L., 1998. Evidence for a novel gene for familial febrile convulsions,
FEB2, linked to chromosome 19p in an extended family
from the Midwest. Hum. Mol. Genet. 7, 63
/67.
Kjeldsen, M.J., Kyvik, K.O., Christensen, K., Friis, M.L., 2001.
Genetic and environmental factors in epilepsy; a population-based study of 11 900 Danish twin pairs. Epilepsy Res.
44, 167
/178.
Kugler, S.L., Johnson, W.G., 1998. Genetics of the febrile
seizure susceptibility trait. Brain Dev. 20, 265
/274.
Kugler, S.L., Stenroos, E.S., Mandelbaum, D.E., Lehner, T.,
McKoy, V.V., Prossick, T., Sasvari, J., Swannick, K., Katz,

J., Johnson, W.G., 1998. Hereditary febrile seizures: phenotype and evidence for a chromosome 19p locus. Am. J.
Med. Genet. 79, 354
/361.
Kyvik, K.O., Green, A., Beck-Nielsen, H., 1995. The new
Danish Twin Register: establishment and analysis of twinning rates. Int. J. Epidemiol. 24, 589
/596.
Lennox-Buchthal, M.A., 1973. Febrile convulsions. A reappraisal. Electroencephalogr. Clin. Neurophysiol. (Suppl.
32), 37
/38.
Lennox-Buchthal, M., 1971. Febrile and nocturnal convulsions
in monozygotic twins. Epilepsia 12, 147
/156.
Lopes-Cendes, I., Scheffer, I.E., Berkovic, S.F., Rousseau, M.,
Andermann, E., Rouleau, G.A., 2000. A new locus for
generalized epilepsy with febrile seizures plus maps to
chromosome 2. Am. J. Hum. Genet. 66, 698
/701.
MacDonald, B.K., Johnson, A.L., Sander, J.W., Shorvon,
S.D., 1999. Febrile convulsions in 220 children */neurological sequelae at 12 years follow-up. Eur. Neurol. 41, 179
/
186.
Magnus, P., Berg, K., Nance, W.E., 1983. Predicting zygosity in
Norwegian twin pairs born 1915
/1960. Clin. Genet. 24,
103
/112.
Martin, N., Boomsma, D., Machin, G., 1997. A twin-pronged
attack on complex traits. Nat. Genet. 17, 387
/392.
McGue, M., 1992. When assessing twin concordance, use the
probandwise not the pairwise rate. Schizophr. Bull. 18,
171
/176.
Miller, L.L., Pellock, J.M., DeLorenzo, R.J., Meyer, J.M.,
Corey, L.A., 1998. Univariate genetic analyses of epilepsy
and seizures in a population-based twin study: the Virginia
Twin Registry. Genet. Epidemiol. 15, 33
/49.
Miller, L.L., Pellock, J.M., Boggs, J.G., DeLorenzo, R.J.,
Meyer, J.M., Corey, L.A., 1999. Epilepsy and seizure
occurrence in a population-based sample of Virginian twins
and their families. Epilepsy Res. 34, 135
/143.
Moulard, B., Guipponi, M., Chaigne, D., Mouthon, D., Buresi,
C., Malafosse, A., 1999. Identification of a new locus for
generalized epilepsy with febrile seizures plus (GEFS/) on
chromosome 2q24
/q33. Am. J. Hum. Genet. 65, 1396
/
1400.
Nakayama, J., Hamano, K., Iwasaki, N., Nakahara, S.,
Horigome, Y., Saitoh, H., Aoki, T., Maki, T., Kikuchi,
M., Migita, T., Ohto, T., Yokouchi, Y., Tanaka, R.,
Hasegawa, M., Matsui, A., Hamaguchi, H., Arinami, T.,
2000. Significant evidence for linkage of febrile seizures to
chromosome 5q14
/q15. Hum. Mol. Genet. 9, 87
/91.
Neale, M.C., Cardon, L.R., 1992. Methodology for Genetic
Studies of Twins and Families. Kluwer Academic Publishers, Dordrecht, Boston, London.
Neale, M.C., Boker, S.M., Xie, G., Maes, H.H., 1999. Mx:
Statistical modeling, fifth ed. Department of Psychiatry,
Box 126 MCV, Richmond, VA 23298.
Pam, A., Kemker, S.S., Ross, C.A., Golden, R., 1996. The
equal environments assumption in MZ
/DZ twin comparisons: an untenable premise of psychiatric genetics. Acta
Genet. Med. Gemellol. (Roma) 45, 349
/360.

