Arch Dis Child 2012;97:260 –265 . do i:10.1136 /ar chd isc hil d-2 011-3 004 82260
Accepted 20 July 2011
Published Online First
7 September 2011
A B S T R A C T
Attention deﬁ cit hyperactivity disorder (ADHD) af fects
around 1–3% of children. There is a high level of
comorbidity with developmental and learning problems
as well as with a variety of psychiatric disorders. ADHD
is highly heritable, although there is no single causal risk
factor and non-inherited factors also contribute to its
aetiology. The genetic and environmental risk factors
that have been implicated appear to be associated with
a range of neurodevelopmental and neuropsychiatric
outcomes, not just ADHD. The evidence to date
suggests that both rare and multiple common genetic
variants likely contribute to ADHD and modif y its
phenotype. ADHD or a similar phenotype also appears
to be more common in extreme low birth weight and
premature children and those exposed to exceptional
early adversity. In this review, the authors consider
recent developments in the understanding of risk factors
that inﬂ uence ADHD.
Hyperkinetic disorder was ﬁ rst described as a
syndrome in 1902 by George Still, a UK paedia-
trician. The disorder is characterised by develop-
mentally inappropriate hyperactivity, inattention
and impulsiveness. These symptoms must be
of early onset, present in more than one setting
and associated with impairment in functioning
(eg, peer relationships, educational achievement).
The current diagnostic terms of hyperkinetic dis-
order, used in the International Classiﬁ cation of
Diseases, 10th revision (ICD-10) and attention
deﬁ cit hyperactivity disorder (A DHD), adopted
by the Diagnostic and statistical manual of mental dis-
orders , fourth edition (DSM-IV) are similar but not
identical (see table 1 for DSM-IV criteria). ICD-10
has more strict criteria, with a threshold number
of symptoms in each of the domains of inatten-
tion, hyperactivity and impulsivity needed for
diagnosis. Prevalence rates overall in the UK vary
from 1.4% for hyperkinetic disorder
1 to 2.23%
for ADHD. Those with intellectual disability (ID)
and boys (3–4:1 male:female ratio) are more com-
Comorbidity is typical. ADHD commonly co-
occurs with speciﬁ c and global developmental and
learning problems that include autistic spectrum
disorders (ASDs), difﬁ culties with speech and lan-
guage, motor co-ordination and reading, as well
as with a range of psychiatric disorders notably
oppositional deﬁ ant disorder, conduct disorder
and tic disorders. Anxiety, depression and more
rarely bipolar affective disorder can also compli-
cate the clinical presentation. Longitudinal stud-
ies show that ADHD symptoms and impairment
often persist into adult life and are associated with
increased risk of antisocial behaviour and sub-
3 poor educational attainment and
workplace performance, unemployment, friend-
ship difﬁ culties and social problems.
CAUSES OF ADHD
ADHD, like other common medical and psychiat-
ric disorders (eg, asthma, schizophrenia), is inﬂ u-
enced by multiple genes, non-inherited factors and
5 There is no single cause of ADHD
and exposure to a risk factor does not necessar-
ily result in disorder. This means that any given
risk factor will only be observed in a proportion of
cases and will also be found in those who are unaf-
fected. Also, risk factors that contribute to the ori-
gins of ADHD might not necessarily be the same
as those that inﬂ uence its course and outcomes.
A further complexity is that genetic factors can
exert indirect risk effects through interplay with
environmental factors. Genes can alter sensitiv-
ity to environmental risks (gene–environment
interaction), for example, environmental toxins or
6 Inherited factors can also
inﬂ uence the probability of exposure to certain
environmental risks (gene–environment correla-
tion; see later). This means that environ mental
and genetic risk effects cannot be considered as
G E N E T I C S
Evidence of an inherited contribution to ADHD
There is robust evidence from a wide range of
study designs of a strong inherited contribu-
tion to ADHD. Family studies have consistently
found higher rates of ADHD (twofold to eightfold
7 in parents and siblings of affected
probands compared with relatives of unaffected
controls. Twin studies have shown that monozy-
gotic twin pairs have much higher concordance
rates for ADHD than dizygotic twin pairs
adoption studies have also found increased rates of
ADHD in the biological parents of ADHD adopt-
ees compared with both the adoptive parents of the
probands and with the parents of controls without
ADHD (eg, Sprich et al
9 ). Mean heritability esti-
mates are around 79%.
10 However, heritability is
not 100%, suggesting non-inherited factors also
ADHD also appears to share an inherited liabil-
ity with other neurodevelopmental and psychiatric
problems, notably ASDs, developmental coordi-
10 reading ability,
and mood problems.
14 These ﬁ ndings suggest the
same inherited and familial risks can result in the
manifestation of different clinical phenotypes.
Searching for ADHD susceptibility genes
The high heritability of ADHD has fuelled efforts
to identify susceptibility genes. As is the case for
1 Department of Psychological
Medicine and Neurology,
Cardiff University School of
Medicine, Cardiff, UK
2 MRC Centre in
Neuropsychiatric Genetics and
Genomics, Cardiff Universit y,
Anita Thapar, Child and
Adolescent Psychiatry Section,
Department of Psychological
Medicine and Neurology,
Cardiff University, School of
Medicine, Heath Park, Cardiff,
CF14 4XN, UK;
t h a p a r @ c f . a c . u k
What causes attention deﬁ cit hyperactivity disorder?
