The British Journal of Psychiatry (2007) 190: 1-3. doi: 10.1192/bjp.bp.106.027003
© 2007 The Royal College of Psychiatrists
Gene–environment interplay in attention-deficit hyperactivity disorder and the importance of a developmental perspective
ANITA THAPAR, FRCPsych and
KATE LANGLEY, PhD
Department of Psychological Medicine, Cardiff University, Cardiff
PHILIP ASHERSON, FRCPsych
Social, Genetic and Developmental Psychiatry Centre, Institute of
Psychiatry, London, UK
MICHAEL GILL, MD, MRCPsych
School of Medicine and Health Sciences, Trinity College, Dublin,
Ireland
Correspondence:
Professor Anita Thapar, Child and Adolescent Psychiatry Section, Department of
Psychological Medicine, Cardiff University School of Medicine, Heath Park,
Cardiff CF14 4XN, UK. Email:
thapar{at}cf.ac.uk
Declaration of interest None.
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ABSTRACT
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Attention-deficit hyperactivity disorder (ADHD) varies in its clinical
presentation and course. Susceptibility gene variants for ADHD and associated
antisocial behaviour are being identified with emerging evidence of
gene–environment interaction. Genes and environmental factors that
influence the origins of disorder are not necessarily the same as those that
contribute to its course and outcome.
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INTRODUCTION
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Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental
disorder of childhood onset characterised by severe, developmentally
inappropriate motor hyperactivity, inattention and impulsiveness that results
in impairment (for example, school failure) and must be present in more than
one setting – usually home and school. There is increasing recognition
that ADHD symptoms and clinically defined disorder can persist into adult life
and are associated with later drug and alcohol misuse and social and work
difficulties. In some cases the disorder is associated with antisocial
behaviour and criminality. When ADHD co-exists with antisocial behaviour, both
problems are clinically more severe and persistent, have a worse prognosis and
show stronger association with neurocognitive deficits than when they occur
alone (Thapar et al,
2006). However the mechanisms by which ADHD leads to antisocial
behaviour are not clear-cut. Thus ADHD is not only the most common reason for
follow-up in child and adolescent mental health services, it is also likely to
be seen in adult psychiatry, learning disability, forensic and substance
misuse services.
There is consistent evidence that genetic factors contribute to the
aetiology of ADHD and that susceptibility genes interact with environmental
risk factors in complex ways. The same risk factors that influence the origins
of ADHD may have a role in the developmental course of the disorder, although
it is also possible that a different set of risk and protective factors
influence the course and outcome of ADHD
(Fig. 1). It is crucial that
research studies consider the developmental nature of ADHD and the variation
in phenotypic manifestation over time, notably the association with antisocial
behaviour (Thapar et al,
2006), and take into consideration the role of environmental
factors.
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EVIDENCE THAT GENES CONTRIBUTE TO ADHD AND ITS DEVELOPMENTAL COURSE
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Attention-deficit hyperactivity disorder runs in families, with
first-degree relatives of affected individuals showing higher rates of the
disorder (relative risk 4–5). The familial risk appears to be higher
among relatives of those with both ADHD and conduct disorder. Twin and
adoption studies have provided consistent evidence that genetic factors
contribute to the aetiology of ADHD, with estimates of heritability of
60–91%; (Thapar et al,
2005b). Twin studies also show that genetic factors are
the main contributor to continuity of ADHD symptoms over time and to the link
between ADHD and antisocial behaviour
(Thapar et al, 2006).
Overall, most studies suggest that there are genetic risk factors that
influence both ADHD and its developmental course. However, it appears that
there are additional risk factors (both genetic and environmental) that do not
influence the origins of ADHD but do contribute to its clinical course and
outcome.
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PROGRESS IN IDENTIFYING SUSCEPTIBILITY GENES
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There are a number of susceptibility gene variants for ADHD for which
findings have been independently replicated and pooled or for which
meta-analyses of data have yielded significant evidence of association. So
far, these gene variants have been identified from functional candidate gene
association studies. This type of design has been criticised because candidate
genes are selected on the a priori assumption of involvement in the
disorder, whereas for neuropsychiatric disorders the pathophysiology is
usually unknown. However, for ADHD a reasonable prior hypothesis supporting
monoaminergic system genes existed, and so far this approach has worked
well.
Association between a variant in the dopamine D4 receptor gene (the
7-repeat allele of a 48 base pair repeat sequence) and ADHD has been widely
replicated, with estimated odds ratios of 1.16–1.45 from meta-analysis
and pooled analysis of data (Faraone et
al, 2005). Pooled analysis of data on a variant
(microsatellite cytosine–adenine repeat) in the dopamine receptor DRD5
gene has also yielded significant evidence of association, with an estimated
odds ratio of 1.24 (Lowe et al,
2004). Finally, the most recent pooled analysis found small but
significant association between a dopamine transporter gene variant – a
variable number of tandem repeats (VNTR) 10-repeat allele – and ADHD, in
which the odds ratio was 1.1 (Faraone
et al, 2005). More recently there have been several
reports of association between variants in the SNAP-25 gene and ADHD (pooled
OR=1.19), although the associated variants have differed between studies. This
gene became of interest following reports that a SNAP-25-deficient mouse
mutant shows hyperactivity. Other gene variants have been examined but these
need further study (Thapar et al,
2005b). Thus, replicated genetic findings are emerging,
but it is necessary to know more about how variants result in disorder, at a
biological and phenotypic level.
