The genetics of attention deficit/hyperactivity disorder in adults, a review

Article · November 2011with77 Reads
DOI: 10.1038/mp.2011.138 · Source: PubMed
Abstract
The adult form of attention deficit/hyperactivity disorder (aADHD) has a prevalence of up to 5% and is the most severe long-term outcome of this common neurodevelopmental disorder. Family studies in clinical samples suggest an increased familial liability for aADHD compared with childhood ADHD (cADHD), whereas twin studies based on self-rated symptoms in adult population samples show moderate heritability estimates of 30-40%. However, using multiple sources of information, the heritability of clinically diagnosed aADHD and cADHD is very similar. Results of candidate gene as well as genome-wide molecular genetic studies in aADHD samples implicate some of the same genes involved in ADHD in children, although in some cases different alleles and different genes may be responsible for adult versus childhood ADHD. Linkage studies have been successful in identifying loci for aADHD and led to the identification of LPHN3 and CDH13 as novel genes associated with ADHD across the lifespan. In addition, studies of rare genetic variants have identified probable causative mutations for aADHD. Use of endophenotypes based on neuropsychology and neuroimaging, as well as next-generation genome analysis and improved statistical and bioinformatic analysis methods hold the promise of identifying additional genetic variants involved in disease etiology. Large, international collaborations have paved the way for well-powered studies. Progress in identifying aADHD risk genes may provide us with tools for the prediction of disease progression in the clinic and better treatment, and ultimately may help to prevent persistence of ADHD into adulthood.
1 Figures
FEATURE REVIEW
The genetics of attention deficit/hyperactivity disorder in
adults, a review
B Franke
1,2
, SV Faraone
3
, P Asherson
4
, J Buitelaar
5
, CHD Bau
6,7
, JA Ramos-Quiroga
8
, E Mick
9
,
EH Grevet
7
, S Johansson
10,11
, J Haavik
11,12
, K-P Lesch
13,14
, B Cormand
15,16,17
and A Reif
18
,
on behalf of the International Multicentre persistent ADHD CollaboraTion (IMpACT)
1
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands;
2
Department of
Psychiatry, Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen Medical Centre, Nijmegen,
The Netherlands;
3
Departments of Psychiatry and of Neuroscience and Physiology, State University of New York Upstate
Medical University, Syracuse, NY, USA;
4
MRC Social Genetic and Developmental Psychiatry, Institute of Psychiatry, Kings
College London, London, UK;
5
Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behavior,
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands;
6
Department of Genetics, Instituto de Biocie
ˆ
ncias,
Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil;
7
Adult ADHD Outpatient Clinic, Hospital de Clı
´
nicas
de Porto Alegre, Porto Alegre, RS, Brazil;
8
Department of Psychiatry, Hospital Universitari Vall d’Hebron, CIBERSAM,
and Department of Psychiatry and Legal Medicine, Universitat Auto
´
noma de Barcelona, Barcelona, Catalonia, Spain;
9
Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA, USA;
10
Center for Medical
Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway;
11
Department of Biomedicine,
KG Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway;
12
Department of
Psychiatry, Haukeland University Hospital, Bergen, Norway;
13
Laboratory of Translational Neuroscience, ADHD Clinical
Research Network, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg,
Germany;
14
Department of Neuroscience, School of Mental Health and Neuroscience (MHENS), Maastricht University,
Maastricht, The Netherlands;
15
Department of Genetics, Faculty of Biology, University of Barcelona, Catalonia, Spain;
16
Biomedical Network Research Centre on Rare Diseases (CIBERER), Barcelona, Catalonia, Spain;
17
Institut de
Biomedicina de la Universitat de Barcelona (IBUB), Catalonia, Spain and
18
Department of Psychiatry, Psychosomatics
and Psychotherapy, University of Wu
¨
rzburg, Wu
¨
rzburg, Germany
The adult form of attention deficit/hyperactivity disorder (aADHD) has a prevalence of up to 5%
and is the most severe long-term outcome of this common neurodevelopmental disorder.
Family studies in clinical samples suggest an increased familial liability for aADHD compared
with childhood ADHD (cADHD), whereas twin studies based on self-rated symptoms in adult
population samples show moderate heritability estimates of 30–40%. However, using multiple
sources of information, the heritability of clinically diagnosed aADHD and cADHD is very
similar. Results of candidate gene as well as genome-wide molecular genetic studies in aADHD
samples implicate some of the same genes involved in ADHD in children, although in some
cases different alleles and different genes may be responsible for adult versus childhood
ADHD. Linkage studies have been successful in identifying loci for aADHD and led to the
identification of LPHN3 and CDH13 as novel genes associated with ADHD across the lifespan.
In addition, studies of rare genetic variants have identified probable causative mutations for
aADHD. Use of endophenotypes based on neuropsychology and neuroimaging, as well as
next-generation genome analysis and improved statistical and bioinformatic analysis methods
hold the promise of identifying additional genetic variants involved in disease etiology. Large,
international collaborations have paved the way for well-powered studies. Progress in
identifying aADHD risk genes may provide us with tools for the prediction of disease
progression in the clinic and better treatment, and ultimately may help to prevent persistence
of ADHD into adulthood.
Molecular Psychiatry advance online publication, 22 November 2011; doi:10.1038/mp.2011.138
Keywords: persistent ADHD; molecular genetics; heritability; endophenotype; IMpACT
Adult ADHD
Attention-deficit/hyperactivity disorder (ADHD) is a
common, childhood onset, chronic neuropsychiatric
disorder characterized by developmentally inap-
propriate inattentiveness, increased impulsivity and
hyperactivity, impairing multiple areas of life.
1
Received 27 October 2010; revised 30 June 2011; accepted 29 July
2011
Correspondence: Dr B Franke, PhD, Department of Human
Genetics (855), Radboud University Nijmegen Medical Centre,
PO Box 9101, 6500 HB Nijmegen, The Netherlands.
E-mail: b.franke@antrg.umcn.nl
Molecular Psychiatry (2011), 1–28
&
2011 Macmillan Publishers Limited All rights reserved 1359-4184/11
www.nature.com/mp
ADHD has long been considered a disorder of child-
hood that resolves with maturation. Symptoms of
inattention, impulsiveness, restlessness and emo-
tional dysregulation in adults were considered not
to reflect ADHD, but to be unspecific problems
secondary to other disorders. This idea was chal-
lenged when systematic follow-up studies of children
documented the persistence of ADHD into adult-
hood.
2
Longitudinal follow-up studies of ADHD
children, community surveys and epidemiological
studies of population samples estimate the average
prevalence of adult ADHD (aADHD) to be between 2.5
and 4.9%.
3
This shows that aADHD is one of the most
common psychiatric disorders in our society and
clinical settings. The notion that the total number of
people affected by aADHD is even larger than those
suffering from ADHD during childhood and adoles-
cence also shows that the societal consequences of
this chronic debilitating condition may have been
vastly underestimated in the past.
4
Clinical research has shown that the predominant
features of aADHD differ from typical ADHD in
children (cADHD), with less obvious symptoms of
hyperactivity or impulsivity and more inattentive
symptoms; importantly, the frequency of psychiatric
comorbidity is also increased in aADHD.
5
Until
recently, aADHD has been diagnosed according to
clinical descriptions originally developed for chil-
dren. The lack of age-appropriate clinical measures
has hampered progress in this field, including genetic
research. Future versions of the Diagnostic and
Statistical Manual of Mental Disorders
1
may provide
diagnostic measures that are better suited for all
relevant age groups.
Heritability, family studies, suitability for
genetic studies
Family and twin studies of cADHD demonstrate a
high heritability, estimated to be around 70–80%
from twin studies.
6,7
Relatively few studies have
investigated the genetic and environmental contri-
butions to the developmental course and outcomes
in adulthood. Longitudinal twin studies show
that the continuity of symptoms from childhood
through to adolescence is predominantly due to
common genetic influences.
8–10
Although such stable
genetic effects are likely to continue beyond the
adolescent years, there are only a few studies
investigating this.
Genetic research on ADHD started with the finding
that hyperactivity tends to aggregate in families.
11,12
Since then, family studies have shown that ADHD
shows familial clustering both within and across
generations. Increased rates of ADHD among the
parents and siblings of ADHD children have been
observed.
13,14
In addition, strongly increased risks
for ADHD (57%) among the offspring of adults with
ADHD have been reported.
15
Also, compared with
the risk for ADHD among the siblings of children
with ADHD (15%), siblings of adults with ADHD
were found to have a strongly increased ADHD risk
(41%).
16
Furthermore, a prospective 4-year follow-up
study of male children into mid-adolescence found
the prevalence of ADHD to be significantly higher
among the parents and siblings of persistent ADHD
child probands compared with the relatives of ADHD
probands in whom ADHD remitted.
17
Taken together,
these studies suggest that the risk for ADHD may be
greater among the first-degree relatives of probands
with ADHD that persists into adolescence and
adulthood than that among the relatives of probands
with ADHD that remits before adulthood.
17,18
Whether such familial risks reflect genetic or
environmental factors can be clarified using adoption
and twin studies. Adoption studies found that ADHD
is transmitted only to biological relatives, which
strongly implicates genetic factors as the main causal
influences on familial risk for the disorder.
11,12,19–21
These studies showed (for both current and retro-
spective symptoms in adults) that cADHD in child
relatives predicts aADHD (or associated symptoms) in
adult relatives. However, both adoption and family
studies identify discrepancies related to different
sources of ratings, with self-evaluation of ADHD
symptoms by adults providing less evidence of
familial effects than informants or cognitive perfor-
mance data.
19,22,23
Recently, four adult population twin studies using
self-ratings of ADHD symptoms have been completed,
which all found heritabilities that are far lower
than those found in similar studies of parent- or
teacher-rated cADHD: 41% for retrospectively
reported childhood ADHD symptoms in a sample of
345 US veterans aged 41–58 years old,
24
40% for
current inattention problems in a Dutch study of
4245 18–30-year olds,
8
30% for current ADHD
symptoms in a Dutch study of over 12 000 twin pairs
with an average age of 31 years
25
and 35% for current
ADHD in a Swedish sample of more than 15 000 twin
pairs aged 20–46 years (Larsson et al., unpublished
data). The situation is similar in adolescence, as
adolescent twin studies using self-ratings show lower
heritability estimates than studies of parent or teacher
ratings,
26,27
suggesting that self-ratings may be a
poorer measure of the underlying genetic liability to
ADHD than informant reports or clinical interviews.
Although the estimated heritability in self-rated
ADHD symptoms in adult populations is lower than
that derived from parent or teacher ratings of cADHD,
the pattern of findings is identical. Both types of
studies find that there are no gender differences
observed in the estimates of heritability, heritability
estimates are stable across the age-span (for each type
of measurement approach), there are similar estimates
of the genetic correlation (the proportion of shared
genetic effects) of 60–70% between inattention and
hyperactivity-impulsivity, familial effects are all
genetic in origin with no shared environmental
influences, and no threshold effects are found.
This suggests that for both child and adult ADHD
the disorder is best perceived as the impairing
Adult ADHD genetics
B Franke et al
2
Molecular Psychiatry
extreme of a quantitative trait (Larsson et al., un-
published data; ref. 28).
Despite these common features, the relatively low
heritability estimates for ADHD symptoms in adults
derived from population twin studies need some
explanation, because they appear to be at odds with
heritability estimates of ADHD symptoms in children,
as well as the family studies that show a high familial
risk for persistent forms of ADHD.
15,18
Several factors
are likely involved. We have already mentioned the
consistent finding that self-ratings of ADHD symp-
toms give lower estimates of heritability compared
with informant ratings in twin studies. One source of
measurement error (that is, variance of the true
diagnostic status that is not predicted by the measure-
ment instrument) is the reliability of the self-rated
measures of ADHD symptoms. In one of the herit-
ability studies by Boomsma and co-workers,
25
this
was estimated to be around 0.66, which is lower than
the mean heritability of cADHD across extant
studies.
29
Psychometric studies also show that,
although self-ratings may be useful as a screening
tool for aADHD, their correspondence with the full
diagnosis is only modest. For example, Kessler et al.
30
reported that the sensitivity of self-ratings as a
measure of diagnosis was high (98%), whereas the
specificity was not (56%). Similar findings were
reported by Daigre Blanco et al.
31
(87.5% sensitivity
and 68.6% specificity). Related to this source of error
are potential effects of having two raters in twin
studies of self-ratings of ADHD (each twin rates him/
herself), whereas informants usually rate both mem-
bers of a twin pair. Since reliability between two
raters will always be less than an individual’s
reliability with their own ratings, and because a
ceiling on heritability is set by the reliability of
ratings, heritability estimates will always be lower
when two separate raters are involved in evaluating
each twin pair compared with only one. Single raters
may inflate identical twin pair similarities, poten-
tially leading to an overestimation of heritability in
the reported studies on cADHD, whereas the lower
reliability of ratings between two raters may lead to
lower estimates. Evidence for the later conclusion
comes from our recent analysis of same versus
different teacher ratings in a study of 5641 12-year-
old twins, with heritability estimates of 75% for same
teacher and 53% for different teacher ratings of twin
pairs (Merwood and Asherson, unpublished data).
Another relevant difference between child and
adult samples is the expected range of ADHD
symptom scores. It is well known that ADHD
symptoms decline through adolescence into adult-
hood.
32
Thus, it is possible that the restricted range of
ADHD symptoms in adulthood could influence
estimates of heritability. Although some of this
symptom decline is likely due to true remission of
ADHD, some have argued that the diagnostic criteria
for ADHD, which were originally developed for
children, are developmentally insensitive and thus
become less sensitive to ADHD with age (see above
and refs. 4,33). Added to this is the possibility that in
cross-sectional studies of adult population twin
studies (that do not apply clinical criteria for ADHD),
ADHD symptoms may emerge in some individuals
owing to adult-onset conditions, such as anxiety,
depression and drug use. These ‘phenocopies’ would
lead to increased measurement error of the genetic
liability for ADHD and lower estimates of heritability.
