The influence of serotonin- and other genes on impulsive behavioral aggression and cognitive impulsivity in children with attention-deficit/hyperactivity disorder (ADHD): Findings from a family-based association test (FBAT) analysis
- Robert D Oades1Email author,
- Jessica Lasky-Su2,
- Hanna Christiansen1,
- Stephen V Faraone3,
- Edmund JS Sonuga-Barke4, 12, 16, 17,
- Tobias Banaschewski5,
- Wai Chen6,
- Richard JL Anney7,
- Jan K Buitelaar8,
- Richard P Ebstein9,
- Barbara Franke8, 10,
- Michael Gill7,
- Ana Miranda11,
- Herbert Roeyers12,
- Aribert Rothenberger13,
- Joseph A Sergeant14,
- Hans-Christoph Steinhausen15,
- Eric A Taylor16,
- Margaret Thompson6 and
- Philip Asherson16
© Oades et al; licensee BioMed Central Ltd. 2008
Received: 02 June 2008
Accepted: 20 October 2008
Published: 20 October 2008
Low serotonergic (5-HT) activity correlates with increased impulsive-aggressive behavior, while the opposite association may apply to cognitive impulsiveness. Both types of impulsivity are associated with attention-deficit/hyperactivity disorder (ADHD), and genes of functional significance for the 5-HT system are implicated in this disorder. Here we demonstrate the separation of aggressive and cognitive components of impulsivity from symptom ratings and test their association with 5-HT and functionally related genes using a family-based association test (FBAT-PC).
Our sample consisted of 1180 offspring from 607 families from the International Multicenter ADHD Genetics (IMAGE) study. Impulsive symptoms were assessed using the long forms of the Conners and the Strengths and Difficulties parent and teacher questionnaires. Factor analysis showed that the symptoms aggregated into parent- and teacher-rated behavioral and cognitive impulsivity. We then selected 582 single nucleotide polymorphisms (SNPs) from 14 genes directly or indirectly related to 5-HT function. Associations between these SNPs and the behavioral/cognitive groupings of impulsive symptoms were evaluated using the FBAT-PC approach.
In the FBAT-PC analysis for cognitive impulsivity 2 SNPs from the gene encoding phenylethanolamine N-methyltransferase (PNMT, the rate-limiting enzyme for adrenalin synthesis) attained corrected gene-wide significance. Nominal significance was shown for 12 SNPs from BDNF, DRD1, HTR1E, HTR2A, HTR3B, DAT1/SLC6A3, and TPH2 genes replicating reported associations with ADHD. For overt aggressive impulsivity nominal significance was shown for 6 SNPs from BDNF, DRD4, HTR1E, PNMT, and TPH2 genes that have also been reported to be associated with ADHD. Associations for cognitive impulsivity with a SERT/SLC6A4 variant (STin2: 12 repeats) and aggressive behavioral impulsivity with a DRD4 variant (exon 3: 3 repeats) are also described.
A genetic influence on monoaminergic involvement in impulsivity shown by children with ADHD was found. There were trends for separate and overlapping influences on impulsive-aggressive behavior and cognitive impulsivity, where an association with PNMT (and arousal mechanisms affected by its activity) was more clearly involved in the latter. Serotonergic and dopaminergic mechanisms were implicated in both forms of impulsivity with a wider range of serotonergic mechanisms (each with a small effect) potentially influencing cognitive impulsivity. These preliminary results should be followed up with an examination of environmental influences and associations with performance on tests of impulsivity in the laboratory.
Attention-deficit/hyperactivity disorder-combined type
brain derived neurotrophic factor
Conners parent/teacher rating scales
dopamine (receptors DRD1, DRD4)
- DAT1 (SLC6A3):
Fatty-acid desaturase gene-2
family-based association test with principle components
International Multicenter ADHD Genetics study
orphan nuclear receptor/transcription factor
Parental account of children's symptoms
Strengths and difficulties questionnaire
Serotonin (receptors 5-HT1a, b, 5-HT2a, c, 5-HT3b)
single nucleotide polymorphism
Serotonin transporter [VNTR] in intron 2
variable number tandem repeat.
Impulsive actions usually damage not only the victim but often their perpetrator. In fights, suicide or fire-setting the aggressive component is immediately apparent. But the risky and overly rapid decisions behind these actions demonstrate a cognitive component that is often revealed in gambling and seeking immediate gratification. Impulsivity is a core construct of many mental disorders . In particular, it is an essential component of the diagnosis of the most prevalent form of attention-deficit/hyperactivity disorder ADHD, namely the 'combined type' (ADHD-ct: ).
