Child and Adolescent Psychiatry Section, Department of Psychological Medicine, University of Wales College of Medicine, Cardiff, UK
University of Manchester Department of Child and Adolescent Psychiatry, Royal Manchester Children's Hospital, Manchester, UK
Social Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, London, UK
Correspondence: Professor Anita Thapar, Department of Psychological Medicine, University of Wales College of Medicine, Heath Park, Cardiff C14 4xN, UK
Declaration of interest This study was funded by the Medical Research Council (UK) G9608217.
See editorial, pp.
189190, this issue.
ABSTRACT
Background Although attention-deficit hyperactivity disorder (ADHD) and conduct disorder (CD) frequently co-occur, the underlying mechanisms for this comorbidity are not well understood.
Aims To examine whether ADHD and conduct problems share common risk factors and whether ADHD+CD is a more heritable variant of ADHD.
Method Questionnaires were sent to 2846 families. Parent-rated data were obtained for 2082 twin pairs and analysed using bivariate genetic analysis and a liability threshold model approach.
Results The overlap of ADHD and conduct problems was explained by common genetic and non-shared environmental factors influencing both categories. Nevertheless, the two categories appeared to be partly distinct in that additional environmental factors influenced conduct problems. It appeared that ADHD+CD was a genetically more severe variant of ADHD.
Conclusions Conduct problems and ADHD share a common genetic aetiology; ADHD+CD appears to be a more severe subtype in terms of genetic loading as well as clinical severity.
It has consistently been observed that attention-deficit hyperactivity disorder (ADHD) and conduct disorder commonly co-occur, and family and twin study findings suggest that much of this overlap is due to a common genetic aetiology (Silberg et al, 1996; Faraone et al, 1998). A separate question is whether the sub-group with both ADHD and conduct disorder (ADHD+CD) is distinct from those with pure ADHD. Children who fulfil ICD-10 diagnostic criteria for both hyperkinetic disorder and conduct disorder (World Health Organization, 1992) are separately categorised under hyperkinetic conduct disorder. There is some clinical support for this distinction in that most studies suggest that ADHD+CD is a more severe condition than either disorder alone (Barkley et al, 1990; Jensen et al, 1997; Kuhne et al, 1997), although findings have not been entirely consistent (Leung et al, 1996; Taylor et al, 1996). Family study findings also suggest that ADHD+CD represents a distinct familial subtype of ADHD (Faraone et al, 2000) although twin data are needed to test whether ADHD+CD is genetically distinct or a more severe category of ADHD in terms of genetic loading.
METHOD
Our aims were first to replicate and extend previous twin work on hyperactivity and conduct symptom scores (Silberg et al, 1996) by examining whether common genetic and environmental risk factors account for the comorbidity between categorically defined ADHD-related problems and conduct problems, and second to use a liability threshold model to examine whether a comorbid category of ADHD +CD represents a genetically more severe variant of ADHD-related behaviours.
Participants
The sample consisted of school-aged twins (aged 5-17 years) included on the
population-based Greater Manchester twin register. This is a register of 2846
live twin births who were identified from community child-health databases for
nine health districts in Greater Manchester and Lancashire. The
characteristics of the twin register and responding families have been
described in detail elsewhere (Thapar
et al, 2000). The final sample for whom data were
available included 767 female twin pairs, 715 male twin pairs and 600
opposite-sex twin pairs. Of the 1920 pairs for whom zygosity could be
assigned, 731 (38.1%) were monozygotic, 590 (30.7%) were same-gender dizygotic
and 599 (31.2%) were opposite-gender dizygotic; 162 twin pairs could not be
assigned zygosity because of incomplete or ambiguous responses.
Measures
Questionnaires were mailed to the families of the twins; non-responders
were sent two postal reminders and given one telephone reminder. The overall
response rate was 73% (2082/2846). A standard twin similarity questionnaire
that has over 90% accuracy (Cohen et
al, 1975) was used to assign zygosity. Parent ratings of ADHD
symptoms for each twin were obtained using a modified version of the DuPaul
ADHD rating scale (DuPaul,
1981). The original scale included the 14 DSMIIIR
symptoms of ADHD (American Psychiatric
Association, 1987) and we added a further four items to cover
additional ICD-10 symptoms of hyperkinetic disorder. Each symptom can be rated
on a four-point scale of severity, and each item was summed to generate a
total ADHD score. Hyperactivity was then defined categorically using the 80th
centile as a cut-off point, chosen on the grounds of previously reported
validating data (Thapar et al,
2000), and in accordance with the approach adopted by others when
analysing extreme scores in twins.