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DO THE SAME OR DIFFERENT SUSCEPTIBILITY GENES INFLUENCE THE DEVELOPMENTAL COURSE OF ADHD?
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So far few studies have examined this question. One study has shown that
the DRD4 7-repeat risk allele influenced persistence of ADHD over
time (El-Faddagh et al,
2004). There has been interest in investigating what gene variants
influence antisocial behaviour in ADHD, and here there have been several sets
of interesting findings. First, the DRD4 7-repeat allele was found to
be associated with antisocial behaviour in ADHD in a joint analysis of data
from Cardiff, London and Dublin. These findings suggest that this allele might
be important in influencing the course as well as the origins of ADHD. More
recently the Cardiff group found that a functional variant in the gene
encoding the enzyme COMT (previously found to be associated with measures of
prefrontal cognitive functioning) was associated with antisocial behaviour in
ADHD but not with ADHD itself (Thapar
et al, 2005a). Finally, a variant in
MAOA, a gene encoding another enzyme involved in neurotransmitter
breakdown, was found to be associated with antisocial behaviour in ADHD but
not with ADHD itself (Thapar et
al, 2006).
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GENE–ENVIRONMENT INTERACTION
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Attention-deficit hyperactivity disorder and its subsequent developmental
course are not entirely explained by genes. There are a number of
environmental factors that also appear to be associated with ADHD, two of
which have withstood meta-analysis or pooled analyses: exposure to maternal
smoking in pregnancy (estimated odds ratio 2.39;
Langley et al, 2005)
and low birth weight/prematurity (odds ratio 2.64;
Bhutta et al, 2002).
It is well recognised that not all of those who are exposed to environmental
adversity go on to develop ADHD. Gene–environment interaction
(GxE), whereby genes operate by influencing
sensitivity or response to environmental adversity, is becomingly increasingly
recognised as important. To date there have been few published studies
examining the contribution of GxE to ADHD and its
course. For example, a recent study found that the association between a
DAT1 haplotype (combination of risk alleles) and ADHD was stronger
when the mother had drunk alcohol during pregnancy
(Brookes et al, 2006).
Another group suggested that the DAT1 risk allele previously found to
be associated with ADHD was only associated with hyperactive–impulsive
symptoms in those who had been exposed to maternal smoking during pregnancy
(Kahn et al, 2003). In
a study that focused on childhood-onset conduct disorder symptoms in ADHD,
those who carried the COMT gene risk variant appeared to be more susceptible
to the adverse effects of lower birth weight
(Thapar et al,
2005a). All these findings now require replication but
the evidence so far suggests that some genes may influence the origins and
developmental course of ADHD by affecting individual sensitivity to
environmental adversity.
In conclusion, genetic factors contribute to ADHD and replicated molecular
genetic findings are now emerging. It is, however, important to recognise the
phenotypic complexity of ADHD and acknowledge that it is a developmental
disorder showing continuity and change in clinical presentation over time that
is influenced by prenatal, biological and psychosocial environmental risk
factors (see Fig. 1). Genes
also appear to contribute to ADHD continuity and the development of antisocial
behaviour in this disorder, and some of these genetic factors interact with
environmental risk factors. However, risk factors for ADHD as a clinically
defined disorder are not necessarily the same as those that influence its
developmental course.
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CLINICAL IMPLICATIONS
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Understanding the aetiology and origins of ADHD, as with all psychiatric
disorders, is important for paving the way to developing new and effective
treatments (biological and non-biological) and for providing information and
understanding to families and clinicians that in turn provides a framework for
clinical management. Identifying genetic and environmental risk factors and
examining how they co-act and interact to increase susceptibility to ADHD also
provide a method of unpacking the heterogeneity of a clinically defined
disorder in a meaningful way. This may lead to different ways of
conceptualising the disorder and its diagnostic boundaries, and influence
current methods of diagnostic classification.
In clinical practice some of the key goals are reducing symptoms,
impairment and associated problems – notably antisocial behaviour in
those already affected. Medication improves symptoms, but the long-term
benefits for wider outcomes, including antisocial behaviour, are uncertain.
Thus, additional risk reduction strategies aimed at reducing adverse outcomes
are important (for example, this could involve reducing family conflict in
those at highest genetic risk). Identifying both genetic and environmental
risk factors that contribute to the course of the disorder is an important
area of research activity so that the risk and protective pathways that lead
to adverse outcomes and impairment can be elucidated. These types of research
findings then provide an evidence base to inform the development of effective
risk reduction strategies in the long-term management of ADHD. Intensive
interventions for all children with ADHD is not pragmatic or necessarily
desirable. Thus, identifying genetic and environmental risk factors as well as
clinical characteristics that predict outcome can also be helpful in targeting
resources and more carefully monitoring those who are at greatest risk of
adverse consequences.
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ACKNOWLEDGMENTS
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We acknowledge funding from the Wellcome Trust (A.T., M.G.) and the Medical
Research Council (P.A.). K.L. is supported by a Wellcome Trust Value in People
Award. We thank Professors Mike Owen and Michael O’Donovan for their
contributions.
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Received for publication May 19, 2006.
Revision received May 24, 2006.
Accepted for publication May 25, 2006.
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ABSTRACT
INTRODUCTION