A n i t a T h a p a r , 1,2 M i r i a m C o o p e r , 1, 2 R a c h e l J e f f e r i e s , 1, 2 E v a n g e l i a S t e r g i a k o u l i 1,2
20_archdischild-2011-300482.indd 26020_archdischild-2011-300482.indd 260 2/12/2012 7:28:43 PM2/12/2012 7:28:43 PM
Arch Dis Child 2012;97:260 –265 . do i:10.1136 /ar chd isc hil d-2 011-3 004 82 261
other complex disorders, molecular genetic studies of ADHD
have so far main ly been based on examining common DNA
variation (the common disease–common variant hypoth-
esis). This was originally investigated using candidate gene
approaches, in which assumptions about the pathophysiology
of the disorder are made, and more recently with ‘hypothesis-
free’ genome wide association studies (GWAS), in which the
frequencies of thousands of single nucleotide polymorphisms
(SNPs) across the genome are compared between cases and
15 There is also emerging interest in the contribution
of rare genetic variants to ADHD.
Examining speciﬁ c genes of interest: candidate gene
There is a very large volume of literature on candidate genes
reported to be associated with A DHD, but only a few have con -
sistently withstood replication ( table 2 ) and meta-analyses.
The most robust evidence of association with ADHD has
been shown for a dopamine D4 receptor gene ( DRD4 ) variant.
This receptor binds both dopamine and norepinephrine and
there is a f unctional polymorphism (variable number tandem
repeat—VNTR) in exon III of the gene that has been exten-
sively studied. The seven-repeat allele of this polymorphism
ha s been found to be assoc iated wit h ADH D in dif ferent met a-
18 The latest meta-analysis shows signiﬁ cant asso-
ciation of small effect size,
19 although there is also evidence of
substantial heterogeneity across studies.
Another dopamine receptor gene, DR D5 , has also been con-
sistently implicated. A microsatellite genetic marker located
close (18.5 kb) but out side the gene region has also been found to
be associated with A DHD in several meta-analyses,
again with evidence of moderate heterogeneit y across studies.
The dopamine transporter gene ( DAT1) was originally con-
sidered the most likely ADHD candidate gene because it is
responsible for the reuptake of dopamine in the presynaptic
20 inhibited by stimulants and also because the DAT1
knockout mouse exhibits hyperactivity and deﬁ cits in inhibi-
21 In the most recent meta-analysis,
19 signiﬁ -
cant evidence of association was found with the 480-bp allele
of the most commonly studied polymorphism (a VNTR in
the 3’ untranslated region (UTR) region of the gene) as well as
with other polymorphisms in the same gene. The substantial
heterogeneity reported could be the result of multiple poly-
morphisms in this gene increasing risk to ADHD or gene–en-
vironment interact ion between the 3’ U TR VNT R and prenatal
factors, such as maternal alcohol consumption
22 or maternal
smoking during pregnancy,
23 although these associations have
not been widely replicated.
The gene encoding catechol O methyl transferase ( COMT ),
which catalyses the degradation of dopamine, has also been
studied extensively in A DHD. A functional polymorphism in
the gene, which results in a valine–methionine transition and
affects enzyme activity, has been the focus of many genetic
studies. Neither meta-analysis
19 nor pooled analysis
found any evidence of association with ADHD. There is how-
ever evidence that COMT could have a modifying effect on the
ADHD phenotype rather than increase the risk of the disorder
itself. The COMT val/val genotype (associated with greater
enzyme activity) was found to be associated with antisocial
behaviour in patients with ADHD,
24 then replicated in two
independent populations as well as shown in a pooled analy-
25 The association ﬁ nding has been subsequently replicated
in other studies and the link with antisocial behaviour appears
to be mediated through impaired social understanding.
association is speciﬁ c to antisocial behaviour in ADHD because
it has not been observed with antisocial behaviour alone.
Searching across the genome for common genetic risk
Candidate gene association studies were relatively successful
for ADHD compared with other neuropsychiatric/develop-
mental disorders. However, GWAS ﬁ ndings for ADHD are
still at an early stage, with no common gene variant having
Table 1 DSM-IV criteria for attention deﬁ cit hyperactivit y disorder
Criteria can be met in either or bo th domains: for inatte ntive type, hyperactive -
impulsive type or combined type
Inattention Hyperactivity impulsivity
At least six of the following
At least six of the following symptoms↓
Fails to sustain attention in t asks or
Often ﬁ dgets wi th hands or squir ms in
Often fails to follow throug h on
instructions from others
Difﬁ culty re maining seated when
Often avoids tasks th at require
sustained men tal ef fort
Runs about or clim bs on things
excessively in situat ions when it is
Often easil y distr acted Exhibits a persistent pat tern of motor
activ ity (al ways on the go)
Often loses things that are necessa ry
for tasks or activitie s
Oft en noisy in playing or dif ﬁ cu lty en gag-
ing quie tly in leisure ac tivities
Appears not to listen to what is be ing
said to him/h er
Difﬁ culty waiting in t urns in games or
Fails to p ay attention t o details, or
makes careles s mista kes
Often blur ts out answers before ques-
tions have been co mpleted
Often forgetfu l in daily activi ties Often interrupt s or intrudes on others
Oft en has difﬁ culty or ganising tasks
Often talks excessi vely
Additional criteria requir ed: Onse t before the age of 7 years, f unctional impairment,
impair ment present in more than one set ting
DSM-IV, Diagnostic and statistical manual of menta l disorders, fourth edition
Table 2 Candidate genes associated with ADHD selecting the most
consistently replicated ﬁ ndings
Gene Polymorphism OR PConsistency
DRD4 7-repeat allele of
VNT R in exon III
1.27 <0.00001 Replicated in four
DRD5 148 -b p mic ro sa t-
1.22 0.000095 Replicated in four
DAT1 480-bp VNTR in
1.1 0.002 Replicated in t wo
pooled analys es, did
not replicate in four
SNAP25 T1065G 1.15 0.03 Replicated in two
but not s ame
2.82 <0.01 Replicated in three
Reported OR and p v alue are from Gizer et al meta-analysis 19 apar t from CO MT , for
which OR and p value are take n from L angley et al . 26
ADHD, attention deﬁ cit hyper activity disorder; COMT, catechol -O-methyltrans-
ferase; DAT1, dopamine trans porter gene; DRD4, dopa mine D4 recepto r gene;
DRD5, dopamine D5 recept or gene; SNAP25, synaptosomal-associate d protein of
25 kD; UTR, unt ranslated region; VN TR, variable n umber tandem re peat.