Parents were also asked to complete the Rutter A scale (Rutter et al, 1970). This scale includes five conduct items, and the scores for these were summed to obtain a total conduct symptom score. A categorical measure of conduct problems was then generated by again using a cut-off above the 80th centile. Children who were assigned to both the ADHD+CD and CD categories were labelled as ADHD+CD for the liability threshold model analyses.
Although diagnostic criteria were not used, for the purposes of simplicity the following discussion refers to the broadly defined study categories as ADHD-related behaviours and Conduct problems, and for the subgroup analysis the terms pure ADHD, pure CD and ADHD+CD are given in quotation marks to emphasise that these are not diagnostic categories.
Genetic analysis
Univariate and bivariate genetic model fitting
Monozygotic (MZ) and dizygotic (DZ) probandwise concordance rates were
calculated and the raw categorical twin data were then summarised in the form
of polychoric and asymptotic covariance matrices which were generated using
PRELIS (Joreskog & Sorbom,
1988). Genetic models were then fitted to these matrices with the
structural equation modelling package Mx
(Neale, 1997), using the
asymptotic weighted least squares method
(Neale & Cardon,
1992).
The full univariate genetic model for a single phenotype includes additive
genetic factors (A), shared environmental factors (C) and
non-shared environmental factors (E). The overall goodness of fit of
a model is given by a chi-squared value, with a smaller value indicating a
better fit. Reduced models where additive genes, shared environment and both
of these factors are dropped (CE, AE, E models) can then be tested
and compared against the fit of the full model by examining the difference in
the 2 goodness-of-fit values.
This method can then be extended to examine to what extent shared genetic and/or environmental influences explain the covariation or correlation between two phenotypes. Bivariate model fitting using a Cholesky decomposition (see Neale & Cardon, 1992) was used to examine the overlap of categorically defined hyper-activity and conduct problems. The full bivariate model (see Fig. 2) includes a common genetic influence and common non-shared environmental influence on both ADHD and CD (shared environment was not included, given the results of the univariate analysis for ADHD; Thapar et al, 2000), and specific genetic, specific shared environmental and specific non-shared environmental factors for conduct problems. Reduced models where the common factors and specific factors were dropped in turn were tested. The model accepted as the most satisfactory explanation of the data was chosen on the basis of the goodness of fit and parsimony (simplicity of the model). In the results section we also present Akaike's Information Criteria (AIC; Neale & Cardon, 1992) for each model, which provides an indication of goodness of fit and parsimony. The model with the lowest AIC value is chosen as the most satisfactory (Neale & Cardon, 1992).
|
Using a liability threshold model to examine the relationship between
ADHD+CD and pure ADHD
Twins were assigned to a broad category if they were either
ADHD+CD or pure ADHD and to a narrow category if
they had been assigned to the ADHD+CD group.
Probandwise concordance rates for the broad and narrow categories were
first calculated. For categorical data, the correlation between twins
(tetrachoric correlation) can be estimated from the twin concordance and
prevalence rates of the disorder assuming an underlying continuously
distributed liability. A two-threshold liability model
(Fig. 1)
(Reich et al, 1979)
was fitted using the FORTRAN program TWIN2. This uses the GEMINI subroutine
(Lalouel, 1983) to minimise a
goodness-of-fit 2. Applying the two-threshold model entails
estimating four correlations (broad probandbroad co-twin, broad
probandnarrow co-twin, narrow probandbroad co-twin and narrow
probandnarrow co-twin). We assume no shared environmental effects, so
that the MZ correlations are double the DZ correlations. First, a general
model was tested in which all four correlations were estimated. A nested
isocorrelational model (Reich et
al, 1979), which tests whether ADHD+CD is a
more extreme genetic variant than pure ADHD but lies on the same
continuum of liability, was then fitted
(Fig. 1). In this model, as the
name implies, the four correlations are constrained to be equal. An
independent model was also applied to test whether pure ADHD and
ADHD+CD are genetically distinct. Here the narrowbroad
and broadnarrow twin correlations are constrained to be zero. The
models were compared using the difference in
2 (see
Reich et al, 1979,
for detailed explanation).
|
RESULTS
Univariate genetic models
Previous analyses suggested no significant gender effects
(Thapar et al, 2000). Given that this study focused on categorical data, opposite-gender DZ twin
pairs were not included.