Across a group of youngsters with ADHD-ct there are many who show abrupt bursts of impulsive aggression (related to conduct disorder), but many others who (merely) make rapid and wrong decisions in everyday life, or abhor delayed gratification to their cost . Here, we consider that these two forms of impulsivity may have distinct pathophysiological features with relation to ADHD. In particular, this article focuses on serotonin activity, ) and heritable features of ADHD, where a 70–80% heritability has been clearly demonstrated .
Impulsivity has been briefly and broadly defined as "action without foresight" . More generally impulsivity covers actions that appear "poorly conceived, prematurely expressed, and are unduly risky or inappropriate to the situation. They often result in undesirable consequences" . Impulsivity has been linked strongly to outbreaks of aggression in adults (here considered as overt impulsive behavioral aggression) that are associated with increased 5-HT2a platelet receptor binding (Bmax and Kd), decreased 5-HT1a postmortem binding and low serotonin (5-HT) activity [8–10]. While some studies have failed to find the same relationship of low 5-HT activity with aggression in children [11–13] many others do report an inverse relationship [14–16] sensitive to pharmacotherapy . It may be that the phenocopy for aggression has not always fully developed at the time of study. Impulsive aggression reacts to provocation and is marked after 5-HT synthesis reduction following tryptophan depletion . Indeed, Halperin's group, in showing an apparently protective effect of high 5-HT activity, recently proposed that low activity is important if not sufficient for the emergence of aggression. Consistent with the developmental expression of the trait they reported that low 5-HT responsivity in childhood predicted the development of antisocial personality disorder 9 years later .
More differentiated views of impulsiveness  suggest that, as well as aggressive and behavioral impulsiveness associated with emotional lability and motor control, there are also cognitive or attention-related elements ; for example, there are the cognitive expressions of impulsiveness that are associated with failures of inhibitory executive functions ("executive attention", ). Typically decisions are made hastily and lead to maladaptive outcomes. Such impulsivity is epitomized by errors of commission on a discrimination or Go/no-go task, and is perhaps reflected in more motivationally-based domains where response choice is driven by early reinforcement . This form of cognitive impulsiveness may be regarded as a form of impaired selective attention. However, it is a result of overly rapid, inadequate information processing that leads to inappropriate action. This should be contrasted with absences of conventional attentive processes (inattentiveness) that would normally bring the searchlight, the focus of selective processing to stimulus identification. Inattention leads to the omission of a response. Thus it is important to distinguish the term inattention, as it is usually understood, from impulsive (cognitive) processing that risks non-adaptive responses. Such impulsive decisions about the moment-to-moment organization and planning of responses to stimuli are commonly made by both younger  and older subjects with ADHD .
The goal of the current study is to disentangle the relationship between aggressive impulsivity of a more behavioral nature and cognitive impulsivity in ADHD by exploring the differential patterns of association of these two forms of impulsivity with genes that have significance for 5-HT function, a putative neurobiological marker of impulsivity. There is mounting evidence that polymorphisms for genes influencing several features of the 5-HT system are associated with ADHD , and a case has been made for a differential involvement of 5-HT activity in impulsive aggressive behavior and cognitive impulsivity . For example, in one study increases of platelet 5-HT transporter affinity in 20 children with ADHD correlated with ratings of externalizing behavior, but decreases of affinity were associated with distractibility, impulsivity and the difficulty to withhold a prepotent response on the stop-task . Similarly a study of adolescent prisoners described opposite correlations of 5-HT activity with crime and other measures of impulsivity . On tasks assessing impulsivity (see ), errors of commission are typical of youngsters with ADHD who show an underactivation in the right frontal cortices . An impairment is expressed in similar regions of young healthy subjects treated with a tryptophan-depleting drink .
We therefore explored whether there would be commonalities and differences between the two forms of impulsivity and 5-HT genes controlling the activation or suppression of activity within 5-HT systems, along with other genetic markers of neuronal activity (e.g. dopamine) which influence or are influenced by the activity in 5-HT systems .
Number of genotyped families
Total number of genotyped people
Number of genotyped parents
Number of genotyped offspring
Number of offspring per family
Gender of offspring:
Average age of offspring (Standard Deviation)
Number of affected offspring
Exclusion criteria were genetic or medical disorders associated with behavior mimicking ADHD, autism, epilepsy, IQ<70, and the absence of a medication-free period permitting evaluation in the previous 2 years. Approval for the study was obtained from ethical review boards at each clinic, which were registered with and monitored by the National Institutes of Health, and were in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki).