20_archdischild-2011-300482.indd 26120_archdischild-2011-300482.indd 261 2/12/2012 7:28:43 PM2/12/2012 7:28:43 PM
Arch Dis Child 2012;97:260 –265 . do i:10.1136 /ar chd isc hil d-2 011-3 004 82262
yet been identiﬁ ed.
27 The same has been true for autism. The
lack of genome-wide signiﬁ cant results may be because of
the large sample sizes required. Because of the heavy mul-
tiple testing burden and the small effect sizes expected, tens
of thousands of cases and controls are likely to be required,
as has been shown in other complex disorders such as dia-
28 None of the four published GWAS of ADHD has
achieved genome-wide signiﬁ cant results.
32 A meta-analy-
sis of these studies that included 2064 parent–child trios, 896
cases and 2455 controls had a best p value of 1.2×10
−6 and no
SNP reached genome-wide signiﬁ cance (p=5×10
Although these results appear disappointing, it has to
be remembered that ADHD GWAS studies are still in their
infancy. Apart from sample sizes, which are clearly important,
there is the issue of sample heterogeneity, which has also been
highlighted by meta-analyses of candidate gene studies
can make collaboration and replication of signiﬁ cant results
27 Another view is that disorders such as ADHD and
autism may be better explained by the effect of rare genetic
The contribution of rare genetic variants: chromosomal
anomalies, genetic syndromes and copy number variants
A number of different chromosomal anomalies including
abnormalities in the number of chromosomes (notably sex
chromosome aneuploidies) and chromosomal structure as well
as some single gene disorders have been found to be associ-
ated with higher rates of ADHD. Fragile X syndrome, tuber-
ous sclerosis and several microdeletion syndromes including
Smith Magenis and Velocardiofacial (VCFS; 22q11 microdele-
tion) syndromes are associated with ADHD (more commonly
inattentive type). They are also associated with other neurode-
velopmental and psychiatric disorders (eg, ASD, psychosis in
VCFS). However routine screening in those without ID does
not appear to be indicated.
Copy number variants (CNVs) are a type of chromosomal
struct ural variant. These DNA segments va ry in size between
people and can be either duplications, when there is a gain
of DNA, or deletions, when there is a loss of DNA. They are
part of t he normal variation of t he human genome.
(>500 kb), rare (<1% frequency) duplications and deletions
have been implicated in the aetiology of neurodevelopmental
disorders, such as autism,
37 schizophrenia and ID.
that have examined rare CNVs of all sizes in ADHD have
not found an increased rate of deletions or duplications in
40 but have found CNVs to be enriched for neurode-
velopmental genes. In a UK study that focused on large, rare
CNVs in ADHD (410 cases and 1156 controls), there was a
signiﬁ cantly i ncreased rat e i n c ases compared w it h controls.
This rate was especially high in those with ADHD and ID
but was not restricted to this group. Restricting analysis to
those without ID, this study also reported an overlap of CNVs
found i n A DH D w ith both autism and schizophrenia, further
strengthen ing the notion of ADHD being a neurodevelop-
ENVIRONMENTAL RISK FACTORS
Inherited factors are not the only explanation of ADHD.
Although there are a number of environmental risk factors
that are associated with A DHD ( table 3 ), identif ying which of
these are causal is challenging. This is because many observed
associations m ight arise as a result of sy mptoms/disorder i n the
child or the parent (reverse causation eg, peer rejection, fam-
42 low socioeconomic status
43 or head injury),
Table 3 Environmental factors repor ted to be associated with ADHD
Mater nally r elate d prenatal risks Alcoh ol in pregnancy
Smoking in pregnancy
Drug use in pregnancy
Mater nal stress in pregnancy
Mater nal health in pregnanc y (obesit y)
Pregnancy and birth c omplic ations Bl eeding in pregnancy
Prematurity/low birth weight/intrauterine
Low APGAR score
External agents Infections
Expo sure to lead and ot her toxi ns eg, PCB
Nutritiona l factors
ADHD, attention deﬁ cit hyperactivit y disorder; PCB, polychlorinated biphenyl.
Figure 1 Mother’s genes can inﬂ uence ADHD as well as exposure to
c e r t a i n e n v i r o n m e n t a l f a c t o r s .
or from unmeasured confounders that can include inherited
factors (see ﬁ gure 1 ).
45 Interestingly, time trends studies have
shown no increase in the population rate of A DHD over time,
although identiﬁ cation has increased.
46 Cross-national studies
have not yet found consistent evidence of lower ADHD rates in
certain countries. These ﬁ ndings contrast with data on child-
hood behavioural problems for which rates have risen in the
last 50 years
47 and vary geographically. These results sug-
gest that for ADHD there are more likely to be multiple envi-
ronmental risks, each of small effect, with the overall burden
of these risks remaining similar over time and between coun-
tries. Some of these risk effects might be modiﬁ ed by genetic
inﬂ uences (gene–environment interaction). Environmental
risks can also alter gene function through tissue-speciﬁ c epi-
genetic mechanisms. For example, animal studies have dem-
onstrated how adverse early rearing has an impact on stress
responses through such mechanisms and that these biological
changes can be transmitted to subsequent generations.