Differences in the way that participants are ascer-
tained in different study designs may also impact on
estimates of familial/genetic influences. The family
studies that showed high familial risk for ADHD used
case–control methods to ascertain adult patients who
were self-referred for (severe) ADHD-like problems.
There are notable differences between the clinically
referred and population-based samples. The former
have a more skewed male-to-female ratio, higher rates
of psychiatric comorbidity and lower rates of primar-
ily inattentive ADHD. Moreover, the family and twin
studies used differing assessment methodologies. The
family studies diagnosed subjects with structured
interviews that evaluated childhood onset of impair-
ing symptoms and the presence of impairment in
multiple settings as required by Diagnostic and
Statistical Manual of Mental Disorders, 4th Edition.
In contrast, with the exception of Schultz et al.,
34
the
twin studies used rating scale measures of ADHD
symptoms that do not query for childhood onset and
do not systematically assess impairment in multiple
settings.
Overall, these considerations suggest that the lower
heritability of aADHD compared with cADHD could
be due to increased measurement error in the aADHD
twin studies. Support for this conclusion comes from
a recent Swedish twin study, which found that the
heritability of attention problems in 19–20 year olds
was estimated at 78% when self-rating and parent-
rating data were combined; the heritability for self-
ratings alone was 48% (Larsson et al., unpublished
data). Analogous to this, cluster A personality
disorders show low heritability estimates in analyses
based on limited phenotypic information that become
much higher when adding more information from
interviews.
35
On the other hand, it still remains
feasible that the heritability of aADHD does indeed
decline with increasing age. This might reflect the
importance of developmental processes that are
sensitive to person-specific environmental factors
affecting the longitudinal outcome of ADHD in adults.
Since heritability estimates do not relate directly to
the frequency or effect size of specific genetic risk
factors,
36
it is not yet clear as to what the lower
heritability estimates actually mean for molecular
genetic studies of aADHD. For example, some
disorders with low heritabilities, such as prostate
and breast cancer, have identified genes with moder-
ate to large effects,
37
yet this is not the case for many
highly heritable phenotypes including ADHD.
38
In the
absence of sufficient studies on this issue, it is quite
clear that genetic researchers should preferably use
measures that have been shown in family studies to
Adult ADHD genetics
B Franke et al
3
Molecular Psychiatry
have high rates of familial transmission and in
adoption studies to aggregate in biological, rather
than adoptive relatives. The evidence for strong
familial risks in the relatives of adolescent and adult
ADHD probands suggests that the clinical diagnosis of
aADHD may represent a more familial measure,
although there are no studies to date that directly
address this question. The difference could arise
because the clinical diagnosis takes a developmental
perspective in which the adult phenotype reflects
persistence of the childhood disorder, whereas the
cross-sectional data used in twin studies may include
adult-onset causes of ADHD-like symptoms that
reflect phenocopies involving different etiological
processes.
We conclude that aADHD is influenced by familial
factors that are genetic in origin. The available studies
indicate that self-ratings of Diagnostic and Statistical
Manual of Mental Disorders, 4th Edition-defined
ADHD symptoms may not be the best measure of
the underlying genetic risk for aADHD and that other
factors such as childhood onset, pervasiveness and
impairment should be taken into account.
Molecular genetic studies
Candidate gene association studies in adult ADHD
A search of NCBI’s PubMed database for genetic
association studies revealed 46 publications on
aADHD (published until June 2011). Most of these
studies are based on clinically assessed patients. The
majority of studies examined single (or a few)
polymorphisms in dopaminergic and serotonergic
genes focusing predominantly on the dopamine
transporter (SLC6A3/DAT1) and the dopamine recep-
tor D4 (DRD4), both associated with cADHD in meta-
analysis
39
(Table 1).
40–83
In all, 10 studies looked at the 40-bp variable
number of tandem repeats (VNTR) in the 3
0
-untrans-
lated region (3
0
-UTR) of the SLC6A3/DAT1 gene, or a
haplotype of this and a second 30-bp VNTR in intron
8. Although most studies found no evidence of
association with aADHD,
40,42,43,46,48,49
three stu-
dies
41,44,47
found a consistent association with the
9-repeat allele or the 9-6 haplotype rather than the
10/10 genotype or the 10-6 haplotype associated with
cADHD.
84,85
This association of the 9-6 haplotype and
the 9/9 genotype with aADHD was confirmed by a
meta-analysis of 1440 cases and 1769 controls,
45
which makes it the most robust finding for adult
ADHD, to date. Why the association in adults is
different from the one found in children is not
entirely clear. A number of explanation are possible,
for example, (a) that the 9-repeat allele and the 9-6
haplotype may mark a severe subgroup of ADHD
patients prone to disease persistence, (b) SLC6A3 may
modulate rather than cause ADHD, and (c) that the 9-
repeat allele and 9-6 haplotype only become aberrant
in an adult brain with its lower dopamine levels.
45
For
DRD4, most studies predominantly focused on a
functional tandem repeat polymorphism in exon 3
of DRD4, in which one variant (the 7-repeat allele) is
associated with cADHD.
39
Of six studies from five
independent samples, three were negative,
41,43,49
whereas the three others showed nominal evidence
that the 7-repeat allele increased risk for aADHD.
51–53
A recent study of the long-term outcome of cADHD
suggested that carriers of the 7-repeat allele show a
more persistent outcome of ADHD.
48
While being
reasonably powered, this latter result seems at odds
with an earlier finding showing a normalization of the
cortical thickness in ADHD-relevant brain regions
linked to a better clinical outcome during adolescence
in carriers of the DRD4 7-repeat allele.
86
A large meta-
analysis in 1608 aADHD patient and 2358 control
samples was negative for the 7-repeat allele, although
showing nominal evidence for association of a
haplotype formed by the common 4-repeat allele of
the exon 3 VNTR and the long (L) allele of the 120-bp
insertion/deletion upstream of DRD4.
50
Findings for
DRD4 are the most consistent ones for cADHD,
39
but
more research is clearly needed to understand its role
in aADHD. Among studies on other dopamine
receptor genes (DRD2, DRD3 and DRD5), the findings
for a DRD5 VNTR have been most positive. Although
individually unconvincing, the findings of two of
three studies point in the same direction, indicating
that the same allele associated with cADHD might
also increase risk for aADHD.
43,58
Of the genes
involved in dopamine turnover, COMT and DBH,
the two largest studies (investigating functional
COMT variants) showed association with aADHD.
However, the direction of association in each of the
studies was opposite.
63,69
Among the serotonergic genes, the serotonin trans-
porter gene (SLC6A4/5-HTT/SERT) and its functional
polymorphism, 5-HTTLPR, were studied most of-
ten,
48,56,57,61,64–67,87
with essentially negative or con-
flicting results, even in a large meta-analysis of 1894
patients and 1977 controls.
70
One study used a
tagging approach and investigated a total of 19
serotonergic genes
68
and reported association of
aADHD with single markers or haplotypes in MAOB,
DDC and HTR2A. The latter gene was also found
associated with aADHD in one of two additional
studies, although the polymorphism involved was
different.
49,69
A recent, large study in 1636 patients
and 1923 controls investigated the two TPH genes and
found nominal evidence of association with TPH1,
but not TPH2.
70
Three genes in the noradrenergic system, the
noradrenalin transporter (SLC6A2/NET), ADRA2A
and ADRA2C, have been tested for association with
aADHD. As shown in Table 1, however, there has
been no evidence of association for these genes with
aADHD.
61,62,71,72,88
Two studies have looked at several genes encoding
neurotrophic factors: Ribase
´
s et al.
89
used a full
tagging approach and showed association with
aADHD for CNTFR, but did not replicate earlier
research, suggesting an association with NTF3.
74
There have been five studies of the BDNF functional
Adult ADHD genetics
B Franke et al
4
Molecular Psychiatry
Table 1 Genetic association studies directed at identifying risk factors for adult ADHD or influencing adult ADHD severity
a
(studies in adolescents were not included
in the selection)
Name of gene Gene symbol Polymorphism
investigated
Type of analysis Sample investigated Findings Reference
Dopaminergic genes
Solute carrier family 6
(neurotransmitter transporter,
dopamine), member 3 = dopamine
transporter
SLC6A3/DAT1 40 bp VNTR in
3
0
-UTR
ANOVA,
qualitative and
quantitative FBAT
152 cases; 102 families
(72 overlapping with
case study; 45 triads, 36
pairs, 16 multiple sib
families, 5
multigeneration
families)
No association Muglia et al.
40
Solute carrier family 6
(neurotransmitter transporter,
dopamine), member 3 = dopamine
transporter
SLC6A3/DAT1 40 bp VNTR in
3
0
-UTR
Case–control 122 hyperactive, 67
controls, followed to
adulthood
9/10 genotype more symptoms
(P = 0.01) and more impairment
(work performance (P = 0.02),
grade point average (P = 0.04))
than 10/10 genotype, more
omission errors on a
continuous performance test
Barkley
et al.
41
Solute carrier family 6
(neurotransmitter transporter,
dopamine), member 3 = dopamine
transporter
SLC6A3/DAT1 40 bp VNTR in
3
0
-UTR; 30 bp VNTR
in intron 8
Case–control 122 cases,
174 controls
No association of single
VNTRs or haplotype
Bruggemann
et al.
42
Solute carrier family 6
(neurotransmitter transporter,
dopamine), member 3 = dopamine
transporter
SLC6A3/DAT1 40 bp VNTR in
3
0
-UTR
Case–control 358 cases,
340 controls
No association Johansson
et al.
43
Solute carrier family 6
(neurotransmitter transporter,
dopamine), member 3 = dopamine
transporter
SLC6A3/DAT1 40 bp VNTR in
3
0
-UTR; 30 bp VNTR
in intron 8
Case–control 216 cases,
528 controls
Association of 9-6 haplotype
with ADHD diagnosis
(P = 0.0011)
Franke et al.
44
Solute carrier family 6
(neurotransmitter transporter,
dopamine), member 3 = dopamine
transporter
SLC6A3/DAT1 40 bp VNTR in
3
0
-UTR; 30 bp VNTR
in intron 8
Case–control/
meta-analysis
1440 cases,
1769 controls
Association of 9-6 haplotype
with ADHD diagnosis
(P = 0.03), association of 9/9
genotype with ADHD diagnosis
(P = 0.03)
Franke et al.
45
Solute carrier family 6
(neurotransmitter transporter,
dopamine), member 3 = dopamine
transporter
SLC6A3/DAT1 40 bp VNTR in
3
0
-UTR
Case–control 102 cases,
479 controls
No association da Silva
et al.
46
Solute carrier family 6
(neurotransmitter transporter,
dopamine), member 3 = dopamine
transporter
SLC6A3/DAT1 40 bp VNTR in
3
0
-UTR
Case–control 53 cases,
38 controls
Association of 9-repeat (9R)
allele carriership with ADHD
diagnosis (P = 0.004), marginal
association of 9R with working
memory-related brain activity
Brown
et al.
47
Adult ADHD genetics
B Franke et al
5
Molecular Psychiatry
Table 1 Continued
Name of gene Gene symbol Polymorphism
investigated
Type of analysis Sample investigated Findings Reference
Solute carrier family 6
(neurotransmitter transporter,
dopamine), member 3 = dopamine
transporter; dopamine receptor D4
SLC6A3/DAT1,
DRD4
40 bp VNTR in
3
0
-UTR of SLC6A3/
DAT1,48bpVNTRin
exon 3 of DRD4
Cox proportional
hazard models
ADHD cases and
family members
(n = 563)
By 25 years of age, 76% of
subjects with a DRD4 7-repeat
allele were estimated to have
significantly more persistent
ADHD compared with 66% of
subjects without the risk allele.
No effect of DAT1
Biederman
et al.
48
Solute carrier family 6
(neurotransmitter transporter,
dopamine), member 3 = dopamine
transporter; dopamine
b-hydroxylase; dopamine
receptor D4; dopamine
receptor D5
SLC6A3/DAT1,
DBH, DRD4,
DRD5
SLC6A3/DAT1 40 bp
VNTR in 3
0
-UTR; DBH
TaqI SNP in intron 5
(rs2519152); DRD4
48 bp VNTR in exon 3
and 120 bp VNTR in
promoter; DRD5 (CA)
n
repeat 18.5 kb from
the start codon of
gene
Regression
analysis, taking
life events and
personality factors
into account
110 cases No effects of genes on
ADHD severity
Mu
¨
ller et al.
49
Dopamine receptor D4; solute
carrier family 6 (neurotransmitter
transporter, dopamine), member
3 = dopamine transporter
DRD4, SCL6A3/
DAT1
DRD4 48 bp VNTR in
exon 3 and 120 bp
ins/del in promoter;
SLC6A3/DAT1 40 bp
VNTR in 3
0
UTR
and 30 bp VNTR in
intron 8
Case–control/
meta-analysis
1608 cases,
2358 controls
Nominal association (P = 0.02)
of the L-4R haplotype (dup120–
48 bp VNTR) with aADHD,
especially with the combined
clinical subtype. No interaction
with DAT1 haplotype
Sanchez-
Mora et al.
50
Dopamine receptor D4 DRD4 48 bp VNTR in
exon 3
Case–control,
TDT,
combination
66 cases, 66 controls;
44 families (29 triads,
14 pairs); combination
of all cases (n = 110)
Evidence for association in
case–control (P = 0.01) and
combined sample (P = 0.003)
(7R vs non-7R alleles)
Muglia
et al.
51
Dopamine receptor D4 DRD4 48 bp VNTR in
exon 3 and 120 bp
ins/del in promoter
Association/
linkage (PDT)
14 multigeneration
families from genetic
isolate (Colombia),
children and adults
affected
7R allele of 48 bp VNTR
(P = 0.0578), haplotype of 7R-
240 bp allele overtransmitted
(P = 0.0467)
Arcos-Burgos
et al.