M.J. Kjeldsen et al. / Epilepsy Research 51 (2002) 167
/177

Peiffer, A., Thompson, J., Charlier, C., Otterud, B., Varvil, T.,
Pappas, C., Barnitz, C., Gruenthal, K., Kuhn, R., Leppert,
M., 1999. A locus for febrile seizures (FEB3) maps to
chromosome 2q23
/24 (see comments). Ann. Neurol. 46,
671
/678.
Phillips, D.I., 1993. Twin studies in medical research: can they
tell us whether diseases are genetically determined? (see
comments). Lancet 341, 1008
/1009.
Consensus Development Conference on Febrile Seizures, 1981.
National Institutes of Health, May 19
/21, 1980. Epilepsia
22, 377
/381.
Racacho, L.J., McLachlan, R.S., Ebers, G.C., Maher, J.,
Bulman, D.E., 2000. Evidence favoring genetic heterogeneity for febrile convulsions. Epilepsia 41, 132
/139.
Ramakrishnan, V., Goldberg, J., Henderson, W.G., Eisen,
S.A., True, W., Lyons, M.J., Tsuang, M.T., 1992. Elementary methods for the analysis of dichotomous outcomes in
unselected samples of twins. Genet. Epidemiol. 9, 273
/287.
Rich, S.S., Annegers, J.F., Hauser, W.A., Anderson, V.E.,
1987. Complex segregation analysis of febrile convulsions.
Am. J. Hum. Genet. 41, 249
/257.
Schittz-Christensen, E., 1972. Genetic factors in febrile convulsions. An investigation of 64 same-sexed twin pairs. Acta
Neurol. Scand. 48, 538
/546.
Sugawara, T., Tsurubuchi, Y., Agarwala, K.L., Ito, M.,
Fukuma, G., Mazaki-Miyazaki, E., Nagafuji, H., Noda,
M., Imoto, K., Wada, K., Mitsudome, A., Kaneko, S.,
Montal, M., Nagata, K., Hirose, S., Yamakaw, K., 2001. A
missense mutation of the Na/ channel alpha II subunit
gene Na(v)1.2 in a patient with febrile and afebrile seizures
causes channel dysfunction. Proc. Natl. Acad. Sci. USA 98,
6384
/6389.
Tsuboi, T., 1984. Epidemiology of febrile and afebrile convulsions in children in Japan. Neurology 34, 175
/181.
Tsuboi, T., 1987. Genetic analysis of febrile convulsions: twin
and family studies. Hum. Genet. 75, 7
/14.

177

Tsuboi, T., Endo, S., 1991. Genetic studies of febrile convulsions: analysis of twin and family data. Epilepsy Res. Suppl.
4, 119
/128.
Verity, C.M., Butler, N.R., Golding, J., 1985. Febrile convulsions in a national cohort followed up from birth. I */
Prevalence and recurrence in the first 5 years of life. Br.
Med. J. (Clin. Res. Ed.) 290, 1307
/1310.
Wallace, R.H., Berkovic, S.F., Howell, R.A., Sutherland, G.R.,
Mulley, J.C., 1996. Suggestion of a major gene for familial
febrile convulsions mapping to 8q13
/21. J. Med. Genet. 33,
308
/312.
Wallace, R.H., Wang, D.W., Singh, R., Scheffer, I.E., George,
A.L.J., Phillips, H.A., Saar, K., Reis, A., Johnson, E.W.,
Sutherland, G.R., Berkovic, S.F., Mulley, J.C., 1998.
Febrile seizures and generalized epilepsy associated with a
mutation in the Na/-channel beta1 subunit gene SCN1B.
Nat. Genet. 19, 366
/370.
Wallace, R.H., Marini, C., Petrou, S., Harkin, L.A., Bowser,
D.N., Panchal, R.G., Williams, D.A., Sutherland, G.R.,
Mulley, J.C., Scheffer, I.E., Berkovic, S.F., 2001a. Mutant
GABA(A) receptor gamma2-subunit in childhood absence
epilepsy and febrile seizures. Nat. Genet. 28, 49
/52.
Wallace, R.H., Scheffer, I.E., Barnett, S., Richards, M.,
Dibbens, L., Desai, R.R., Lerman-Sagie, T., Lev, D.,
Mazarib, A., Brand, N., Ben Zeev, B., Goikhman, I., Singh,
R., Kremmidiotis, G., Gardner, A., Sutherland, G.R.,
George, A.L., Jr, Mulley, J.C., Berkovic, S.F., 2001b.
Neuronal sodium-channel alpha1-subunit mutations in
generalized epilepsy with febrile seizures plus. Am. J.
Hum. Genet. 68, 859
/865.
Wallace, R.H., Scheffer, I.E., Parasivam, G., Barnett, S.,
Wallace, G.B., Sutherland, G.R., Berkovic, S.F., Mulley,
J.C., 2002. Generalized epilepsy with febrile seizures plus:
mutation of the sodium channel subunit SCN1 B. Neurology 58, 1426
/1429.