Maternal smoking, alcohol, drug use and stress/anxiety
Clinical and epidemiological associations show a consis-
tent association (OR=2.39)
49 and dose–response relationship
between prenatal exposure to maternal cigarette smoking
(maternal reports and urinar y cotinine levels) and offspring
ADHD. Although biologically plausible, because smoking
is known to have an effect on physiological processes that
may create risks relevant to the origins of ADHD, it is dif-
ﬁ cult to adequately control for familial and social confounds
20_archdischild-2011-300482.indd 26220_archdischild-2011-300482.indd 262 2/12/2012 7:28:43 PM2/12/2012 7:28:43 PM
Arch Dis Child 2012;97:260 –265 . do i:10.1136 /ar chd isc hil d-2 011-3 004 82 263
in observational designs. Recent studies suggest that the asso-
ciation with A DHD (but not with lower birth weight) may
wholly or substantially represent familial and inherited con-
founds (gene–environment correlation).
Alcohol is a known teratogen and prenatal exposure to
heavy maternal drinking can cause foetal alcohol syndrome,
the behavioural aspects of which include symptoms of inat-
tention and hyperactivity. However, associations between less
extreme alcohol use i n pregnanc y and offspring A DHD/ADH D
symptoms are inconsistent.
53 Findings are also inconsistent
with regard to links with prenatal exposure to illicit drugs.
Maternal stress in pregnancy has also been reported to be
associated with offspring A DHD symptoms, although recent
work suggests that for ADH D (but not antisocial behaviour
or anxiety), this might also reﬂ ect inherited links between
mother and child (gene–environment correlation) rather than
54 In summary, with the exception of the extreme
phenotype of foetal alcohol syndrome, the evidence that
maternally related cigarette and substance use and stress in
pregnancy play a major causal role in ADHD remains equivo-
cal, although many of these factors are clearly detrimental for
other offspring outcomes.
Low birth weight and prematurity
Most studies, including meta-analyses of premature and/
or low birth weight children, ﬁ nd evidence of an association
with ADHD (relative risk of 2.64 for ADHD in premature
55 and ADHD symptoms/attentional problems.
The risk appears to be strongest for extreme prematurity and
very low birth weight in relation to inattention symptoms
and ADHD inattentive subt ype.
58 Some preliminary stud-
ies also suggest the likely importance of intrauterine growth
restriction (small for gestational age).
60 However it is not
known whether low birth weight and/or prematurity and
other associated pre/perinatal risks (see table 3 ) are risk mark-
ers of ADHD or whether they are causal. The ﬁ ndings at least
suggest the need for heightened awareness of possible ADHD
in very premature/low birth weight children.
Toxins and diet
Speciﬁ c environmental exposures that seem to have relevance
to the ADHD phenotype include organic pollutants (eg, pes-
ticides, polychlorinated biphenyl (PCBs)) and lead. These may
damage cognitive and neural systems known to be implicated
Associations between organophosphate pesticide exposure
and ADHD have been investigated cross-sectionally,
prospectively (eg, Eskenazi et al , Marks et al , Rauh et al
using assessments of prenatal and postnatal (childhood) uri-
nary organophosphate metabolites and umbilical cord plasma
levels of pesticides.
PCBs are a large group of toxic manufactured organic com-
pounds that were previously mass produced. Both human
and animal studies have examined the effect of PCB expo-
sure on neurobehavioural outcomes similar to those affected
in ADHD, and these have found evidence of impairments in
working memory, response inhibition and cognitive ﬂ exi-
66 A recent prospective study also found a positive
association between low-level prenatal PCB exposure and
ADHD-type behaviour in middle childhood, with a dose–re-
67 Both human and animal studies of lead
exposure have shown similar impairments in executive func-
tions and attention, with cognitive ﬂ exibility, vigilance and
alertness being most reliably affected.
66 There is also emerging
evidence from several studies that lead could be implicated in
ADHD even at low levels, but causality cannot be assumed
from the evidence to date. Similarly, further work is needed
to draw ﬁ rm conclusions about how important pesticides and
PCBs are as causes of ADHD.
Dietary constituents that have been studied in relation to
ADH D symptom s include sugar, a rtiﬁ cial food colourings, zinc,
iron, magnesium and omega-3 fatty acids. There is no convinc-
ing evidence yet that diet plays a major causal role in A DHD.
However, a separate issue relates to using dietary change to
modify symptoms. Overall, the value of the studies looking
at diet and A DHD are limited by small sized trials, subjective
measures of outcome and varied protocols for intervention, and
on this basis there has been inadequate evidence to suggest
that dietar y manipulation can ameliorate ADHD symptoms
68 However, a recent randomised controlled trial of
a restricted elimination diet based on high or low IgG foods
suggests a beneﬁ cial effect of a restricted elimination diet on
ADHD and oppositional deﬁ ant disorder symptoms.
Adverse social and family environments such as low parental
education, social class, poverty, bullying/peer victimisation,
negative parenting, maltreatment and family discord are asso-
ciated with ADHD. However, the designs used so far have not
been able to show that these are deﬁ nite causes of ADHD. For
example, longitudinal and treatment studies suggest that nega-
70 and peer relationships arise in response to
child ADHD symptoms. This contrasts with ﬁ ndings for child
antisocial behaviour/conduct disorder in which a variety of
designs including treatment trials have consistently found that
adverse social and family environments are causal. However,
psychosocial factors might modify ADHD expression espe-
cially in those who are genetically susceptible, for example
by inﬂ uencing comorbidities such as conduct disorder, depres-
sion symptoms and level of impairment. This needs further
One exception is exposure to extreme early deprivation.
A study of Romanian orphans adopted in the UK found a
deprivation-speciﬁ c inattentive and overactive pattern of
71 It remains to be examined whether a similar pat-
tern of deﬁ cits arises in response to less extreme adversit y.