52
Dopamine receptor D4 DRD4 48 bp VNTR in
exon 3
Model fitting on
Temperament/
Character
Inventory (TCI)
and DRD4
genotype
171 subjects from 96
families ( = parents of
ADHD sib pairs; 33%
with lifetime ADHD,
15% with current
ADHD)
DRD4 correlates with
ADHD symptoms (r
2
= 0.05), but
not with novelty
seeking (7R vs non-7R
genotypes)
Lynn et al.
53
Dopamine receptor D4 DRD4 48 bp VNTR in
exon 3
Case–control 122 hyperactive, 67
controls, followed to
adulthood
No association Barkley
et al.
41
Adult ADHD genetics
B Franke et al
6
Molecular Psychiatry
Table 1 Continued
Name of gene Gene symbol Polymorphism
investigated
Type of analysis Sample investigated Findings Reference
Dopamine receptor D4 DRD4 48 bp VNTR in
exon 3
Case–control 358 cases, 340 controls No association Johansson
et al.
43
Dopamine receptor D3 DRD3 rs6280 (Ser9Gly) TDT 39 families (25 triads,
14 pairs)
No association Muglia
et al.
54
Dopamine receptor D3 DRD3 rs2399504,
rs7611535,
rs1394016, rs6280
(Ser9Gly), rs167770,
rs2134655, rs2087017
Regression
analysis
60 binge eating
disorder cases,
60 obese and
60 non-obese
controls assessed
for adult ADHD
symptoms
Haplotypes containing the
Ser9 allele higher hyperactive/
impulsivity scores compared
with those containing Gly9
for a haplotype window
containing rs1394016 and
Ser9Gly (global P = 0.00038),
as well as that containing
Ser9Gly and rs167770
(global P = 0.00017)
Davis et al.
55
Dopamine receptor D2 DRD2 rs1800497
(TaqIA C > T)
Case–control 85 alcoholics, 32.9%
diagnosed with ADHD
No association Kim et al.
56
Dopamine receptor D2 DRD2 rs1800497
(TaqIA C > T)
ANOVA,
comparison
between patients
with autism (ASD)
and ADHD, with
and without
substance use
disorders
49 ADHD cases,
61 ASD patients
No association Sizoo et al.
57
Dopamine receptor D5 DRD5 (CA)
n
repeat 18.5 kb
from the start codon
of gene
TDT,
case–control
119 families with adult
ADHD probands;
88 cases,
88 controls
Nonsignificant trend for
association between the 148 bp
allele and ADHD (P = 0.055);
excess of non-transmissions
was detected for the 150 bp
(P = 0.023) and 152 bp
(P = 0.028) alleles; quantitative
analyses for 150 bp allele with
lower scores (lowest P = 0.008)
Squassina
et al.
58
Dopamine receptor D5 DRD5 (CA)
n
repeat 18.5 kb
from the start codon
of gene
Case–control 358 cases,
340 controls
Nominally significant
association with adult ADHD
(P = 0.04), trend toward
increased risk for 148 bp allele;
strongest association with
combined and inattentive
subtypes (P = 0.02; OR = 1.27)
Johansson
et al.
43
Adult ADHD genetics
B Franke et al
7
Molecular Psychiatry
Table 1 Continued
Name of gene Gene symbol Polymorphism
investigated
Type of analysis Sample investigated Findings Reference
Dopamine b-hydroxylase DBH TaqI SNP in intron
5 (rs2519152)
TDT, case–control 97 triads; 112 cases,
matched controls
Borderline significance in
case–control comparison
(P = 0.057), risk allele under-
represented in cases
Inkster
et al.
59
Dopamine b-hydroxylase DBH TaqI SNP in intron
5 (rs2519152)
Case–control 122 hyperactive
children, 67 controls,
followed to adulthood
Adult A2 allele homozygotes
take more risk in Card
playing task (P = 0.021)
Barkley
et al.
41
Dopamine b-hydroxylase DBH rs1611115
(1021C > T)
Case–control,
regression
analysis
Four independent
samples: healthy
volunteers (n = 387),
patients with affective
disorders (n = 182),
adult (ADHD cases
(n = 407), patients
with personality
disorders (n = 637)
No association with ADHD (or
other psychiatric diagnoses);
association with neuroticism in
ADHD, and conscientiousness
in combined analysis of
ADHD þ personality disorder
samples
Hess et al.
60
Catechol O-methyl transferase COMT rs4680 (Val158Met) Regression
analysis
203 healthy subjects
assessed with ASRS
for adult ADHD
symptoms
Association of Val with
inattention (P = 0.008),
hyperactivity/impulsivity
(P = 0.039) and total ASRS
scale (P = 0.006), highest
scores Met/Met
Reuter
et al.
69
Catechol O-methyl transferase COMT rs4680 (Val158Met) Case–control 85 alcoholics, 32.9%
diagnosed with ADHD
No association Kim et al.
56
Catechol O-methyl transferase COMT rs4680 (Val158Met) Regression
analysis
110 cases No association Mu
¨
ller
et al.
61
Catechol O-methyl transferase COMT rs4680 (Val158Met),
rs4818
Regression
analysis
184 men referred for
psychiatric
examination, frequency
of adult ADHD unclear
No association with ADHD,
no gene–environment
interaction with psychosocial
adversity in childhood;
nominal association with
ADHD scores of combination
of two haplotypes of SLC6A4
and COMT
Retz et al.
62
Catechol O-methyl transferase COMT rs6269, rs4633,
rs4818, rs4680
(Val158Met)
Regression
analysis
435 cases, 383 controls Trend for association with
hyperactivity/impulsivity
scores for all markers, peaking
at marker rs6269 (P = 0.007);
haplotype analysis showed
association of suggested high
COMT-activity haplotype with
highest hyperactivity/
impulsivity score (P = 0.01)
Halleland
et al.
63
Adult ADHD genetics
B Franke et al
8
Molecular Psychiatry
Table 1 Continued
Name of gene Gene symbol Polymorphism
investigated
Type of analysis Sample investigated Findings Reference
Serotonergic genes
Solute carrier family 6
(neurotransmitter transporter,
dopamine), member 4 = serotonin
transporter
SLC6A4/5-HTT 5-HTTLPR Case–control 30 (of 314) alcoholics
with ADHD þ anti-
social personality
disorder vs alcoholics
without comorbidity vs
matched controls
No association Johann
et al.
64
Solute carrier family 6
(neurotransmitter transporter,
dopamine), member 4 = serotonin
transporter
SLC6A4/5-HTT 5-HTTLPR Case–control 312 cases,
236 controls
No association with ADHD;
nominal association with
higher inattention and novelty-
seeking scores, and a higher
frequency of drug dependence
Grevet
et al.
65
Solute carrier family 6
(neurotransmitter transporter,
dopamine), member 4 = serotonin
transporter
SLC6A4/5-HTT 5-HTTLPR Case–control 85 alcoholics, 32.9%
diagnosed with ADHD
No association Kim et al.
56
Solute carrier family 6
(neurotransmitter transporter,
dopamine), member 4 = serotonin
transporter
SLC6A4/5-HTT 5-HTTLPR Regression
analysis
184 men referred for
psychiatric
examination, frequency
of adult ADHD unclear
L/L genotype associated with
persistent ADHD (P = 0.047);
gene–environment interaction:
carriers of at least one S allele
are more sensitive to childhood
environment adversity than
carriers of L/L (P = 0.025)
Retz et al.
62
Solute carrier family 6
(neurotransmitter transporter,
dopamine), member 4 = serotonin
transporter
SLC6A4/5-HTT 5-HTTLPR;
rs25531 in LPR
Regression
analysis
110 cases Taking into account stressors,
the L allele showed association
with increased ADHD severity,
particularly as regard affective
dysregulations (P = 0.002); in
subjects exposed to early
stressors, the L allele
showed a protective effect
compared with the S allele
(P = 0.003)
Mu
¨
ller
et al.
61
Solute carrier family 6
(neurotransmitter transporter,
dopamine), member 4 = serotonin
transporter
SLC6A4/5-HTT 5-HTTLPR and seven
tag-SNPs in discovery
sample;
5-HTTLPR and one
SNP in meta-analysis
Case–control 448 patients and 580
controls in discovery
sample, 1894 patients
and 1977 controls in
meta-analysis
Association with rs140700
(P = 0.00084, in women) and
S allele of the 5-HTTLPR
(P = 0.06) in discovery; only
S allele associated with adult
ADHD at P = 0.06 in replication.
Potential findings for rare
variants
Landaas
et al.
66
Adult ADHD genetics
B Franke et al
9
Molecular Psychiatry
Table 1 Continued
Name of gene Gene symbol Polymorphism
investigated
Type of analysis Sample investigated Findings Reference
Solute carrier family 6
(neurotransmitter transporter,
dopamine), member 4 = serotonin
transporter
SLC6A4/5-HTT 5-HTTLPR Regression
analysis, gene–
environment
interaction
123 cases with adult
ADHD (and 183
patients suffering from
personality disorders)
No association with adult
ADHD, no G E effects
Jacob et al.
67
Solute carrier family 6
(neurotransmitter transporter,
dopamine), member 4 = serotonin
transporter
SLC6A4/5-HTT 5-HTTLPR Cox proportional
hazard models
ADHD cases and family
members (n = 563)
No effect of 5-HTT Biederman
et al.
48
Solute carrier family 6
(neurotransmitter transporter,
dopamine), member 4 = serotonin
transporter; tryptophan
hydroxylase 2
SLC6A4/5-HTT,
TPH2
5-HTTLPR in
SLC6A4/5-HTT,
rs1843809 in
TPH2
ANOVA,
comparison
between patients
with autism (ASD)
and ADHD, with
and without
substance use
disorders
49 ADHD cases,
61 ASD patients
Carriership of G-allele of TPH2
rs1843809 and of L-allele of the
5-HTTLPR was less frequent in
ADHD compared with ASD
patients (P = 0.041 and 0.04,
respectively)
Sizoo et al.
57
Serotonin receptors 1A, 1B, 1D, 1E,
1F, 2A, 2B, 2C, 3A, 3B, 4, 5A, 6, 7;
solute carrier family 6
(neurotransmitter transporter,
dopamine), member 4 = serotonin
transporter; tryptophan
hydroxylase 1; dopa decarboxylase;
monoamine oxidase A, B
HTR1A, HTR1B,
HTR1D, HTR1E,
HTR1F, HTR2A,
HTR2B, HTR2C,
HTR3A, HTR3B,
HTR4, HTR5A,
HTR6, HTR7,
SLC6A4/5-HTT,
TPH1, DDC,
MAOA, MAOB
132 tag-SNPs Case–control 188 adult cases
( þ 263 children),
400 controls
DDC: associated with adult
(lowest P = 00053, OR 2.17)
and childhood ADHD; MAOB:
associated with adult ADHD
(lowest P = 0.0029, OR 1.9);
HTR2A: association with
combined subtype in adults
(lowest P = 0.0036, OR 1.63)
and children
Ribases
et al.
68
Serotonin receptor 2A HTR2C Cys23Ser Case–control 30 (of 314) alcoholics
with ADHD þ anti-
social personality
disorder vs alcoholics
without comorbidity vs
matched controls
No association Johann
et al.
64
Serotonin receptor 2A HTR2A 102T > C Regression
analysis
203 healthy subjects
assessed with ASRS for
adult ADHD symptoms
Association of C allele with
hyperactivity/impulsivity
(P = 0.020) and total ASRS scale
(P = 0.042), highest scores in
T/T genotype
Reuter
et al.
69
Serotonin receptor 2A HTR2A rs6314 (His452Tyr) Regression
analysis, taking
life events and
personality factors
into account
110 cases No effects of genes on
ADHD severity
Mu
¨
ller et al.
49
Adult ADHD genetics
B Franke et al
10
Molecular Psychiatry
Table 1 Continued
Name of gene Gene symbol Polymorphism
investigated
Type of analysis Sample investigated Findings Reference
Serotonin receptor 1A HTR1A rs6295 Regression
analysis, gene–
environment
interaction
123 cases with adult
ADHD (and 183
patients suffering from
personality disorders)
Decrease the risk of anxious–
fearful cluster C personality
disorders in adult ADHD
(P = 0.016)
Jacob et al.
67
Tryptophan hydroxylase 2 TPH2 rs4570625 Regression
analysis, gene–
environment
interaction
123 cases with adult
ADHD (and 183
patients suffering from
personality disorders)
No association with adult
ADHD, no G E effects
Jacob et al.
67
Tryptophan hydroxylase 2 TPH2 18 SNPs in
discovery sample,
5 SNPs in meta-
analysis
Regression
analysis;
meta-analysis
1636 cases, 1923
controls in meta-
analysis
TPH1: nominal association for
rs17794760; TPH2:no
association
Johansson
et al.
70
Tryptophan hydroxylase 1 TPH1 9 SNPs in discovery
sample, 1 SNP
(rs17794760) in
meta-analysis
Noradrenergic genes
Solute carrier family 6
(neurotransmitter transporter,
dopamine), member
2 = norepinephrine transporter
SLC6A2/NET1 rs998424 (intron 9) ANOVA,
qualitative and
quantitative FBAT
128 triads No association De Luca
et al.
71
Solute carrier family 6
(neurotransmitter transporter,
dopamine), member
2 = norepinephrine transporter
SLC6A2/NET1 rs5569, rs998424,
rs2242447
Regression
analysis
184 men referred for
psychiatric
examination, frequency
of adult ADHD unclear
No association with ADHD, no
gene–environment interaction
with psychosocial adversity in
childhood; nominal association
with ADHD scores of
combination of two haplotypes
of SLC6A4 and COMT
Retz et al.
62
Solute carrier family 6
(neurotransmitter transporter,
dopamine), member
2 = norepinephrine transporter
SLC6A2/NET1 rs998424
(intron 9)
Regression
analysis
110 cases No association Mu
¨
ller
et al.
61
Adrenergic a-2A-receptor ADRA2A rs1800544,
rs1800544, rs553668
Case–control 403 cases,
232 controls
No association de Cerqueira
et al.