Table 1 shows the results of
univariate genetic model fitting for ADHD-related behaviours and conduct
problems (for more detailed results for ADHD-related behaviours such as
teacher ratings and continuous data, see
Thapar et al, 2000).
For conduct problems, an AE model where shared environmental effects
are dropped results in a significant deterioration in fit compared with the
full model (2=8.3, d.f.=1). A CE model also provides
a poorer fit (
2=11.65) and a model of no familial transmission
(E) results in a very much worse fit. We thus accept the ACE
model as providing the most satisfactory explanation for conduct problems with
a heritability estimate of 47%, a shared environment component of 36% and the
non-shared environment component estimated as 17%. For ADHD-related behaviours
the most acceptable model is an AE model with a heritability estimate
of 80%.
|
Bivariate genetic model fitting
The results of the bivariate model fitting (see
Fig. 2 for full model) are
shown in Table 2.
|
It can be seen that neither the common genetic (a2) nor the non-shared environmental component (e2) for conduct problems can be dropped without a significant deterioration in fit. However, the specific additive genetic factor (a3) for conduct problems can be removed. Given the results of the univariate model fitting for conduct problems, not surprisingly a reduced model without a shared environment component (c3) for conduct problems results in a deterioration of fit. Similarly, a specific non-shared environment component (e3) for conduct problems is also needed to explain the data. The accepted model on grounds of fit and parsimony (lowest AIC value) is shown in Fig. 3.
|
Examining ADHD+CD using a liability threshold model approach
In Table 3, the probandwise
concordance rates for the broad and narrow categories are presented for MZ and
DZ twins. The results of threshold analysis are shown in
Table 4. For the
isocorrelational model testing whether ADHD and ADHD+CD lie on
the same continuum of liability, a single correlation was estimated and this
resulted in no significant deterioration in fit compared with the general
model where four correlations were estimated (2=2.48, d.f.=3,
P=0.48). However, the independent model, which tests whether the
broad and narrow categories are transmitted independently, that is whether
they are genetically distinct, provided a very poor fit
(
2=229, d.f.=2, P<0.001). On grounds of parsimony
we thus accept the isocorrelational model, where ADHD+CD (the
narrow category) represents a genetically more extreme variant of ADHD, as
providing the most satisfactory explanation of the data.
|
|
DISCUSSION
Conduct problems and ADHD share a common genetic aetiology
We first considered ADHD-related behaviours and conduct problems as two
separate phenotypes and examined the genetic and environmental contribution to
the comorbidity of these two categories. Bivariate genetic analysis showed
that the genetic contribution to conduct problems was entirely explained by
the same genetic factor influencing ADHD-related behaviours. The comorbidity
between the two categories was mostly explained by this common genetic risk
factor although a common non-shared environmental factor also contributed to
the phenotypic overlap. These findings are consistent with family studies
based on clinical diagnoses of ADHD, where ADHD and conduct disorder have been
shown to share a common familial risk (Faraone et al,
1991,
1998). The twin study findings
suggest that this common familial risk is genetic in origin. Our findings are
similar to those of Silberg et al
(1996), who found that a
common genetic influence accounted for the covariation in symptoms of ADHD and
conduct disorder. It is interesting that genetic findings on the comorbidity
of ADHD-related behaviours and conduct problems from these three studies have
been so consistent, despite phenotypic definition having ranged from
questionnaire symptom counts and questionnaire-derived categories to
interview-based clinical diagnosis.