C O N C L U S I O N
In summary, there is strong evidence of an inherited contri-
bution to ADHD, although non-inherited factors that likely
include environmental risks and chance events (including de
novo genetic changes) are also important. There is no single
cause of ADHD and the risk factors that have been identiﬁ ed
so far appear to be non-speciﬁ c. That is, risks such as chro-
mosomal microdeletions (eg, VCFS), large, rare CNVs, extreme
low birth weight and prematurity appear to affect a range of
different neurodevelopmental and psychiatric phenotypes.
Genetic risks likely also include multiple common gene vari-
ants of small effect size that have yet to be identiﬁ ed, with
the possible exception of a few dopaminergic genes. With the
costs of DNA sequencing dropping, there is likely to be an
increasing focus on identifying rare genetic variants, including
structural variants such as CNVs and other rare mutations
with larger risk effects.
Despite the rapid advances in genetics, there is still a need
for further research into environmental risks. Although many
20_archdischild-2011-300482.indd 26320_archdischild-2011-300482.indd 263 2/12/2012 7:28:43 PM2/12/2012 7:28:43 PM
Arch Dis Child 2012;97:260 –265 . do i:10.1136 /ar chd isc hil d-2 011-3 004 82264
factor s are associat ed with AD HD, differen t designs are n eeded
to test which are causal.
45 T he strongest evidence relates to the
links between ADHD/ADHD-like behaviours and relatively
rare extreme adversities, speciﬁ cally extreme prematurity,
very low birth weight, foetal alcohol syndrome and a pat-
tern of behaviours associated with institut ional deprivation in
the early years. Less is k nown about risk factors that modify
ADHD outcomes. One exception is the association bet ween
COMT and antisocial behaviour in ADHD that is well repli-
cated now and highlights that behavioural problems in those
with A DHD may have different origins to behavioural prob-
lems in general.
Cumulatively, the available evidence goes some way
towards highlighting groups who are at higher risk; speciﬁ -
cally those who have a family history of ADH D and/or neu-
rodevelopmental or learning problems, and those who have
been exposed to the environmental adversities described ear-
lier. However, none of these risks, including the genetic ones,
provide tests or biomarkers of ADHD. It is hoped that, in the
future, improved identiﬁ cation of ADHD risk factors and path-
ways will increase our understanding of the as yet unknown
pathogenesis of ADHD and pave the way for improving diag-
nosis and treatment.
A c k n o w l e d g e m e n t s Ongoing ADHD research supported by the Wellcome Trust.
Competing interests None.
Provenance and peer review Commissioned; externally peer reviewed.
1 . Meltzer H. The mental health of children and adolescents in Great Britain . L o n d o n :
T h e S t a t i o n e r y O f ﬁ c e 2 0 0 0 .
2 . Ford T, G o o d m a n R , M e l t z e r H . T h e B r i t i s h C h i l d a n d A d o l e s c e n t M e n t a l H e a l t h
Survey 1999: the prevalence of DSM- IV disorders. J Am Acad Child Adolesc
Psychiatry 2 0 0 3 ; 42 : 1 2 0 3 – 1 1 .
3 . Barkley RA, F i s c h e r M , S m a l l i s h L , et al. Young ad ult follow -up of hype ractive c hildren:
antisocial activities and drug use. J Child Psychol Psychiatry 2 0 0 4 ; 45 : 1 9 5 – 2 1 1 .
4 . Barkley RA, F i s c h e r M , S m a l l i s h L , et al. Young adult outcome of hy peractive
children: adaptive func tioning in major li fe acti vities. J Am Acad Child A dolesc
Psychiatry 2 0 0 6 ; 45 : 1 9 2 – 2 0 2 .
5 . Thapar A, L a n g l e y K , A s h e r s o n P , et al. G e n e – e n v i r o n m e n t i n t e r p l a y i n a t t e n t i o n -
deﬁ cit hyperactivity disorder and the importance of a developmental perspective.
Br J Psychiatry 2 0 0 7 ; 19 0 : 1 – 3 .
6 . Rutter M, T h a p a r A , P i c k l e s A . G e n e – e n v i r o n m e n t i n t e r a c t i o n s : b i o l o g i c a l l y v a l i d
pathway or artifact? Arch Gen Psychiatry 2 0 0 9 ; 66 : 1 2 8 7 – 9 .
7 . Biederman J. Attention-deﬁ cit/hyperactivity disorder: a selecti ve over view.
Biol Psychiatry 2 0 0 5 ; 57 : 1 2 1 5 – 2 0 .
8 . Thapar A, H o l m e s J , P o u l t o n K , et al. Genetic basis of attent ion deﬁ cit and
hyperactivity. Br J Psychiatry 1 9 9 9 ; 174 : 1 0 5 – 1 1 .
9 . Sprich S, B i e d e r m a n J , C r a w f o r d M H , et al. A doptive and biological families
of children and adolescents with A DHD. J Am Acad Child Adolesc Psychiatry
2 0 0 0 ; 39 : 1 4 3 2 – 7 .
1 0 . Lichtenstein P, C a r l s t r ö m E , R å s t a m M , et al. The genetics of autism spectrum
disorders and related neuropsychiatric disorder s in childhood. Am J Psychiatry
2 0 1 0 ; 167 : 1 3 5 7 – 6 3 .
1 1 . Paloyelis Y, R i j s d i j k F , W o o d A C , et al. The genetic association between
ADHD sy mptoms and reading difﬁ culties: the role of inatten tiveness and IQ.
J Abnorm Child Psychol 2 0 1 0 ; 38 : 1 0 8 3 – 9 5 .
1 2 . Kuntsi J, E l e y T C , T a y l o r A , et al. Co-occurrence of ADHD and low IQ has genetic
origins. Am J Med Genet B Neuropsychiatr Genet 2 0 0 4 ; 124B : 4 1 – 7 .
1 3 . Cole J, B a l l H A , M a r t i n N C , et al. Genetic overlap bet ween measures o f
hyperactivity/inattention and mood in children and adolescents. J Am Acad Child
Adolesc Psychiatry 2 0 0 9 ; 48 : 1 0 9 4 – 1 0 1 .