72
Adrenergic a-2C-receptor ADRA2C (TG)
n
15 kb upstream
of start codon
TDT 128 triads No association (TG
16
and
TG
17
alleles)
De Luca
et al.
71
Adult ADHD genetics
B Franke et al
11
Molecular Psychiatry
Table 1 Continued
Name of gene Gene symbol Polymorphism
investigated
Type of analysis Sample investigated Findings Reference
Neurotrophic genes
Nerve growth factor; brain-
derived neurotrophic factor;
neurotrophin 3; neurotrophin
4/5; ciliary neurotrophic factor;
neurotrophic tyrosine kinase,
receptor, types 1, 2, 3; nerve growth
factor receptor; ciliary neurotrophic
factor receptor
NGF, BDNF,
NTF3, NTF4/5,
CNTF, NTRK1,
NTRK2, NTRK3,
NGFR, CNTFR
183 tag-SNPs Case–control 216 adults
(330 children),
546 controls
Single-marker and haplotype-
based association of CNTFR
and both adulthood (lowest
P = 0.0077, OR = 1.38) and
childhood ADHD
Ribases
et al.
89
Neurotrophin 3; neurotrophic
tyrosine kinase, receptor, types
2, 3; brain-derived neurotrophic
factor; nerve growth factor receptor
NTF3, NTRK2,
NTRK3, BDNF,
NGFR
NTF3 rs6332 and
rs4930767, NTRK2
rs1212171, NTRK3
rs1017412, BDNF
rs6265 (Val66Met),
p75(NTR) rs2072446
Regression
analysis
143 men referred
for psychiatric
examination, frequency
of adult ADHD unclear
Exonic NTF3 variant (rs6332)
showed nominal trend toward
association with increased
scores of retrospective
childhood analysis Wender–
Utah Rating Scale (WURS-k)
(P = 0.05) and adult ADHD
assessment Wender–Reimherr
interview (P = 0.03)
Conner
et al.
74
Brain-derived neurotrophic factor BDNF rs6265 (Val66Met) Case–control/
meta-analysis,
regression analysis
1445 cases,
2247 controls
No association Sanchez-
Mora et al.
75
Brain-derived neurotrophic factor BDNF rs6265, rs4923463,
rs2049045,
rs7103411
Regression
analysis, taking
life events and
personality factors
into account
110 cases No effects of genes on
ADHD severity
Mu
¨
ller et al.
49
Brain-derived neurotrophic factor;
lin-7 homolog A
BDNF, LIN-7 rs4923463, rs6265
(Val66Met),
rs11030104,
rs2049045 and
rs7103411 in BDNF;
rs10835188 and
rs3763965 in LIN-7
TDT,
case–control
80 trios of adult
ADHD proband and
parents; 121 cases,
121 controls
BDNF Val66Met, BDNF
rs11030104, LIN-7 rs10835188
associated with ADHD in
combined analysis
Lanktree
et al.
76
Others
Protein kinase, cGMP-dependent,
type I
PRKG1 2276C > T TDT 63 informative nuclear
families
No association De Luca
et al.
77
Cholinergic receptor, nicotinic, a7;
protein kinase, cGMP-dependent,
type I; trace amine-associated
receptor 9
CHRNA7,
PRKG1, TAAR9
CHRNA7 D15S1360;
PRKG1 2276C > T;
TAAR9 181A > T
Regression
analysis, taking
life events and
personality factors
into account
110 cases No effects of genes on
ADHD severity
Mu
¨
ller et al.
49
Adult ADHD genetics
B Franke et al
12
Molecular Psychiatry
Table 1 Continued
Name of gene Gene symbol Polymorphism
investigated
Type of analysis Sample investigated Findings Reference
Clock homolog CLOCK rs1801260, 3
0
-UTR Regression
analysis
143 men referred
for psychiatric
examination, frequency
of adult ADHD unclear
Association of genotypes with
at least one T allele with self-
reported and interview ADHD
scores (lowest P = 0.00002)
Kissling
et al.
78
Aldehyde dehydrogenase
2 family (mitochondrial)
ALDH2 SNP, identity
unclear
Case–control 85 alcoholics, 32.9%
diagnosed with ADHD
No association Kim et al.
56
Cannabinoid receptor 1 CNR1 4 tag-SNPs Relevant for
adult ADHD:
case–control
Unselected adolescent
sample and family-
based sample of trios
(ADHD child plus
parents). Trio parents
(with and without
ADHD) used as
additional case–control
sample of adults
(n = 320; 46% affected)
Association with childhood
ADHD, but no association with
adult ADHD
Lu et al.
79
Nitric oxide synthase 1 NOS1 Ex1f VNTR Case–control Personality disorder
cases (n = 403), adult
ADHD (n = 383),
familial ADHD
(n = 151), suicide
attempters (n = 189),
criminal offenders
(n = 182), controls
(n = 1954)
Short variant more frequent in
adult ADHD (P = 0.002), cluster
B personality disorder
(P = 0.01), autoaggressive
(P = 0.02)/heteroaggressive
(P = 0.04) behavior
Reif et al.
80
Latrophilin 3 LPHN3 Different sets,
rs6551665, rs1947274
and rs2345039 were
investigated in the
largest sample
Case–control 2627 (childhood and
adult) ADHD cases and
2531 controls
rs6551665 (P = 0.000346),
rs1947274 (P = 0.000541) and
rs2345039 (P = 0.000897) were
significant after correction for
multiple testing
Arcos-Burgos
et al.
81
Latrophilin 3 LPHN3 44 SNPs tagging
the gene
Case–control 334 cases,
334 controls
rs6858066: P = 0.0019,
OR = 1.82 (1.25-2.70); three-
marker haplotype
(rs1868790/rs6813183/
rs12503398): P = 5.1e-05,
OR = 2.25 (1.52–3.34) for
association with
combined ADHD
Ribases
et al.
82
Adult ADHD genetics
B Franke et al
13
Molecular Psychiatry
Table 1 Continued
Name of gene Gene symbol Polymorphism
investigated
Type of analysis Sample investigated Findings Reference
BAI1-associated protein 2; dapper,
antagonist of b-catenin, homolog 1;
LIM domain only 4; neurogenic
differentiation 6; ATPase, Ca
2 þ
transporting, plasma membrane 3;
inhibitor of DNA binding 2,
dominant negative helix–loop–
helix protein
BAIAP2,
DAPPER1,
LMO4,
NEUROD6,
ATP2B3, ID2
30 tag-SNPs Case–control Exploration sample:
270 adults (317
children), 587 controls;
replication samples:
639 adult ADHD cases,
612 controls and 417
adult ADHD cases, 469
controls
Single- and multiple-marker
analysis showed association of
BAIAP2 with adult ADHD
(P = 0.0026 and 0.0016,
respectively); replication in the
larger one of the two replication
samples (P = 0.0062)
Ribases
et al.
73
Calcium channel, voltage-
dependent, L-type, a 1C subunit;
ankyrin 3, node of Ranvier (ankyrin
G); myosin VB; tetraspanin 8;
zinc-finger protein 804A
CACNA1C,
ANK3, MYO5B,
TSPAN8 and
ZNF804A
ZNF804A rs1344706,
ANK3 rs9804190 and
rs10994336,
CACNA1C rs1006737,
TSPAN8 rs1705236,
MYO5B rs4939921
Regression
analysis
561 ADHD cases,
711 controls
No association Landaas
et al.
83
Contactin-associated
protein-like 2; cadherin 13
CNTNAP2,
CDH13
rs7794745 in
CNTNAP2, rs6565113
in
CDH13
ANOVA,
comparison
between patients
with autism (ASD)
and ADHD, with
and without
substance use
disorders
49 ADHD cases, 61
ASD patients
Carriership of T-allele
of the CNTNAP2 rs7794745
polymorphism more often
present in the ADHD group
compared with the ASD group
(P = 0.025)
Sizoo et al.
57
Abbreviations: ADHD, attention deficit/hyperactivity disorder; aADHD, adult form of ADHD; ANOVA, analysis of variance; ASRS, Adult Self-Report Scale; BDNF, brain-
derived neurotrophic factor; COMT, catechol-O-methyltransferase; CNTFR, ciliary neurotrophic factor receptor; DAT1, dopamine transporter gene; DRD4, dopamine
receptor D4; FBAT, family-based association test; 5-HTTLPR, serotonin transporter; MAOB, monoamine oxidase B; OR, odds ratio; PDT, pedigree disequilibrium test;
SNP, single-nucleotide polymorphism; TDT, transmission disequilibrium test; TPH2, tryptophan hydroxylase 2; VNTR, variable number of tandem repeats; 3
0
-UTR, 3
0
-
untranslated region.
a
Individual studies may appear in the list several times.
Adult ADHD genetics
B Franke et al
14
Molecular Psychiatry
Val66Met polymorphism,
49,74,76,90
including a meta-
analysis of 1445 cases and 2247 controls,
75
that found
no evidence for association.
A number of novel candidate genes have been
associated with aADHD in isolated studies and are in
need of independent replication. Of particular inter-
est may be LPHN3, which was selected for study from
fine mapping of a significant linkage region on
chromosome 4q13.
81
LPHN3 was associated with
ADHD in a large sample of children and adults,
81
and subsequently replicated in an independent
aADHD sample.
82
The function of this gene, which
encodes a G-protein-coupled receptor, is still not well
understood.
91
BAIAP2 was found to be associated
with aADHD in aarej/F10 6tGTj/F10 1 Tf9.dg/F10le.ix6(a)-37 of
phenotypic information for studies on ADHD (but
also on autism spectrum disorder, major depression,
bipolar disorder and schizophrenia, see below)
(http://www.pgc.unc.edu/index.php).
113
Recently, a
meta-analysis of ADHD GWASs in the PGC database
was performed, including 2064 child–parent trios,
896 cases and 2455 controls.
110
This did not yield
genome-wide significant findings, yet, potentially due
to small effect sizes of individual variants, disease
heterogeneity and gene–environment interactions (for
a more extensive review of potential reasons for the
‘missing heritability’, see ref. 114). The absence of
genome-wide significant findings in a meta-analysis
of the current size is not unexpected: a comparison
with data on the other disorders within PGC shows a
strong correlation between minimal P-values and
sample size (Figure 1), suggesting that genome-wide
significant findings can only be expected at sample
sizes of more than 12 000 individuals (cases and
controls combined). These data clearly emphasize the
need for multisite collaborations between researchers
in ADHD genetics.
In such multisite studies of ADHD, one problem is
the potential disease heterogeneity among sites due to
genetic or cultural differences. However, in this
regard it is reassuring that the presentation of ADHD
and its prevalence is similar across different coun-
tries. Meta-analyses and systematic reviews of epide-
miological studies show that there are no differences
in the prevalence of ADHD between European
countries or between Europe and the United
States.
115,116
Similarly, as we reviewed elsewhere,
6,29
the heritability of ADHD does not vary with geo-
graphic location. Although these similarities in
prevalence and heritability between countries do not
assure disease homogeneity, they are consistent with
the idea of substantial homogeneity between coun-
tries. Furthermore, a large body of literature suggests
cross-cultural stability of the ADHD phenotype.
Cross-cultural diagnostic studies find no cross-cultur-
al differences in prevalence or expression, when
methods of diagnosis are systematized across sites.
117
Factor analysis studies have shown that the covaria-
tion of ADHD symptoms is invariant across many
cultures,
118–121
and cross-cultural studies have also
shown considerable stability in the psychiatric and
neuropsychological correlates of ADHD.
117,122–126
In
addition to these findings, which were based on the
binary diagnosis of ADHD, studies that have used
quantitative measures of ADHD show cross-cultural
stability in both clinical comorbidity and develop-
mental trends.
127–130
These findings are so compelling
that a systematic review of ADHD cross-cultural
issues concluded that ‘taken together, these findings
suggest that ADHD is not a cultural construct’.
131
It is
still possible that different sites in a multisite study
identify clinically different types of ADHD due to
differences in ascertainment (for example, from the
population versus clinical samples), exclusion criter-
ia (for example, excluding comorbid disorders) or
methodology (for example, the use of different
structured diagnostic interviews). The best approach
to this problem would be to require sites to use
similar methods of ascertainment and assessment.
As mentioned above, the PGC not only brings
together data sets for disease-specific GWAS meta-
analyses, but also stimulates cross-disorder analyses.
This is inspired by the high degree of overlap that has
been noted in findings from phenotypic dimensional
and molecular genetic studies (for example, refs.
38,132,133); especially, autism and bipolar disorder
have a high degree of comorbidity with ADHD, which
seems to be caused—at least in part—by overlapping
genetic factors.
134–137
Findings from disease-specific
GWAS also show association across diagnoses, like
the findings that the bipolar risk gene diagylglycerol
kinase H (DGKH) is also associated with adult
ADHD,
138
whereas the ADHD risk gene DIRAS family,
GTP-binding RAS-like 2 (DIRAS2), vice versa, is also
associated with bipolar disorder.
139
Such candidate
studies exemplify how common variants might
influence disorders on the dimensional, syndromic
level—for example, emotional dysregulation—while
not being associated with a specific disorder per se.
Although this seems plausible for common genetic
variants, intuitively one would say that rare variants
should be more specific for certain diseases.
However, previous examples from studies of rare
variants in ADHD, namely copy number variants
(CNVs), show an enrichment of CNVs at sites linked
to autism and schizophrenia
140
(IMAGE II Consor-
tium, under review). Classical approaches relying on
Figure 1 Plotted is the sample size (cases þ controls)
analyzed in the first meta-analyses of the Psychiatric
Genome-Wide Association Study (GWAS) Consortium on
schizophrenia, bipolar disorder, major depressive disorder,
autistic spectrum disorders and attention deficit/hyperac-
tivity disorder (ADHD) against the log of the minimal
association P-value observed in the GWAS. The P-value
indicating genome-wide significance of findings is indi-
cated. The data show the strong (r = 0.91) and significant
(P = 0.03) correlation between the two parameters. Drawing
a line through the points suggests that at least 12 000
samples (cases þ controls) will be needed before genome-
wide significant findings for ADHD will be observed.