Assessments: diagnosis and impulsivity
Clinical assessments were made during medication free periods or based on recall of such periods in the last 2 years. Diagnoses of ADHD-ct were based on the semi-structured Parental Account of Children's Symptoms (PACS; ). Interviewers received formal training in administration of the PACS. PACS includes 4 subscales, representing the different DSM-IV categories for ADHD and disruptive behaviors (hyperactivity, defiance, emotionality, and comorbid disorders). An age adjustment for symptom thresholds is built into the PACS algorithm. Detailed descriptions of the child's typical behavior in a range of specified situations defined by the context (e.g. play) or the behavior shown (e.g. crying) that had occurred in the previous week and in the previous year were rated on a 4-point scale for frequency and severity. Situational pervasiveness was determined by the different situations investigated within the interview and the presence of at least one symptom in each domain reported in the Conners teacher rating (CTRS) ADHD sub-scales. Autism spectrum disorders were screened for all children using the Social Communication Questionnaire (≥ 15) in conjunction with the pro-social scale from the Strengths and Difficulties Questionnaire (SDQ ≤ 4). Inter-rater reliability was high with product-moment correlations for pairs of interviewers ranging from 0.79 to 0.96. A mean kappa coefficient across all the sites of 0.88 (range 0.71–1.00) and an average agreement percentage of 96.6% (range 78.6–100) were obtained. Concurrent validity of the PACS diagnosis was confirmed by the biserial correlation between PACS diagnosis of ADHD-ct with the CTRS N-scale (18 DSM-items) scores at 0.68 and with Conners' Parent rating scale (CPRS) N-scale scores at 0.78 [34–36].
Principle components analysis (oblique rotation) of 47 items of impulsivity: Parent and teacher ratings from Conners and SDQ questionnaires (CP, SP and CT, ST, respectively).
Part 1 – The aggressive behavioral form of impulsivity (factors 1 and 2)
Often has temper tantrums
Touchy or easily annoyed
Mood changes quickly
Angry and resentful
Actively defies or refuses to
Argues with adults
Demands to be met at once
Spiteful or vindictive
Often fights with other children
Disturbs other children
Get upset if someone rearranges
Generally obedient, usually ...
Often has temper tantrums
Temper outbursts; explosive,
Demands must be met at once
Mood changes quickly, drastically
Argues with adults
Interrupts or intrudes on others
Has difficulty waiting in turn
Blurts out answers to question
Often fights with other children
Spiteful or vindictive
Leaves seat in classroom or
Generally obedient, usually
Good attention span sees
Squared Multiple Correlation
Principle components analysis (oblique rotation) of 47 items of impulsivity: Parent and teacher ratings from Conners and SDQ questionnaires (CP, SP and CT, ST, respectively).
Part 2 -The cognitive form of impulsivity (factors 3 and 4)
Easily distracted by extraneous ...
Fails to finish things started
Easily distracted, poor concentration
Fails to complete assignment
Get distracted even when instructed
Does not follow instructions through
Blurts out answers to questions
Has difficulty waiting in line
Thinks things out before acting
Good attention span, sees ...
Inattentive easily distracted
Distractibility, or attention span poor
Easily distracted, poor concentration
Easily distracted by extraneous
Does not follow instructions through
Fails to finish things started
Thinks things out before acting
Good attention span sees
Squared Multiple Correlation
We selected 14 genes with 582 single nucleotide polymorphisms (SNPs) from the data available from the IMAGE study for the core analysis reported here. For the 5-HT system, markers for pre- and post-synaptic receptors (HTR1A, HTR1B, HTR1E, HTR2A, HTR3B), and synaptic availability controlled by synthesis (TPH2) and re-uptake (SERT/SLC6A4) were chosen. We reasoned that some dopaminergic (DA) biomarkers should be included in view of widespread interactions between 5-HT and DA systems in the brain (reviews in [32, 40]). These included SNPs for the receptors DRD1, DRD4 and DAT1/SLC6A3. There have been reports of associations for each of these genes with ADHD that were subsequently replicated (reviews: [4, 5, 41]). We also decided to include 4 genes for comparison that might be expected to have a less specific outcome on neural activity and behavior than those targeting neurotransmitter synthesis and receptor function (BDNF, NURR-1, FADS2, and PNMT: see discussion). For an additional analysis genotype information on repeat polymorphisms (microsatellites) was available for the DRD4 (exon 3 variable number tandem repeat [VNTR]), the DAT1/SLC6A3 (3' untranslated region VNTR), the SERT/SLC6A4 (a VNTR polymorphism in intron 2: STin2) and an in/del promoter polymorphism (5-HTTLPR), from an analysis based on 1116 ADHD families.