1 4 . Thapar A, H a r r i n g t o n R , M c G u f ﬁ n P . E x a m i n i n g t h e c o m o r b i d i t y o f A D H D - r e l a t e d
behaviours and conduct problems using a twin study design. Br J Psychiatry
2 0 0 1 ; 179 : 2 2 4 – 9 .
1 5 . Thapar A, S t e r g i a k o u l i E . G e n e t i c i n ﬂ u e n c e s o n t h e d e v e l o p m e n t o f c h i l d h o o d
psychiatric disorders . Psychiatry 2 0 0 8 ; 7 : 2 7 7 – 8 1 .
1 6 . Faraone SV, D o y l e A E , M i c k E , et al. Meta-analysis of the association between
the 7-repeat allele of the dop amine D(4) receptor gene and attention deﬁ cit
hyperactivity disorder. Am J Psychiatry 2 0 0 1 ; 15 8 : 1 0 5 2 – 7 .
1 7 . Faraone SV, P e r l i s R H , D o y l e A E , et al. M o l e c u l a r g e n e t i c s o f a t t e n t i o n - d e ﬁ c i t /
hyperactivity disorder. Biol Psychiatry 2 0 0 5 ; 57 : 1 3 1 3 – 2 3 .
1 8 . Li D, S h a m P C , O w e n M J , et al. Met a-analysis shows signi ﬁ c ant association
between dopamine system genes and attention deﬁ cit hyperactivity disorder
(ADHD). Hum Mol Genet 2 0 0 6 ; 15 : 2 2 7 6 – 8 4 .
1 9 . Gizer IR, Ficks C, Waldman ID. C andida te gene studies of A DHD: a meta-analytic
review. Hum Genet 2 0 0 9 ; 126 : 5 1 – 9 0 .
2 0 . DiMaio S, G r i z e n k o N , J o o b e r R . D o p a m i n e g e n e s a n d a t t e n t i o n - d e ﬁ c i t
hyperactivity disorder: a review. J Psychiatry Neurosci 2 0 0 3 ; 28 : 2 7 – 3 8 .
2 1 . Gainetdinov RR. Dopamine tr anspor ter mutant mice in experimental
n e u r o p h a r m a c o l o g y . N aunyn Schmiedebergs Arch Pharmacol
2 0 0 8 ; 377 : 3 0 1 – 1 3 .
2 2 . Brookes KJ, M i l l J , G u i n d a l i n i C , et al. A common haploty pe of the dopamine
transp orter gene associated with attention-deﬁ cit/ hyperacti vity disorder and
interacting with maternal use o f alcohol during pregnancy. Arch Gen Psychiatry
2 0 0 6 ; 63 : 7 4 – 8 1 .
2 3 . Becker K, E l - F a d d a g h M , S c h m i d t M H , et al. Interaction o f dopamine transporter
genot ype with prenatal smoke exposure on ADHD sy mptoms. J Pedi atr
2 0 0 8 ; 15 2 : 2 6 3 – 9 .
2 4 . Thapar A, L a n g l e y K , F o w l e r T , et al. Catechol O-methy ltransferase gene variant
and bir th weight predict early-onset antisocial behav ior in children with attention-
deﬁ cit/hyperactivity disorder. Arch Gen Psychiatry 2 0 0 5 ; 62 : 1 2 7 5 – 8 .
2 5 . Caspi A, L a n g l e y K , M i l n e B , et al. A replicated molecular genetic basis f or
subty ping antisocial b ehavior in children with attention-deﬁ cit/hyperac tivity
disorder. Arch Gen Psychiatr y 2 0 0 8 ; 65 : 2 0 3 – 1 0 .
2 6 . Langley K, H e r o n J , O ’ D o n o v a n M C , et al. Genotype link with extreme
antisocial behavior: the contribution of cogni tive pathways. Arch Gen Psychiatry
2 0 1 0 ; 67 : 1 3 1 7 – 2 3 .
2 7 . Franke B, Neale BM, Faraone S V. Genome-wide association studies in A DHD.
Hum Genet 2 0 0 9 ; 12 6 : 1 3 – 5 0 .
2 8 . Pe’er I, Y e l e n s k y R , A l t s h u l e r D , et al. Estimation o f the multiple testing
burden f or genomewide association studies of near ly all common variants.
Genet Epidemiol 2 0 0 8 ; 32 : 3 8 1 – 5 .
2 9 . Lasky-Su J, N e a l e B M , F r a n k e B , et al. Genome-wide association sc an of
quantitative trait s for attention deﬁ cit hyperactivity disorder identiﬁ es novel
associations and conﬁ rms candidate gene associa tions. Am J Med Genet B
Neuropsychiatr Genet 2 0 0 8 ; 147B : 1 3 4 5 – 5 4 .
3 0 . Lesch KP, T i m m e s f e l d N , R e n n e r T J , et al. Molecular genetics of adult ADHD:
converging evidence from genome-wide association and ex tended pedigree
linkage studies. J Neural Transm 2 0 0 8 ; 115 : 1 5 7 3 – 8 5 .
3 1 . Mick E, T o d o r o v A , S m a l l e y S , et al. Family-based genome-wide association scan
of attention-deﬁ cit/ hyperacti vity disorder. J Am Acad Child Adolesc Psychiatry
2 0 1 0 ; 49 : 8 9 8 – 9 0 5 . e 3 .
3 2 . Neale BM, L a s k y - S u J , A n n e y R , et al. Genome-wide association scan of
attention deﬁ cit hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet
2 0 0 8 ; 147B : 1 3 3 7 – 4 4 .