Adult ADHD genetics
B Franke et al
16
Molecular Psychiatry
traditional nosology fall short to explain such data.
As the edge of dawn of more biologically orientated
diagnostic systems might be near, the large-scale
cross-disorder studies might be one step to elucidate
functional genetic networks underlying psychiatric
dysfunctioning.
Studies on endophenotype and intermediate
phenotypes
Intermediate phenotypes are traits that mediate the
association between clinical phenotypes and
genes.
141,142
Following the recently suggested termi-
nology from Kendler and Neale,
143
endophenotypes
reflect measures of brain function that are genetically
correlated with a clinical disorder or trait (that is, they
share genetic risk factors), whereas the term inter-
mediate phenotype should be reserved for measures
that mediate the association between genes and
clinical phenotypes. To be considered an endophe-
notype, a trait must meet several requirements, which
include heritability, co-segregation with disease in
families, association with disease in the population
and higher trait scores in unaffected siblings of
patients compared with controls, as well as a criterion
relating to the measurement having to be highly
accurate and reliable.
144
The endophenotypes identi-
fied according to these criteria are variables that index
genetic risk for disorders, such as ADHD, and include
mediating pathways (intermediate phenotypes) as
well as pleiotropic phenotypes that reflect multiple
different effects of genes. To identify an intermediate
phenotype among the endophenotypes requires the
additional step of demonstrating mediation between
genes and disorder, which can only be tested once
one or more genetic markers are found that show
association to both the clinical disorder and the
endophenotype.
135,143
An example relevant to the
study of ADHD is the finding that social cognition
mediates the association between the COMT gene and
antisocial behavior in cADHD, whereas measures of
executive function that were also associated with
COMT were found to reflect pleiotropic (multiple
outcomes of genes) rather than mediating effects.
145
Compared with categorical diagnoses such as
ADHD, endophenotypes are assumed to be more
proximal to genes in biological pathways (whether
they represent intermediate or pleiotropic effects) and
to be genetically less complex and giving rise to
greater effect sizes of genetic variants. This makes
endophenotypes better suited for genetic studies than
clinical phenotypes.
36,38
Both endophenotypes and
intermediate phenotypes may be used to map genes
associated with ADHD, but only intermediate pheno-
types can be used to identify the processes that are
involved directly in the etiology of ADHD.
Several neurocognitive traits may serve as candi-
date intermediate phenotypes, because the core
features of ADHD (inattention and hyperactivity) are
conceptually related with cognitive domains such as
executive function, attention, arousal, memory and
intelligence.
146–148
Most research in this area has
focused on children.
149
A meta-analysis of 83 studies
involving executive functions (EFs) in cADHD con-
sistently identified deficits on group measures of
response inhibition, vigilance, working memory and
planning, but noted moderate effect sizes and lack of
universality.
150
Indeed, (c)ADHD shows considerable
heterogeneity with regard to any single cognitive
deficit.
147
For example, nearly 80% of children with
ADHD have a deficit on at least one measure of
executive function, but this can also be said of around
half of control subjects.
151
Temporal processing
(response variability),
152,153
visuospatial and verbal
working memory,
152,154
response inhibition as mea-
sured by the stop-signal reaction time task and
interference control
149,154–158
seem to fulfill the basic
criteria for endophenotypes of ADHD and may
represent mediating processes. Recently, multivariate
analysis of a large cADHD proband, sibling and
control sample identified two main familial cognitive
factors. The larger factor, which reflected 85% of the
familial variance of ADHD, captured all familial
influences on response times and response time
variability, whereas a second smaller factor reflecting
12.5% of the familial effects on ADHD captured
influences on omission errors and commission errors
on a go/no-go task.
159
These findings may be particu-
larly relevant to aADHD because they reflect two
separate developmental processes indexing arousal
and attention processes that are hypothesized to
underlie persistence and remission of ADHD during
the transition into adulthood.
160,161
In aADHD, a range of neurocognitive deficits has
also been reported, including problems in sustained
attention,
162–165
verbal fluency,
166
set shifting,
162,165,166
word reading,
167
color naming,
167
verbal and visual
working memory,
167,168
interference control
165,169
and
response inhibition.
163,166,170–173
A meta-analysis of 33
studies concluded that neurocognitive deficits in
adults with ADHD are found across a range of
domains, in particular involving attention, behavioral
inhibition and working memory, with normal perfor-
mance for simple reaction times.
174
Which of these
measures satisfy the formal criteria for endopheno-
types and intermediate phenotypes of aADHD has yet
to be fully investigated.
Despite these promising findings, few neuropsy-
chological phenotypes have yet been used in mole-
cular genetic studies of ADHD, let alone aADHD.
There is currently no robust evidence for association
between candidate intermediate phenotypes and
ADHD candidate genes.
175
For aADHD, only two
neuropsychological endophenotype studies have
been published. Barkley and co-workers
41
found
association between the 3
0
-UTR VNTR of the
SLC6A3/DAT1 and making more omission errors on
a continuous performance test, and the DBH TaqI A2
allele-homozygous participants took more risks in a
card playing game. The DRD4 exon 3 VNTR did not
have any effects (Table 1). A pilot study in 45 adults
with ADHD compared the performance of carriers and
non-carriers of ADHD risk alleles in DRD4 (exon 3
Adult ADHD genetics
B Franke et al
17
Molecular Psychiatry
VNTR, 120 bp promoter insertion/deletion), SLC6A3/
DAT1 (3
0
-UTR VNTR) and COMT (Val158Met) on a
large battery of neurocognitive tests. The study
showed COMT to be related to differences in IQ and
reaction time, an association of DRD4 with verbal
memory skills, and linked SLC6A3/DAT1 to differ-
ences in inhibition.
176
Two linkage studies reported
suggestive loci for traits derived from several neuro-
psychological tasks.
177,178
With one important prere-
quisite for endophenotypes suitable for use in genetic
studies being measurement errors smaller than
those of the related clinical phenotype, single neuro-
cognitive tests may not be the most suitable targets
for genetic testing, as they can be prone to several
sources of measurement error due to fluctuations in
mental state and motivation, stress, fatigue or time
of the day.
143
A potentially better situation is provi-
ded by the use of aggregated measures across neuro-
psychological tasks in the same way that aggregation
of tests is used to estimate IQ. Studies showing the
general feasibility of such an approach for gene
finding have been performed in children with ADHD
(see above; ref. 159).
Structural and functional neuroimaging measures,
including both magnetic resonance imaging and
cognitive electrophysiology, may be even better suited
as endophenotypes, as they generally show strong
test–retest reliability in adolescents and adults.
179–182
Two recent meta-analyses suggest that genetic effect
sizes at the level of brain activity may be consider-
able.
183,184
There is ample evidence for dysfunction
and subtle structural brain anomalies in ADHD.
Most studies have focused on functional aspects of
dysfunction reporting deficits in the domains of
verbal working memory,
185–188
response inhibi-
tion,
189,190
error monitoring
191–193
as well as reward
processing and delay aversion.
194,195
Again, only a few
studies in aADHD have been published, and there are
almost no findings that can be considered replicated
(see for a review ref. 196). Studies vary largely by
imaging method (functional magnetic resonance
imaging or event-related potentials) and paradigm,
and almost every research group uses slightly differ-
ent versions of a given task. In structural imaging,
brain volumetry studies in aADHD patients reported
reductions of brain volume in the prefrontal cor-
tex
196,197
and anterior cingulate cortex,
198
caudate
nucleus
199,200
and amygdala,
201
as well as a marginal
increase of nucleus accumbens volume.
196
Only some
of these findings have been replicated, to date.
200,202
Interesting recent findings also show structural and
functional brain connectivity to be disturbed in
ADHD.
203,204
Few studies yet have reported effects of ADHD
candidate genes on imaging phenotypes in aADHD.
By means of event-related potentials elicited by a go/
no-go paradigm and subsequent topographical analy-
sis, it was shown that TPH2 risk alleles previously
linked to ADHD
205
were associated with reduced no-
go anteriorization (suggested to reflect prefrontal
brain activity) in aADHD patients as well as healthy
controls.
206
Likewise, the 9-repeat allele of the
SLC6A3/DAT1 3
0
-UTR VNTR (associated with
aADHD
45
) resulted in a reduction of the no-go
anteriorization,
207
whereas homozygosity for the 10-
repeat allele (which is linked to a higher expression of
the transporter in striatum, at least in healthy adults
using SPECT
208,209
) was associated with hypoactiva-
tion in the left dorsal anterior cingulate cortex
compared with 9-repeat allele carriership in aADHD
patients,
210
and a stronger working memory task-
related suppression in left medial prefrontal cortex
was found in 9-repeat allele carriers compared with
10/10 homozygotes.
47
The ADHD risk haplotype of
LPHN3 was found associated with no-go anterioriza-
tion,
211
and was also shown by proton magnetic
resonance spectroscopy to decrease the N-acetylas-
partate to creatine ratio in the left lateral and medial
thalamus and the right striatum, regions altered
volumetrically and/or functionally in ADHD.
81
Also,
the NOS1 exon 1f VNTR showed reduced no-go
anteriorization in the controls of a study of impulse-
disorder patients (including aADHD patients) homo-
zygous for the short allele of the VNTR, the ADHD
risk genotype.
212
More recently, an investigation of
this variant showed both homozygous short allele
aADHD patients and healthy controls to display
higher ventral striatal activity during reward antici-
pation than subjects with the other genotypes.
213
A
study investigating electroencephalogram measures
found an effect of the DRD4 7-repeat allele on the
power in the electroencephalogram beta band.
214
Furthermore, subjects with this allele were found to
have a significantly smaller mean volume in the
superior frontal cortex and cerebellum cortex com-
pared with subjects without this allele.
215
Based on the above, endophenotypes may be very
promising tools for the characterization of biological
pathways from gene to disease on the one hand and
for gene finding in ADHD on the other. However, as
discussed, one should not automatically assume
a simple mediational relationship between an
endophenotype and a clinical phenotype. Reality
may be much more complex. Endophenotypes may
be risk indicators of the occurrence or the severity of
the clinical phenotype, without exerting a causal
influence, genetic influences are expected to be
only partially shared between endophenotype and
clinical phenotype, and even where mediation is
demonstrated, the influences between intermediate
phenotype and clinical phenotype could be bi-
directional.
135,143
This all complicates the use of
endophenotypes in a straightforward way to identify
genes for ADHD. Moreover, as has been shown in
research of autism, similar genetic variants may
influence a very broad range of endophenotypes,
suggesting that the effective distance between varia-
tions in the sequence or structure of the DNA and
resulting brain endophenotypes may be still quite
large.
216
Nonetheless, using endophenotypes con-
tinues to be a powerful way to unravel the genetic
architecture of multifactorial disorders such as
Adult ADHD genetics
B Franke et al
18
Molecular Psychiatry
aADHD, but its effective application may require
moving to more comprehensive approaches that
include the simultaneous modeling of multiple
endophenotypes, innovative statistical methods and
the combination of those with bioinformatics.
217
Assessing endophenotypes in multisite collabora-
tive studies would additionally require prospective
studies using identical measures across sites, or the
definition of derived (aggregate) measures that capture
the underlying trait optimally while reducing task-
specific measurement noise (for example, ref. 159).
New methods for the statistical analysis of genetic
association
Hypothesis-driven candidate gene studies have been
the focus of many research groups, as, with current
sample sizes, they provide superior power. However,
instead of investigating single polymorphisms, entire
genes or even entire functional networks are currently
being investigated. The first examples of these studies
have focused on the association of neurotrophic
factors,
90,74
the serotonergic system
68
and brain later-
ality-related genes
73
with aADHD (see Table 1). Tools
like the KEGG Pathway Database (http://www.geno-
me.jp/kegg/pathway.html), Gene Ontology (http://
www.geneontology.org) or DAVID (http://www.david.
abcc.ncifcrf.gov) are useful for identifying possible
candidate systems and selecting the constituent
genes. This approach may also be applied to the
analysis of data from genome-wide genotyping efforts,
by calculating association scores between the disorder
and functional groups. An example of a statistical
approach for this was recently published for the
analysis of IQ in a sample of children with ADHD,
218
but similar univariate as well as multivariate
approaches have been suggested.
219–222
With the improvement of statistical methods, the
investigation of gene-by-environment (G E) and
gene-by-gene (G G) interactions is becoming more
and more feasible. So far, only very few studies have
addressed this issue in aADHD (Table1 and above), in
largely underpowered studies. In cADHD, more
literature is available, but results for individual genes
are still conflicting.
223–225
Bioinformatic analyses are becoming more and
more important as a tool for the integration of genetic
findings. Such analyses can indicate biological
processes and pathways enriched in the data from
GWASs.
226
In ADHD, a study on copy number
variants (see below) showed enrichment for genes
important for learning, behavior, synaptic transmis-
sion and central nervous system development
227
using bioinformatics. Another recent study integrated
the top-ranked findings of all published GWAS in
ADHD and found a strong enrichment of genes related
to neurite outgrowth.
228
Investigation of rare genetic causes of ADHD and
alternative patterns of genetic transmission
Judging from the high prevalence of ADHD in the
general population and the strong decline of disease
risk from first- to second-degree relatives, a multi-
factorial polygenic inheritance model has been
considered most likely for ADHD.
229,230
With the
involvement of environmental factors, the disorder
seems best described as being of multifactorial origin.
The multifactorial polygenic model has motivated the
search for common DNA variants, as described above,
using candidate gene, genome-wide linkage and
GWAS. However, given the limited success of GWAS
in ADHD, thus far,
110,231
in conjunction with reports
on increased burden of rare copy number variants in,
for example, schizophrenia and autism (for example,
refs. 232,233), ADHD researchers have begun the
search for rare variants that might account for some of
ADHD’s heritability.