Additional environmental influences on conduct problems
Despite the overlap of ADHD-related behaviours and conduct problems,
inspection of our twin data strongly supported the distinction of these two
categories, in that for both MZ and DZ twins ADHD-related behaviours in one
twin rarely predicted conduct problems in the other, and vice versa. The
bivariate genetic findings more formally support a degree of aetiological
distinction of ADHD-related behaviours and conduct problems in that additional
shared environmental and non-shared environmental factors were found for
conduct problems. A considerable amount of clinical research has focused on
examining the differences between ADHD and conduct disorder. Although there
have been some inconsistencies in findings, most results suggest that ADHD and
conduct disorder differ in terms of outcome
(Taylor et al, 1996)
and in their pattern of correlates, with ADHD being more commonly associated
with neurodevelopmental problems while conduct disorder shows a greater
association with social adversity (Taylor
et al, 1991; Schachar
& Tannock, 1995; Leung
et al, 1996). Our finding of a shared environmental
component for conduct problems is in keeping with clinical and epidemiological
research, which has consistently shown that conduct disorder is strongly
associated with social and family adversity
(Rutter et al,
1998).
Examining the subgroup of those with both ADHD and conduct
problems
The second aim of this study was to examine how ADHD+CD is
genetically related to ADHD-related behaviours. Using a liability threshold
model approach, our results suggest that ADHD+CD is a
quantitative variant of ADHD-related behaviours and represents a category
associated with a higher genetic loading. Twin data have not been used
previously to examine this issue, although there have been a series of family
study-based papers on this topic (Faraone et al,
1991,
1998) and a number of studies
have focused on the clinical severity, correlates and outcome of
ADHD+CD (Jensen et
al, 1997; Kuhne et
al, 1997). Most of these studies have shown that
ADHD+CD is a more severe variant of ADHD (and conduct disorder
alone) in so far as it is associated with more severe symptoms
(Jensen et al, 1997;
Kuhne et al, 1997)
and a worse outcome (Barkley et
al, 1990; Jensen et
al, 1997). Family study findings have suggested that
ADHD+CD represents a more familial subtype
(Faraone et al, 2000)
and our twin findings add a further dimension to this by suggesting that
ADHD+CD is also a more severe variant of ADHD in terms of
genetic loading. One possibility that has to be considered is that our finding
of a higher genetic loading for ADHD+CD is an artefact of higher
ADHD symptom scores in this subgroup. Although we found that ADHD symptom
scores were significantly higher in the ADHD+CD group compared
with the pure ADHD group, further analysing twin concordance
rates for the ADHD+CD group suggested that the genetic findings
did not vary according to symptom severity. Moreover, there is now good
evidence from twin studies that the genetic aetiology of high ADHD symptom
scores is no different from that for scores across the normal range
(Stevenson, 1992;
Levy et al, 1997).
Thus, our results add genetic validational support for the ICD-10
classificatory system whereby ADHD+CD is considered as a category which is
related to ADHD, in that hyperkinetic conduct disorder is classified under
hyperkinetic disorders, but because it appears to be a more severe genetic (as
well as clinical) variant it warrants a separate category.
Limitations
Finally, we have to consider the limitations of this study and how these
might have influenced our findings. The results reported here are entirely
based on categories defined using questionnaire data, which cannot be equated
with clinical diagnoses. Our sample is also population-based, and for these
two reasons caution is required in extrapolating the results to clinical
populations. Nevertheless, it also has to be emphasised that twin studies
based on systematically ascertained population samples are free from the
referral and selection biases of clinically referred twin samples. Given that
even the largest of population-based twin samples will not yield a sufficient
number of twins who meet clinical diagnostic criteria for ADHD and ADHD+CD, at
present we have to resort to this sort of phenotypic approximation. However,
from an aetiological and more specifically a genetic
perspective, this may not be such an important problem, given that for ADHD at
least there is little evidence to suggest genetic discontinuities between
extreme and more broad categories and scores
(Levy et al,
1997).
Clinical Implications and Limitations
CLINICAL IMPLICATIONS
LIMITATIONS
ACKNOWLEDGMENTS
Lydia White, Nicole Perrin Trent, Hilary Hood, Amanda Tew and Justine Porter assisted with establishing the twin register and data collection. Kenny Ross assisted with questionnaire design and data coding. We thank Eric Taylor of the Institute of Psychiatry for his comments on the potential confound of more severe symptoms in the ADHD+CD group.
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Received for publication March 13, 2000. Revision received September 28, 2000. Accepted for publication October 2, 2000.
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