3 3 . Neale BM, M e d l a n d S E , R i p k e S , et al. M eta-analysis of genome -wide
association studies of attention-deﬁ cit/hy peractivity disorder. J Am Acad Child
Adolesc Psychiatry 2 0 1 0 ; 49 : 8 8 4 – 9 7 .
3 4 . Bastain TM, L e w c z y k C M , S h a r p W S , et al. Cy togene tic abnormalities in
attention-deﬁ cit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry
2002 ; 41 : 8 0 6 – 1 0 .
3 5 . Stephen E, Kindley A D. Should children w ith ADHD and normal intelligence
be routinely screened for underlying cy togenetic abnormalities? Arch Dis Child
2 0 0 6 ; 91 : 8 6 0 – 1 .
3 6 . Scherer SW, L e e C , B i r n e y E , et al. Challenges and standards in in tegrating
surveys of str uctur al variation. Nat Genet 2 0 0 7 ; 39 : S 7 – 1 5 .
3 7 . Sebat J, L a k s h m i B , M a l h o t r a D , et al. Strong associa tion of de n ovo copy
number mutations with autism. Science 2 0 0 7 ; 316 : 4 4 5 – 9 .
3 8 . Sebat J, L e v y D L , M c C a r t h y S E . R a r e s t r u c t u r a l v a r i a n t s i n s c h i z o p h r e n i a : o n e
disorder, multiple mutations; one mu tation, multiple disorders. Trends G enet
2 0 0 9 ; 25 : 5 2 8 – 3 5 .
3 9 . Elia J, G a i X , X i e H M , et al. Rare structural variants found in attention-deﬁ cit
hyperactivity disorder are preferentiall y associated wit h neurodevelopmental
g e n e s . Mol Psychiatry 2 0 1 0 ; 15 : 6 3 7 – 4 6 .
4 0 . Lesch KP, S e l c h S , R e n n e r T J , et al. Genome-wide copy number var iation
analysis in attention-deﬁ cit/ hyperacti vity disorder: associa tion with neuropeptide
Y gene dos age in an ex tended pedigree. Mol Psychiatry 2 0 1 1 ; 16 : 4 9 1 – 5 0 3 .
4 1 . Williams NM, Z a h a r i e v a I , M a r t i n A , et al. Rare chromosomal deletions and
duplications in attention-deﬁ cit hyperactivity disorder: a genome-wide anal ysis.
Lancet 2 0 1 0 ; 376 : 1 4 0 1 – 8 .
4 2 . Counts CA, N i g g J T , S t a w i c k i J A , et al. Family adversit y in DSM-IV ADHD
combined and inattentive subt ypes and associated disruptive behavior problems.
J Am Acad Child Adolesc Psychiatry 2 0 0 5 ; 44 : 6 9 0 – 8 .
4 3 . Pineda D, A r d i l a A , R o s s e l l i M , et al. P r e v a l e n c e o f a t t e n t i o n - d e ﬁ c i t /
hyper activ ity disorder sy mptoms in 4- to 17-year-old children in the general
popula tion. J Abnorm Child Psychol 1 9 9 9 ; 27 : 4 5 5 – 6 2 .
4 4 . Keenan HT, H a l l G C , M a r s h a l l S W . E a r l y h e a d i n j u r y a n d a t t e n t i o n d e ﬁ c i t
hyperactivity disorder: retrospective cohort s tudy. BMJ 2 0 0 8 ; 337 : a 1 9 8 4 .
20_archdischild-2011-300482.indd 26420_archdischild-2011-300482.indd 264 2/12/2012 7:28:43 PM2/12/2012 7:28:43 PM
Arch Dis Child 2012;97:260 –265 . do i:10.1136 /ar chd isc hil d-2 011-3 004 82 265
45. Academy of Medical Sciences . Identifyi ng the environmental causes of disease:
how should we decide what to believe and when to take action? L o n d o n : A c a d e m y
of Medical Sciences , 2007 .
4 6 . Collishaw S, M a u g h a n B , G o o d m a n R , et al. Time trends in adolescent mental
health. J Child Psychol Psychiatr y 2 0 0 4 ; 45 : 1 3 5 0 – 6 2 .
4 7 . Rutter M, S m i t h D . , e d s . Psychosocial disorders in you ng people: time trends and
their causes . C h i c h e s t e r : J o h n W i l e y & S o n s 1 9 9 5 .
4 8 . Meaney MJ. Epigenetics and the biological deﬁ nition of gene x environment
interactions. Child Dev 2 0 1 0 ; 81 : 4 1 – 7 9 .
4 9 . Langley K, R i c e F , v a n d e n B r e e M B , et al. Maternal smok ing during pregn ancy as
an envir onment al risk factor for attention deﬁ cit hyperactivity disorder behaviour.
A review. Mi nerva Pediatr 2 0 0 5 ; 57 : 3 5 9 – 7 1 .
5 0 . D’Onofrio BM, V a n H u l l e C A , W a l d m a n I D , et al. Smok ing during pregnancy and
offspring externalizing problems: an explor ation of genetic and environment al
confounds. Dev Psychopathol 2 0 0 8 ; 20 : 1 3 9 – 6 4 .
5 1 . Thapar A, R i c e F , H a y D , et al. Pren atal smoking might not cause attention -deﬁ cit/
hyper activity disorder : evidence fro m a novel design. Biol Psychiatry 2 0 0 9 ; 66 : 7 2 2 – 7 .
5 2 . Linnet KM, D a l s g a a r d S , O b e l C , et al. Maternal lif esty le factors in pregnancy risk
of attention deﬁ cit hyperactivity disorder and associated behaviors: review of the
current evidence. Am J Psychiatry 2 0 0 3 ; 160 : 1 0 2 8 – 4 0 .