From case reports, we have known for a long time
that unique mutations can lead to ADHD. Examples
include a translocation involving the solute carrier
family 9 member 9 gene, SLC9A9,
234
and an inactivat-
ing mutation in TPH2,
235
both found to co-segregate
with ADHD in two different families, but also larger
chromosomal abnormalities.
236–241
In addition, several
syndromes caused by rare genetic mutations (includ-
ing the 22q11 deletion syndrome and Klinefelter
syndrome) are known to show increased incidence
of ADHD(-like phenotypes),
242,243
although adult
forms of ADHD are often not part of the clinical
assessment of these patients.
Most of the earlier studies have not systematically
investigated the entire genome for rare, deleterious
mutations, nor did they indicate whether such
mutations also cause ADHD in adults. A first
systematic analysis of microdeletions and duplica-
tions (CNVs), including adults with ADHD, has
been published recently.
244
This study revealed
de novo as well as inherited CNVs associated with
ADHD. A particularly interesting finding from this
study includes an extended pedigree with multiple
cases of ADHD and obesity, in which a duplication
of the gene encoding neuropeptide Y (NPY) was
observed. From this, in conjunction with a number
of studies systematically investigating CNVs in
data from GWASs of cADHD (published,
227,245,246
or
currently under review), it becomes clear that some
ADHD cases—rather than being caused by multiple
common variants—may be caused by rare genetic
variants with relatively large effect sizes. What
fraction of ADHD cases can be explained by such
oligogenic (or perhaps even monogenic) causes,
however, will have to await studies involving gen-
ome-wide sequencing,
247,248
as microdeletions and
duplications are likely to be not the only type of
genetic variant involved. The study of extended
pedigrees with multiple affected members might
provide a shortcut to finding some of the altered
genes. Intriguingly, a recent publication also suggests
that some associations found in GWAS studies—
seemingly caused by common variants—might actu-
ally be based on synthetic association with rare
variants in partial linkage disequilibrium with the
common variants.
249
Adult ADHD genetics
B Franke et al
19
Molecular Psychiatry
In addition to considering rare versus common
genetic variants, alternative patterns of genetic trans-
mission should be considered. Based on studies of
rare coding variants affecting the function of TPH1,a
strong maternal transmission of the risk allele was
suggested.
250
Parent of origin effects have also been
suggested for common variants in cADHD.
251,252
Similar specific patterns of genetic transmission
could occur for many candidate genes, but the effects
would easily be obscured in case–control studies.
Clinical impact of understanding the genetics of adult
ADHD
Compared with other clinical neurosciences, little
progress has been made in the application of
molecular diagnostics to the common psychiatric
disorders. Notably, genetic tests are now commonly
being used in the diagnosis of early-onset neuro-
degenerative disorders. Although Parkinson’s disease
has traditionally been considered a non-genetic
disease, during the past 15 years many rare Mende-
lian and common low-risk loci for this disease have
been successfully identified. Taken together, these
loci account for about half of the accumulated risk of
developing early-onset Parkinson’s disease and genet-
ic testing of these markers has rapidly become useful
for diagnosis and for defining new therapeutic
strategies.
253
In analogy with such examples, it may
be possible to identify susceptibility genes in sub-
groups of patients with monogenic or oligogenic
forms of aADHD by sequencing and genotyping
pedigrees with a high load of this disorder. Genotyp-
ing of such rare, highly penetrant genetic variants
may have clinical utility where aADHD needs to be
differentiated from progressive neurological condi-
tions or other somatic or psychiatric disorders.
Although our current understanding of the genetic
models of transmission and the variants involved is
still limited, with increasing knowledge of these
variants, and in the hands of experts in psychiatric
genetics, this might become feasible in the future.
However, as the susceptibility genes that have been
robustly identified in GWASs of psychiatric disorders
so far seem to confer vulnerability across a range of
psychiatric phenotypes and the genetic markers have
very low predictive value,
38,133,254,255
it is expected
that such a clinical application of aADHD genetics
will only appear gradually.
Another way of incorporating the results of genetic
research into clinical practice is pharmacogenetics,
the individualization of treatment strategies based on
the association of DNA variants with drug efficacy or
adverse events. Pharmacogenetic testing may be able
to help clinicians in individualizing the treatment
option for any ADHD patient, in terms of efficacy and
tolerability.
256,257
In all, 30% of aADHD patients do
not respond favorably to stimulant treatment (methyl-
phenidate or amphetamines) and 40% exhibit non-
response to atomoxetine. In addition, many patients
present side effects with these drugs, like an increase
in arterial tension or insomnia, that can cause them to
drop out of treatment.
258
However, efforts at under-
standing the putative role of candidate genes in the
response to pharmacotherapy for ADHD have been
inconclusive,
259
a pharmacogenetic GWAS found no
genome-wide significant associations,
260
and—with
the exception of a few studies
261–263
—the pertinent
literature is exclusively focused on pediatric samples
and on a few genes.
Prediction of outcome and prevention of persis-
tence through intervention is a particularly relevant
clinical issue. Knowing that ADHD remits in a
percentage of cases,
2
and that both genetic and
environmental factors are involved in its etiology
provides a basis for hypothesizing that ADHD
persistence into adulthood might be preventable in
some patients by intervention early in childhood.
Indeed, the finding from longitudinal twin studies of
ADHD throughout child and adolescent development
suggest a role for newly developing genetic influences
at different developmental states,
9,264
but further twin
studies are needed that span from adolescence
through into adulthood. The literature on the prog-
nostic value of individual genetic factors is still
contradictory. In this regard, ADHD children carrying
the DRD4 7-repeat allele show normalization of the
cortical thinning in the right parietal cortical region, a
pattern that linked with better clinical outcome.
86
In
contrast, others showed that in ADHD patients
reassessed after 5 years, carriers of the DRD4 7-repeat
allele showed less decline in severity than those
without the risk allele.
265
Other findings indicate that
DRD4 7-repeat allele carriers are more persistently
affected than those not carrying this risk allele,
48
and
no effect of DRD4 was observed in another study.
41
A
meta-analysis of SLC6A3/DAT1 by IMpACT suggests
that a different haplotype from that reported asso-
ciated with cADHD is associated with aADHD,
44,45
see
above. In line with this, carriers of the 9/10 genotype
of the 3
0
-UTR VNTR were earlier shown to have a
worse prognosis than those with the 10/10 geno-
type.
41
Additional genetic analyses in large long-
itudinal studies will be needed to investigate
(patterns of) genetic variants of potential value.
Looking forward
In this paper, we critically reviewed current literature
on the genetics of aADHD, the most severe form of the
disorder. So far, this is still limited, as most work has
been concentrated on the disorder in children.
The extent of heritability of ADHD in adults has not
been firmly established, and stringently characterized
samples should be used to provide more exact
estimates.
Adult ADHD etiology is likely to involve both
common and rare genetic variants. Although the
search for common DNA variants predisposing for
ADHD has not yet successfully achieved the level of
genome-wide significance, recently reported genome-
wide significant effects for other psychiatric disorders
(for example, ref. 266) suggest that similar findings for
Adult ADHD genetics
B Franke et al
20
Molecular Psychiatry
ADHD will be forthcoming. Given that the effects of
common genetic variants are expected to be very
small, their relevance to ADHD cannot be ruled out in
currently available samples. Therefore, more genome-
wide studies of common as well as rare variants are
absolutely necessary. In addition, we should strive for
improvements in the statistical tools used to perform
such studies as well as those enabling integration of
the findings.
Circumventing clinical heterogeneity, endopheno-
types based on neuroimaging and multivariate mea-
sures of neuropsychology can help to identify new
genes for aADHD. In addition, such brain phenotypes
can provide more insight into the mechanisms under-
lying disease etiology by enabling the mapping of
biological pathways from gene to disease.
First indications suggest that the genetic compo-
nent of aADHD is partly different from the one
observed in children, which may leave room for
differentiating persisters from desisters in the future.
Given this prospect, in conjunction with the pro-
spects of using genetics in the clinic to improve
treatment for ADHD in adults, halt the progression of
the disorder and/or improve coping when the dis-
order does persist, large-scale studies of aADHD
(genetics), especially those with longitudinal designs,
seem warranted.
Acknowledgments
The work of KPL and AR was supported by the
Deutsche Forschungsgemeinschaft (KFO 125, SFB
581, SFB TRR 58, GRK 1156, GRK 1253) and the
Bundesministerium fu
¨
r Bildung und Forschung (KPL,
BMBF 01GV0605). BC is supported by the Age
`
ncia de
Gestio
´
d’Ajuts Universitaris i de Recerca-AGAUR
(2009GR00971) and JAR-Q by Health Department
(Government of Catalonia), Alicia Koplowitz Founda-
tion, Fundacio
´
La Marato
´
de TV3 (092330/31) and
Instituto de Salud Carlos III-FIS (PI080519). BF and
JB are supported by the Netherlands Organization
for Scientific Research (NWO, Brain and Cognition
433-09-229 and 433-09-242). CHDB is supported by the
Brazilian funding agencies CNPq, CAPES, PRONEX
and FAPERGS-DECIT-PPSUS. JH and SJ receive support
from the Research Council of Norway, the KG Jebsen
CentreforResearchonNeuropsychiatric Disorders and
the Western Norway Regional Health Authority.
References
1 American Psychiatric Association. Diagnostic and Statistical
Manual of Mental Disorders, 4th edn, revised. American
Psychiatric Press: Washington, DC 2000.
2 Faraone SV, Biederman J, Mick E. The age-dependent decline of
attention deficit hyperactivity disorder: a meta-analysis of follow-
up studies. Psychol Med 2006; 36: 159–165.
3 Simon V, Czobor P, Balint S, Meszaros A, Bitter I. Prevalence and
correlates of adult attention-deficit hyperactivity disorder: meta-
analysis. Br J Psychiatry 2009; 194: 204–211.
4 Barkley RA, Murphy KR, Fischer M. ADHD in Adults: What the
Science Says. Guilford Press: New York, NY, 2008.
5 Haavik J, Halmoy A, Lundervold AJ, Fasmer OB. Clinical
assessment and diagnosis of adults with attention-deficit/hyper-
activity disorder. Expert Rev Neurother 2010; 10: 1569–1580.
6 Faraone SV, Perlis RH, Doyle AE, Smoller JW, Goralnick JJ,
Holmgren MA et al. Molecular genetics of attention-deficit/
hyperactivity disorder. Biol Psychiatry 2005; 57: 1313–1323.
7 Burt SA. Rethinking environmental contributions to child and
adolescent psychopathology: a meta-analysis of shared environ-
mental influences. Psychol Bull 2009; 135: 608–637.
8 van den Berg SM, Willemsen G, de Geus EJ, Boomsma DI. Genetic
etiology of stability of attention problems in young adulthood. Am
J Med Genet B 2006; 141B: 55–60.
9 Larsson JO, Larsson H, Lichtenstein P. Genetic and environmental
contributions to stability and change of ADHD symptoms between
8 and 13 years of age: a longitudinal twin study. J Am Acad Child
Adolesc Psychiatry 2004; 43: 1267–1275.
10 Kuntsi J, Rijsdijk F, Ronald A, Asherson P, Plomin R. Genetic
influences on the stability of attention-deficit/hyperactivity
disorder symptoms from early to middle childhood. Biol
Psychiatry 2005; 57: 647–654.
11 Morrison JR, Stewart MA. A family study of the hyperactive child
syndrome. Biol Psychiatry 1971; 3: 189–195.
12 Cantwell DP. Psychiatric illness in the families of hyperactive
children. Arch Gen Psychiatry 1972; 27: 414–417.
13 Biederman J, Faraone SV, Keenan K, Knee D, Tsuang MT. Family-
genetic and psychosocial risk factors in DSM-III attention deficit
disorder. J Am Acad Child Adolesc Psychiatry 1990; 29: 526–533.
14 Faraone SV, Biederman J, Keenan K, Tsuang MT. Separation of
DSM-III attention deficit disorder and conduct disorder: evidence
from a family-genetic study of American child psychiatric
patients. Psychol Med 1991; 21: 109–121.
15 Biederman J, Faraone SV, Mick E, Spencer T, Wilens T, Kiely K
et al. High risk for attention deficit hyperactivity disorder among
children of parents with childhood onset of the disorder: a pilot
study. Am J Psychiatry 1995; 152: 431–435.
16 Manshadi M, Lippmann S, O’Daniel RG, Blackman A. Alcohol
abuse and attention deficit disorder. J Clin Psychiatry 1983;
44:
379–380.
17 Biederman J, Faraone S, Milberger S, Curtis S, Chen L, Marrs A
et al. Predictors of persistence and remission of ADHD into
adolescence: results from a four-year prospective follow-up
study. J Am Acad Child Adolesc Psychiatry 1996; 35: 343–351.
18 Faraone SV, Biederman J, Monuteaux MC. Toward guidelines for
pedigree selection in genetic studies of attention deficit hyper-
activity disorder. Genet Epidemiol 2000; 18: 1–16.
19 Alberts-Corush J, Firestone P, Goodman JT. Attention and
impulsivity characteristics of the biological and adoptive parents
of hyperactive and normal control children. Am J Orthopsychia-
try 1986; 56: 413–423.
20 Sprich S, Biederman J, Crawford MH, Mundy E, Faraone SV.
Adoptive and biological families of children and adolescents
with ADHD. J Am Acad Child Adolesc Psychiatry 2000; 39:
1432–1437.
21 Epstein JN, Conners CK, Erhardt D, Arnold LE, Hechtman L,
Hinshaw SP et al. Familial aggregation of ADHD characteristics.
J Abnorm Child Psychol 2000; 28: 585–594.
22 Epstein J, Johnson DE, Conners CK (ed). Conners’ Adult ADHD
Diagnostic Interview for DSM-IV (CAADID). Multi-Health Sys-
tems: North Tonawanda, NY, 2001.