DNA and SNP collection
The DNA sample used here is a part of a larger genetic sample from the IMAGE study. Details of the DNA isolation and SNP selection can be found elsewhere . Briefly, blood samples were sent to Rutgers University Cell and DNA repository, New Jersey, U.S.A., where DNA was extracted. In a limited number of cases where individuals were not able to supply a blood sample, DNA was extracted from a mouth swab sample at the SGDP laboratories in London, U.K. . DNA stocks were collated in London where they were stored, organized and plated out for further analysis. Geneservice Ltd. Cambridge (UK) performed whole genome amplification on all samples with less than 100 μg stock DNA, using the REPLI-g kit (Quiagen Ltd., Crawley, UK). DNA samples were arrayed into 96-well plates at a concentration of 50 ng/μl and delivered to Illumina Inc. (San Diego, US) under dry ice. A total of 582 SNPs were genotyped throughout 14 genes, as part of a larger set of SNPs/genes described elsewhere . These SNPs were selected as tag-SNPs to explain the linkage disequilibrium structure throughout the gene. Additional polymorphisms genotyped were the repeat polymorphisms in DRD4, SLC6A3/DAT1 and SLC6A4/SERT. Genotyping was by simple sequence analysis on agarose gel, as described previously [43–45]. Each polymorphism was evaluated to ensure Hardy-Weinberg equilibrium, initially at α = 0.0001, then at α = 0.05. Data cleaning procedures were performed previously on the entire IMAGE set of SNP data and have been described .
Analytical strategy: family based association test – principle components (FBAT-PC)
To determine that the 47 symptoms selected for association analysis would indeed group into major factors of cognitive and aggressive behavioral impulsivity we ran a preliminary factor analysis (Promax) with an oblique rotation in the SAS statistical package. This rotation is in line with clinical experience that subjects present concurrently with symptoms from different dimensions . Four factors based on an eigenvalue cutoff of = 1.0 confirmed these groupings: namely, A) impulsive aggressive behavior based on 1) parent ratings, 2) teacher ratings, and B) cognitive impulsivity rated by 3) parents, and 4) teachers (tables 2 and 3). The names of these groupings reflect the items that emphasize temper outbursts and anger (2A), and distraction (despite understanding the task) that reflects responding to inappropriate stimuli (commission rather than omission: 2B). A look at tables 2 and 3 shows that few variables loading on one factor had strong weightings on the other. Three examples for factors 1 and 2 are "excitable impulsive" (CP28), "disturbs other children" (CP66) and "generally obedient" (SP7). Of interest is the item "blurts out answers before the question is finished" that loads modestly on factor 2 (CT46) with a similar value to that on factor 3 (CP80). This item could be construed as an example of impulsive behavior overlying a cognitively impulsive decision. A previous factor analysis of ADHD symptom domains in 10–14 y-old children confirmed that behavioral impulsivity related to aggression and delinquency, while inattentive items related to hyperactivity .
We then performed separate association analyses at each SNP for each of the two groupings while applying the FBAT-PC approach. The FBAT-PC approach generates a composite phenotype by using a weighted sum of the individual phenotypes (details in [48, 49], for applications see [50, 51]). The weights for this composite phenotype are selected to maximize the heritability at each SNP.
Screening procedures were employed to limit the number of statistical tests performed using the PBAT computer program. An outline of the screening procedure can be summarized as follows: 1) the conditional mean model is used to calculate the power to detect an association using the composite phenotype; 2) SNP/genetic model combinations are selected based on the power to detect an association and then ranked; 3) for the top ten power rankings in the FBAT-PC statistics are calculated for the selected SNP/genetic model combinations and their associated phenotypes; 4) the results are adjusted for multiple comparisons using the False Discovery Rate (FDR: . For these analyses, we considered additive (0), dominant (1) and recessive (2) genetic models. We required our results to have at least 20 informative families.