5 3 . Mick E, B i e d e r m a n J , F a r a o n e S V , et al. Case –control study of attention-deﬁ cit
hyperactivity disorder and m aternal smoking, alcohol use, and dr ug use during
p r e g n a n c y . J Am A cad Child Adolesc Psychiatry 2 0 0 2 ; 41 : 378 – 85 .
5 4 . Rice F, H a r o l d G T , B o i v i n J , et al. The links between prenatal st ress and o ffspring
development and psychop athology: disentangling environmental and inherited
inﬂ uences. Psychol Med 2 0 1 0 ; 40 : 3 3 5 – 4 5 .
5 5 . Bhutta AT, C l e v e s M A , C a s e y P H , et al. Cognitive and behav ioral outcomes
of school-aged children who were born preterm: a meta-anal ysis. JAMA
2002 ; 288 : 7 2 8 – 3 7 .
5 6 . Aarnoudse-Moens CS, W e i s g l a s - K u p e r u s N , v a n G o u d o e v e r J B , et al. M e t a -
analysis of neurobehavioral outcomes in very preterm and/or ver y low birth
weight children. Pediatrics 2 0 0 9 ; 124 : 7 1 7 – 2 8 .
5 7 . Hack M, Y o u n g s t r o m E A , C a r t a r L , et al. Behavioral outcomes and evidence of
psychopathology among very low birth weight in fants at age 20 years. Pediatrics
2 0 0 4 ; 114 : 9 3 2 – 4 0 .
5 8 . Johnson S, H o l l i s C , K o c h h a r P, et al. Psychiatric disorders in extremely preterm
children: longitudinal ﬁ nding at age 11 years in the EPICur e study. J Am Acad Child
Adolesc Psychiatry 2 0 1 0 ; 49 : 4 5 3 – 6 3 . e 1 .
5 9 . Heinonen K, R ä i k k ö n e n K , P e s o n e n A K , et al. B e h a v i o u r a l s y m p t o m s o f
attention deﬁ cit/hyperactivity disorder in preterm and term children born
small and appropriate for gestational age: a longitudinal study. BMC Pediatr
2 0 1 0 ; 10 : 9 1 .
6 0 . Lahti J, R ä i k k ö n e n K , K a j a n t i e E , et al. Sm all body size at bir th and behavioural
symptoms of ADH D in children aged ﬁ ve to six years. J Child Psychol Psychiatry
2 0 0 6 ; 47 : 1 1 6 7 – 7 4 .
6 1 . Nigg JT. ADHD, lead exposure and prevention: how much lead or how much
eviden ce is needed? Expert Rev N eurother 2 0 0 8 ; 8 : 5 1 9 – 2 1 .
6 2 . Bouchard MF, B e l l i n g e r D C , W r i g h t R O , et al. A t t e n t i o n - d e ﬁ c i t / h y p e r a c t i v i t y
disorder and urin ary metabolites of organophosphate pesticides.
2 0 1 0 ; 125 : e 1 2 7 0 – 7 .
6 3 . Eskenazi B, M a r k s A R , B r a d m a n A , et al. Or ganophosphate pesticide exposure
and neurodevelopment in young Mexican-Americ an children. Environ Health
Perspect 2 0 0 7 ; 115 : 7 9 2 – 8 .
6 4 . Marks AR, H a r l e y K , B r a d m a n A , et al. Organophosphate pes ticide exposure and
attention in young Mexican-American children: the CHA MACOS study. Environ
Health Perspect 2 0 1 0 ; 118 : 1 7 6 8 – 7 4 .
6 5 . Rauh VA , G a r ﬁ n k e l R , P e r e r a F P , et al. Impact of prenatal chlorpyrifos exposure
on neurodevelopment in the ﬁ rst 3 years o f life among inner- city children.
Pediatrics 2 0 0 6 ; 118 : e 1 8 4 5 – 5 9 .
6 6 . Eubig PA, A g u i a r A , S c h a n t z S L . L e a d a n d P C B s a s r i s k f a c t o r s f o r a t t e n t i o n
deﬁ cit/hyperactivity disorder. Environ Health Perspect 2 0 1 0 ; 118 : 1 6 5 4 – 6 7 .
6 7 . Sagiv SK, T h u r s t o n S W , B e l l i n g e r D C , et al. P r e n a t a l o r g a n o c h l o r i n e e x p o s u r e a n d
behaviors associated with attention deﬁ cit hyperactivity disorder in school-aged
children. Am J Epidemiol 2 0 1 0 ; 171 : 5 9 3 – 6 0 1 .
6 8 . Ballard W, H a l l M N , K a u f m a n n L . C l i n i c a l i n q u i r i e s . D o d i e t a r y i n t e r v e n t i o n s
improve ADHD symptoms in children? J Fam Pract 2 0 1 0 ; 59 : 2 3 4 – 5 .
6 9 . Pelsser LM, F r a n k e n a K , T o o r m a n J , et al. Effects of a restricted elimination diet
on the behaviour o f children with attention-de ﬁ cit hyperactivity disorder (INCA
study): a randomised controlled trial. Lancet 2 0 1 1 ; 377 : 4 9 4 – 5 0 3 .
7 0 . Lifford KJ, H a r o l d G T , T h a p a r A . P a r e n t – c h i l d r e l a t i o n s h i p s a n d A D H D
symptoms: a longi tudinal analysis. J Abnorm Child Psychol 2 0 0 8 ; 36 : 2 8 5 – 9 6 .
7 1 . Kreppner J, K u m s t a R , R u t t e r M , et al. IV. Developmental course of deprivation-
speciﬁ c psychological patterns: early manifes tations, persis tence to age 15, and
clinical features. Monogr Soc Res Child Dev 2 0 1 0 ; 75 : 7 9 – 1 0 1 .
20_archdischild-2011-300482.indd 26520_archdischild-2011-300482.indd 265 2/12/2012 7:28:44 PM2/12/2012 7:28:44 PM