23 Curko Kera EA, Marks DJ, Berwid OG, Santra A, Halperin JM.
Self-report and objective measures of ADHD-related behaviors in
parents of preschool children at risk for ADHD. CNS Spectr 2004;
9: 639–647.
24 Schultz MR, Rabi K, Faraone SV, Kremen W, Lyons MJ. Efficacy
of retrospective recall of attention-deficit hyperactivity dis-
order symptoms: a twin study. Twin Res Hum Genet 2006; 9:
220–232.
25 Boomsma DI, Saviouk V, Hottenga JJ, Distel MA, de Moor MH,
Vink JM. et al. Genetic epidemiology of attention deficit
hyperactivity disorder (ADHD index) in adults. PLoS One 2010;
5: e10621.
26 Martin N, Scourfield J, McGuffin P. Observer effects and
heritability of childhood attention-deficit hyperactivity disorder
symptoms. Br J Psychiatry 2002; 180: 260–265.
Adult ADHD genetics
B Franke et al
21
Molecular Psychiatry
27 Ehringer MA, Rhee SH, Young S, Corley R, Hewitt JK. Genetic
and environmental contributions to common psychopathologies
of childhood and adolescence: a study of twins and their siblings.
J Abnorm Child Psychol 2006; 34: 1–17.
28 McLoughlin G, Ronald A, Kuntsi J, Asherson P, Plomin R.
Genetic support for the dual nature of attention deficit hyper-
activity disorder: substantial genetic overlap between the
inattentive and hyperactive-impulsive components. J Abnorm
Child Psychol 2007; 35: 999–1008.
29 Faraone SV, Mick E. Molecular genetics of attention deficit
hyperactivity disorder. Psychiatr Clin N Am 2010; 33: 159–180.
30 Kessler RC, Adler L, Ames M, Demler O, Faraone S, Hiripi E et al.
The World Health Organization Adult ADHD Self-Report Scale
(ASRS): a short screening scale for use in the general population.
Psychol Med 2005; 35: 245–256.
31 Daigre BC, Ramos-Quiroga JA, Valero S, Bosch R, Roncero C,
Gonzalvo B et al. Adult ADHD Self-Report Scale (ASRS-v1.1)
symptom checklist in patients with substance use disorders.
Actas Esp Psiquiatr 2009; 37: 299–305.
32 Biederman J, Mick E, Faraone SV. Age-dependent decline of
symptoms of attention deficit hyperactivity disorder: impact of
remission definition and symptom type. Am J Psychiatry 2000;
157: 816–818.
33 Faraone SV. Attention deficit hyperactivity disorder in adults:
implications for theories of diagnosis. Curr Direct Psychol Sci
2000; 9: 33–36.
34 Schultz MR, Rabi K, Faraone SV, Kremen W, Lyons MJ. Efficacy
of retrospective recall of attention-deficit hyperactivity
disorder symptoms: A twin study. Twin Res Hum Genet 2006;
9: 220–232.
35 Kendler KS, Myers J, Torgersen S, Neale MC, Reichborn-
Kjennerud T. The heritability of cluster A personality disorders
assessed by both p ersonal interview and questionnaire. Psychol
Med 2007; 37: 655–665.
36 Flint J, Munafo MR. The endophenotype concept in psychiatric
genetics. Psychol Med 2007; 37: 163–180.
37 Park JH, Wacholder S, Gail MH, Peters U, Jacobs KB, Chanock SJ
et al. Estimation of effect size distribution from genome-wide
association studies and implications for future discoveries. Nat
Genet 2010; 42: 570–575.
38 Franke B, Neale BM, Faraone SV. Genome-wide association
studies in ADHD. Hum Genet 2009; 126: 13–50.
39 Gizer IR, Ficks C, Waldman ID. Candidate gene studies of ADHD:
a meta-analytic review. Hum Genet 2009; 126: 51–90.
40 Muglia P, Jain U, Inkster B, Kennedy JL. A quantitative trait locus
analysis of the dopamine transporter gene in adults with ADHD.
Neuropsychopharmacology 2002; 27: 655–662.
41 Barkley RA, Smith KM, Fischer M, Navia B. An examination
of the behavioral and neuropsychological correla tes of
three ADHD candidate gene polymorphisms (DRD4 7 þ , DBH
TaqI A2, and DAT1 40 bp VNTR) in hyperactive and normal
children followed to adulthood. Am J Med Genet B 2006;
141:
487–498.
42 Bruggemann D, Sobanski E, Alm B, Schubert T, Schmalzried H,
Philipsen A et al. No association between a common haplotype of
the 6 and 10-repeat alleles in intron 8 and the 3
0
UTR of the DAT1
gene and adult attention deficit hyperactivity disorder. Psychiatr
Genet 2007; 17: 121.
43 Johansson S, Halleland H, Halmoy A, Jacobsen KK, Landaas ET,
Dramsdahl M et al. Genetic analyses of dopamine related genes in
adult ADHD patients suggest an association with th e DRD5-
microsatellite repeat, but not with DRD4 or SLC6A3 VNTRs. Am J
Med Genet B 2008; 147B: 1470–1475.
44 Franke B, Hoogman M, Arias VA, Heister JG, Savelkoul PJ, Naber
M et al. Association of the dopamine transporter (SLC6A3/DAT1)
gene 9-6 haplotype with adult ADHD. Am J Med Genet B 2008;
147B: 1576–1579.
45 Franke B, Vasquez AA, Johansson S, Hoogman M, Romanos J,
Boreatti-Hummer A et al. Multicenter analysis of the SLC6A3/
DAT1 VNTR haplotype in persistent ADHD suggests differential
involvement of the gene in childhood and persistent ADHD.
Neuropsychopharmacology 2010; 35: 656–664.
46 da Silva MA, Cordeiro Q, Louza M, Vallada H. Lack of association
between a 3
0
UTR VNTR polymorphism of dopamine transporter
gene (SLC6A3) and ADHD in a Brazilian sample of adult patients.
J Atten Disord 2011; 15: 305–309.
47 Brown AB, Biederman J, Valera E, Makris N, Doyle A, Whitfield-
Gabrieli S et al. Relationship of DAT1 and adult ADHD to task-
positive and task-negative working memory networks. Psychiatry
Res 2011; 193: 7–16.
48 Biederman J, Petty CR, Ten Haagen KS, Small J, Doyle AE,
Spencer T et al. Effect of candidate gene polymorphisms on the
course of attention deficit hyperactivity disorder. Psychiatry Res
2009; 170: 199–203.
49 Muller DJ, Chiesa A, Mandelli L, De LV, De RD, Jain U et al.
Correlation of a set of gene variants, life events an d personality
features on adult ADHD severity. J Psychiatr Res 2010; 44:
598–604.
50 Sanchez-Mora C, Ribases M, Casas M, Bayes M, Bosch R,
Fernandez-Castillo N et al. Exploring DRD4 and its interaction
with SLC6A3 as possible risk factors for adult ADHD: a meta-
analysis in four European populations. Am J Med Genet B 2011;
156: 600–612.
51 Muglia P, Jain U, Macciardi F, Kennedy JL. Adult attention deficit
hyperactivity disorder and the dopamine D4 receptor gene. Am J
Med Genet 2000; 96: 273–277.
52 Arcos-Burgos M, Castellanos FX, Konecki D, Lopera F, Pineda D,
Palacio JD et al. Pedigree disequilibrium test (PDT) replicates
association and linkage between DRD4 and ADHD in multi-
generational and extended pedigrees from a genetic isolate. Mol
Psychiatry 2004; 9: 252–259.
53 Lynn DE, Lubke G, Yang M, McCracken JT, McGough JJ,
Ishii J et al. Temperament and character profiles and the
dopamine D4 receptor gene in ADHD. Am J Psychiatry 2005;
162: 906–913.
54 Muglia P, Jain U, Kennedy JL. A transmission disequilibrium test
of the Ser9/Gly dopamine D3 receptor gene polymorphism in
adult attention-deficit hyperactivity disorder. Behav Brain Res
2002; 130: 91–95.
55 Davis C, Patte K, Levitan RD, Carter J, Kaplan AS, Zai C et al. A
psycho-genetic study of associations between the symptom s of
binge eating disorder and those of attention deficit (hyperactiv-
ity) disorder. J Psychiatr Res 2009; 43: 687–696.
56 Kim JW, Park CS, Hwang JW, Shin MS, Hong KE, Cho SC et al.
Clinical and genetic characteristics of Korean male alcoholics
with and without attention deficit hyperactivity disorder.
Alcohol Alcohol 2006; 41: 407–411.
57 Sizoo B, van den BW, Franke B, Vasquez AA, van Wijngaarden-
Cremers P, van der Gaag RJ. Do candidate genes discriminate
patients with an autism spectrum disorder from those with
attention deficit/hyperactivity disorder and is there an effect of
lifetime substance use disorders? World J Biol Psychiatry 2010;
11: 699–708.
58 Squassina A, Lanktree M, De LV, Jain U, Krinsky M, Kennedy JL
et al. Investigation of the dopamine D5 receptor gene (DRD5) in
adult attention deficit hyperactivity disorder. Neurosci Lett 2008;
432: 50–53.
59 Inkster B, Muglia P, Jain U, Kennedy JL. Linkage disequilibrium
analysis of the dopamine beta-hydroxylase gene in persistent
attention deficit hyperactivity disorder. Psychiatr Genet 2004; 14:
117–120.
60 Hess C, Reif A, Strobel A, Boreatti-Hummer A, Heine M,
Lesch KP et al. A functional dopamine-beta-hydroxylase gene
promoter polymorphism is associated with impulsive personality
styles, but not with affective disorders. J Neural Transm 2009;
116: 121–130.
61 Muller DJ, Mandelli L, Serretti A, DeYoung CG, De LV, Sicard T
et al. Serotonin transporter gene and adverse life events in adult
ADHD. Am J Med Genet B 2008; 147B: 1461–1469.
62 Retz W, Rosler M, Kissling C, Wiemann S, Hunnerkopf R, Coogan
A et al. Norepinephrine transporter and catecholamine-O-
methyltransferase gene variants and attention-deficit/hyperactiv-
ity disorder symptoms in adults. J Neural Transm 2008; 115: 323–
329.
63 Halleland H, Lundervold AJ, Halmoy A, Haavik J, Johansson S.
Association between catechol O-methyltrans ferase (COMT) hap-
lotypes and severity of hyperactivity symptoms in adults. Am J
Med Genet B 2009; 150B: 403–410.
Adult ADHD genetics
B Franke et al
22
Molecular Psychiatry
64 Johann M, Bobbe G, Putzhammer A, Wodarz N. Comorbidity of
alcohol dependence with attention-deficit hyperactivity disorder:
differences in phenotype with increased severity of the substance
disorder, but not in genotype (serotonin transporter and 5-
hydroxytryptamine-2c receptor). Alcohol Clin Exp Res 2003; 27:
1527–1534.
65 Grevet EH, Marques FZ, Salgado CA, Fischer AG, Kalil KL, Victor
MM et al. Serotonin transporter gene polymorphism and the
phenotypic heterogeneity of adult ADHD. J Neural Transm 2007;
114: 1631–1636.
66 Landaas ET, Johansson S, Jacobsen KK, Ribases M, Bosch R,
Sanchez-Mora C et al. An international multicenter association
study of the serotonin transporter gene in persistent ADHD.
Genes Brain Behav 2010; 9: 449–458.
67 Jacob CP, Nguyen TT, Dempfle A, Heine M, Windemuth-
Kieselbach C, Baumann K et al. A gene–environment investiga-
tion on personality traits in two independent clinical sets of adult
patients with personality disorder and attention deficit/hyper-
active disorder. Eur Arch Psychiatry Clin Neurosci 2010; 260:
317–326.
68 Ribases M, Ramos-Quiroga JA, Hervas A, Bosch R, Bielsa A,
Gastaminza X et al. Exploration of 19 serotoninergic candidate
genes in adults and children with attention-deficit/hyperactivity
disorder identifies association for 5HT2A, DDC and MAOB. Mol
Psychiatry 2009; 14: 71–85.
69 Reuter M, Kirsch P, Hennig J. Inferring candidate genes for
attention deficit hyperactivity disorder (ADHD) assessed by the
World Health Organization Adult ADHD Self-Report Scale
(ASRS). J Neural Transm 2006; 113: 929–938.
70 Johansson S, Halmoy A, Mavroconstanti T, Jacobsen KK, Landaas
ET, Reif A et al. Common variants in the TPH1 and TPH2 regions
are not associated with persistent ADHD in a combined sample of
1,636 adult cases and 1,923 controls from four European
populations. Am J Med Genet B 2010; 153B: 1008–1015.
71 De Luca V, Muglia P, Vincent JB, Lanktree M, Jain U,
Kennedy JL. Adrenergic alpha 2C receptor genomic organization:
association study in adult ADHD. Am J Med Genet B 2004; 127B:
65–67.
72 de Cerqueira CC, Polina ER, Contini V, Marques FZ, Grevet EH,
Salgado CA et al. ADRA2A polymorphisms and ADHD in adults:
possible mediating effect of personality. Psychiatry Res 2011;
186: 345–350.
73 Ribases M, Bosch R, Hervas A, Ramos-Quiroga JA, Sanchez-Mora
C, Bielsa A et al. Case–control study of six genes asymmetrically
expressed in the two cerebral hemispheres: association of
BAIAP2 with attention-deficit/hyperactivity disorder. Biol Psy-
chiatry 2009; 66: 926–934.
74 Conner AC, Kissling C, Hodges E, Hunnerkopf R, Clement RM,
Dudley E et al. Neurotrophic factor-related gene polymorphisms
and adult attention deficit hyperactivity disorder (ADHD) score
in a high-risk male population. Am J Med Genet B 2008; 147B:
1476–1480.
75 Sanchez-Mora C, Ribases M, Ramos-Quiroga JA, Casas M, Bosch
R, Boreatti-Hummer A et al. Meta-analysis of brain-derived
neurotrophic factor p.Val66Met in adult ADHD in four European
populations. Am J Med Genet B 2010; 153B: 512–523.
76 Lanktree M, Squassina A, Krinsky M, Strauss J, Jain U, Macciardi
F et al. Association study of brain-derived neurotrophic factor
(BDNF) and LIN-7 homolog (LIN-7) genes with adult attention-
deficit/hyperactivity disorder. Am J Med Genet B 2008; 147B:
945–951.
77 De Luca V, Muglia P, Jain U, Basile VS, Sokolowski MB, Kennedy
JL. A Drosophila model for attention deficit hyperactivity
disorder (ADHD): No evidence of association with PRKG1 gene.
Neuromolecular Med 2002; 2: 281–287.
78 Kissling C, Retz W, Wiemann S, Coogan AN, Clement RM,
Hunnerkopf R et al. A polymorphism at the 3
0
-untranslated
region of the CLOCK gene is associated with adult attention-
deficit hyperactivity disorder. Am J Med Genet B 2008; 147: 333–
338.
79 Lu AT, Ogdie MN, Jarvelin MR, Moilanen IK, Loo SK, McCracken
JT et al. Association of the cannabinoid receptor gene (CNR1)
with ADHD and post-traumatic stress disorder. Am J Med Genet B
2008; 147B: 1488–1494.
80 Reif A, Jacob CP, Rujescu D, Herterich S, Lang S, Gutknecht L et
al. Influence of functional variant of neuronal nitric oxide
synthase on impulsive behaviors in humans. Arch Gen Psychia-
try 2009; 66: 41–50.
81 Arcos-Burgos M, Jain M, Acosta MT, Shively S, Stanescu H,
Wallis D et al. A common variant of the latrophilin 3 gene,
LPHN3, confers susceptibility to ADHD and predicts effective-
ness of stimulant medication. Mol Psychiatry 2010; 15:
1053–1066.
82 Ribases M, Ramos-Quiroga JA, Sanchez-Mora C, Bosch R,
Richarte V, Alvarez I et al. Contribution of L atrophilin 3 (LPHN3)
to the genetic susceptibility to ADHD in adulthood: a replication
study. Genes Brain Behav 2011; 10: 149–157.
83 Landaas ET, Johansson S, Halmoy A, Oedegaard KJ, Fasmer OB,
Haavik J. Bipolar disorder risk alleles in adult ADHD patients.
Genes Brain Behav 2011; 10: 418–423.
84 Asherson P, Brookes K, Franke B, Chen W, Gill M, Ebstein RP et
al. Confirmation that a specific haplotype of the dopamine
transporter gene is associated with combined-type ADHD. Am J
Psychiatry 2007; 164: 674–677.
85 Brookes KJ, Mill J, Guindalini C, Curran S, Xu X, Knight J et al.
A common haplotype of the dopamine transporter gene asso-
ciated with attention-deficit/hyperactivity disorder and interact-
ing with maternal use of alcohol during pregnancy. Arch Gen
Psychiatry 2006; 63: 74–81.
86 Shaw P, Gornick M, Lerch J, Addington A, Seal J, Greenstein D
et al. Polymorphisms of the dopamine D4 receptor, clinical
outcome, and cortical structure in attention-deficit/hyperactivity
disorder. Arch Gen Psychiatry 2007; 64: 921–931.
87 Retz W, Freitag CM, Retz-Junginger P, Wenzler D, Schneider M,
Kissling C et al. A functional serotonin transporter promoter gene
polymorphism increases ADHD symptoms0 TD.00stein t-
98 Romanos M, Freitag C, Jacob C, Craig DW, Dempfle A, Nguyen TT
et al. Genome-wide linkage analysis of ADHD using high-density
SNP arrays: novel loci at 5q13.1 and 14q12. Mol Psychiatry 2008;
13: 522–530.
99 Fisher SE, Francks C, McCracken JT, McGough JJ, Marlow AJ,
Macphie IL et al. A genomewide scan for loci involved in
attention-deficit/hyperactivity disorder. Am J Hum Genet 2002;
70: 1183–1196.
100 Ogdie MN, Bakker SC, Fisher SE, Francks C, Yang MH, Cantor
RM et al. Pooled genome-wide linkage data on 424 ADHD ASPs
suggests genetic heterogeneity and a common risk locus at 5p13.
Mol Psychiatry 2006; 11: 5–8.
101 Bakker SC, van der Meulen EM, Buitelaar JK, Sandkuijl LA, Pauls
DL, Monsuur AJ et al. A whole-genome scan in 164 Dutch sib
pairs with attention-deficit/hyperactivity disorder: suggestive
evidence for linkage on chromosomes 7p and 15q. Am J Hum
Genet 2003; 72: 1251–1260.
102 Hebebrand J, Dempfle A, Saar K, Thiele H, Herpertz-Dahlmann B,
Linder M et al. A genome-wide scan for attention-deficit/
hyperactivity d isorder in 155 German sib-pairs. Mol Psychiatry
2006; 11: 196–205.
103 Asherson P, Zhou K, Anney RJ, Franke B, Buitelaar J, Ebstein R et
al. A high-density SNP linkage scan with 142 combined subtype
ADHD sib pairs identifies linkage regions on chromosomes 9 and
16. Mol Psychiatry 2008; 13: 514–521.
104 Zhou K, Asherson P, Sham P, Franke B, Anney RJ, Buitelaar J et
al. Linkage to chromosome 1p36 for attention-deficit/hyperactiv-
ity disorder traits in school and home settings. Biol Psychiatry
2008; 64: 571–576.
105 Vegt R, Bertoli-Avella AM, Tulen JH, de GB, Verkerk AJ, Vervoort J
et al. Genome-wide linkage analysis in a Dutch multigenerational
family with attention deficit hyperactivity disorder. Eur J Hum
Genet 2010; 18: 206–211.
106 Saviouk V, Hottenga JJ, Slagboom EP, Distel MA, de Geus EJ,
Willemsen G et al. ADHD in Dutch adults: heritability and
linkage study. Am J Med Genet B 2011; 156B: 352–362.
107 Zhou K, Dempfle A, Arcos-Burgos M, Bakker SC, Banaschewski
T, Biederman J et al. Meta-analysis of genome-wide linkage scans
of attention deficit hyperactivity disorder. Am J Med Genet B
2008; 147B: 1392–1398.
108 Risch N, Merikangas K. The future of genetic studies of complex
human diseases. Science 1996; 273: 1516–1517.
109 Lesch KP, Timmesfeld N, Renner TJ, Halperin R, Roser C, Nguyen
TT et al. Molecular genetics of adult ADHD: converging evidence
from genome-wide association and extended pedigree linkage
studies.
J Neural Transm 2008; 115: 1573–1585.
110 Neale BM, Medland SE, Ripke S, Asherson P, Franke B, Lesch KP
et al. Meta-analysis of genome-wide association studies of
attention-deficit/hyperactivity disorder. J Am Acad Child Ado-
lesc Psychiatry 2010; 49: 884–897.
111 Faraone SV. Report from the 4th international meeting of the
attention deficit hyperactivity disorder molecular genetics net-
work. Am J Med Genet B 2003; 121: 55–59.
112 Cichon S, Craddock N, Daly M, Faraone SV, Gejman PV, Kelsoe J
et al. Genomewide association studies: history, rationale, and
prospects for psychiatric disorders. Am J Psychiatry 2009; 166:
540–556.
113 Psychiatric GWAS Consortium Steering Committee. A framework
for interpreting genome-wide association studies of psychiatric
disorders. Mol Psychiatry 2009; 14: 10–17.
114 Maher B. Personal genomes: the case of the missing heritability.
Nature 2008; 456: 18–21.
115 Faraone SV, Sergeant J, Gillberg C, Biederman J. The worldwide
prevalence of ADHD: is it an American condition? World
Psychiatry 2003; 2: 104–113.
116 Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA. The
worldwide prevalence of ADHD: a systematic review and
metaregression analysis. Am J Psychiatry 2007; 164: 942–948.
117 Prendergast M, Taylor E, Rapoport JL, Bartko J, Donnelly M,
Zametkin A et al. The diagnosis of childhood hyperactivity. A
US–U.K. cross-national study of DSM-III and ICD-9. J Child
Psychol Psychiatry 1988; 29: 289–300.
118 Bauermeister JJ, Alegria M, Bird HR, Rubio-Stipec M, Canino G.
Are attentional-hyperactivity deficits unidimensional or multi-
dimensional syndromes? Empirical findings from a comm-
unity survey. J Am Acad Child Adolesc Psychiatry 1992; 31:
423–431.
119 Beiser M, Dion R, Gotowiec A. The structure of attention-deficit
and hyperactivity symptoms among native and non-native
elementary school children. J Abnorm Child Psychol 2000; 28:
425–437.
120 Lahey BB, Applegate B, McBurnett K, Biederman J, Greenhill L,
Hynd GW et al. DSM-IV field trials for attention deficit
hyperactivity disorder in children and adolescents. Am J
Psychiatry 1994; 151: 1673–1685.
121 Magnusson P, Smari J, Gretarsdottir H, Prandardottir H. Atten-
tion-deficit/hyperactivity symptoms in Icelandic schoolchildren:
assessment with the attention deficit/hyperactivity rating scale-
IV. Scand J Psychol 1999; 40 : 301–306.
122 Baumgaertel A, Wolraich ML, Dietrich M. Comparison of
diagnostic criteria for attention deficit disorders in a German
elementary school sample. J Am Acad Child Adolesc Psychiatry
1995; 34: 629–638.
123 Rohde LA, Biederman J, Busnello EA, Zimmermann H, Schmitz
M, Martins S et al. ADHD in a school sample of Brazilian
adolescents: a stud y of prevalence, comorbid conditions, and
impairments. J Am Acad Child Adolesc Psychiatry 1999; 38:
716–722.
124 Samuel VJ, George P, Thornell A, Curtis S, Taylor A, Brome D et
al. A pilot controlled family study of DSM-III-R and DSM-IV
ADHD in African-American children. J Am Acad Child Adolesc
Psychiatry 1999; 38: 34–39.
125 Samuel VJ, Biederman J, Faraone SV, George P, Mick E, Thornell
A et al. Clinical characteristics of attention deficit hyperactivity
disorder in African American children. Am J Psychiatry 1998;
155: 696–698.
126 Taylor E, Sandberg S. Hyperactive behavior in English school-
children: a questionnaire survey. J Abnorm Child Psychol 1984;
12: 143–155.
127 Auerbach JG, Lerner Y. Syndromes derived from the child
behavior checklist for clinically referred Israeli boys aged
6–11: a research note. J Child Psychol Psychiatry 1991; 32:
1017–1024.
128 Crijnen AA, Achenbach TM, Verhulst FC. Problems reported by
parents of children in multiple cultures: the child behavior
checklist syndrome constructs. Am J Psychiatry 1999; 156:
569–574.
129 Rasmussen ER, Todd RD, Neuman RJ, Heath AC, Reich W, Rohde
LA. Comparison of male adolescent-report of attention-deficit/
hyperactivity disorder (ADHD) symptoms across two cultures
using latent class and principal components analysis. J Child
Psychol Psychiatry 2002; 43: 797–805.
130 Weine AM, Phillips JS, Achenbach TM. Behavioral and emo-
tional problems among Chinese and American children: parent
and teacher reports for ages 6 to 13. J Abnorm Child Psychol 1995;
23: 619–639.
131 Rohde LA, Szobot C, Polanczyk G, Schmitz M, Martins S,
Tramontina S. Attention-deficit/hyperactivity disorder in a
diverse culture: do research and clinical findings support the
notion of a cultural construct for the disorder? Biol Psychiatry
2005; 57: 1436–1441.
132 Lahey BB, Van Hulle CA, Singh AL, Waldman ID, Rathouz PJ.
Higher-order genetic and environmental structure of prevalent
forms of child and adolescent psychopathology. Arch Gen
Psychiatry 2011; 68: 181–189.
133 Green EK, Grozeva D, Jones I, Jones L, Kirov G, Caesar S et al. The
bipolar disorder risk allele at CACNA1C also confers risk of
recurrent major depression and of schizophrenia. Mol Psychiatry
2010; 15: 1016–1022.
134 Rommelse NN, Franke B, Geurts HM, Hartman CA, Buitelaar JK.
Shared heritability of attention-deficit/hyperactivity disorder
and autism spectrum disorder. Eur Child Adolesc Psychiatry
2010; 19: 281–295.
135 Rommelse NN, Geurts HM, Franke B, Buitelaar JK, Hartman CA.
A review on cognitive and brain endophenotypes that may be
common in autism spectrum disorder and attention-deficit/
hyperactivity disorder and facilitate the search for pleiotropic
genes. Neurosci Biobehav Rev
2011; 35: 1363–1396 .
Adult ADHD genetics
B Franke et al
24
Molecular Psychiatry
136 Taurines R, Schmitt J, Renner T, Conner AC, Warnke A, Romanos
M. Developmental comorbidity in attention-deficit/hyperactivity
disorder. Atten Defic Hyperact Disord 2010; 2: 267–289.
137 Pliszka SR. Comorbidity of attention-deficit/hyperactivity dis-
order with psychiatric disorder: an overview. J Clin Psychiatry
1998; 59(Suppl 7): 50–58.
138 Weber H, Kittel-Schneider S, Gessner A, Domschke K, Neuner M,
Jacob CP et al. Cross-disorder analysis of bipolar risk genes:
further evidence of DGKH as a risk gene for bipolar disorder, but
also unipolar depression and adult ADHD. Neuropsychopharma-
cology 2011; 36: 2076–2085.
139 Reif A, Nguyen TT, Weissflog L, Jacob C, Romanos M, Renner T et
al. DIRAS2 is associated with adult ADHD, related traits, and co-
morbid disorders. Neuropsychopharmacology 2011; 36: 2318–
2327.
140 Williams NM, Zaharieva I, Martin A, Langley K, Mantripragada
K, Fossdal R