Table 1 summarizes the characteristics of the IMAGE sample used in this analysis. There were 607 families, each with between 1 and 4 offspring who had complete genotype and phenotype information. Two thirds of the offspring were male and 603 had a diagnosis of ADHD-ct. The predominant ethnic make-up of the sample was northern European with subsets from Spain and Israel. As family-based tests are robust to population stratification all individuals were included in the analysis. Previous analyses of these data have shown that the findings did not change substantially when the Spanish and Israeli groups were removed.
We applied the FBAT-PC approach to the items making up 'impulsive aggression' and 'cognitive impulsivity' variables separately. For both analyses the associations were ranked by power and the first ten were selected for further consideration. No SNPs survived gene-wide corrections for an association with both forms of impulsivity.
FBAT-PC results for behavioral (factors 1 + 2) and cognitive impulsivity (factors 3 + 4)
Factors 1 & 2 (behavioral impulsivity)
Factors 3 & 4 (cognitive impulsivity)
Gene wide significance
For cognitive impulsivity one SNP from the PNMT gene attained gene-wide statistical significance following an FDR correction for multiple testing in both additive and dominant models (p ≤ 0.05: table 4). In addition, 12 SNPs from 7 genes attained nominal significance (p ≤ 0.05) for an association with cognitive impulsivity. These genes were BDNF, DAT1/SLC6A3, DRD1, HTR1E, HTR2A, HTR3B, and TPH2.
Genotype information on repeat polymorphisms (microsatellites) was available for the DRD4 (exon 3, VNTR), the DAT1/SLC6A3 (3' untranslated region VNTR) and the SERT/SLC6A4 (a VNTR in intron 2: STin2) and an in/del promoter polymorphism (5-HTTLPR) from an analysis based on 1116 ADHD families. There were nominally significant associations on an additive model for the 3-repeat DRD4 allele (p = 0.014) with impulsive aggressive behavior, and the SERT VNTR (STin2: 12 vs. 9 and 10 repeat alleles; p = 0.050) with cognitive impulsivity. Other tests for association (e.g. for the promoter region, 5-HTTLPR long and short repeats) proved not to be significant.
Having identified the SNP/model combinations listed in table 4, we examined the associations with ADHD affection status. In addition to being the only gene where there was gene-wide significance, PNMT was also the only gene that was nominally associated with ADHD affection status. SNP rs200173 had associations with ADHD affection status for both the additive and dominant genetic models (unadjusted p-value = 0.0065 and 0.012 respectively) and rs2934966 had an association with the dominant model (unadjusted p-value = 0.0458).
After separating the 47 items from the SDQ and Conners symptom ratings into the two dimensions of aggressive and cognitive impulsivity, we used the FBAT-PC software to evaluate their possible associations with 582 SNPs distributed through 14 relevant genes. The genes were selected because their expression affects 5-HT activity and closely-related neural functions and they have previously been reported to be associated with a diagnosis of ADHD. The focus on 5-HT-related features was based on descriptions of the relevance of this transmitter to the expression of impulsivity [4, 26, 53] and for the preferential transmission of polymorphisms influencing 5-HT function in ADHD (see introduction). Gene-wide significance was achieved only for a variant of the gene encoding the enzyme for the synthesis of adrenalin (PNMT) in cognitive impulsivity. However nominal significance was shown for genes affecting a range of elements of the 5-HT and DA systems in both forms of impulsivity, and that have previously been reported to be associated with ADHD.
The absence of prominent associations for neurotransmitter markers, apart from that with adrenalin synthesis through PNMT variants, was surprising. A gene-wide significant association was found for one SNP for PNMT with cognitive impulsivity, and a second was nominally associated with behavioral aggressive impulsivity from the 4 SNPs for PNMT that were examined. In both instances the trait was over-expressed (table 4). This was partly anticipated by a similar significant finding in a candidate gene analysis for association with ADHD from the IMAGE sample . PNMT is the rate-limiting enzyme in the synthesis of adrenalin that has transmitter and endocrine influences on brain function which can be stimulatory or inhibitory, respectively . The association of adrenalin with CNS arousal is significant in the context of the common attribution of hypoarousal to ADHD function (review: ). Further, one might anticipate that arousal levels would be pertinent to both forms of impulsivity under investigation here, but especially the cognitive attention-related form that could be a precursor to the behavioral, aggression-related form. Indeed, adrenalin levels in ADHD children are usually lower than normal [56–58] unless they show anxiety [59–61]. Low levels are associated with restlessness and aggressive outbursts . Response to treatment with methylphenidate tends to normalize levels of adrenalin [58, 63] and improve autonomic measures of low arousal (skin conductance levels: ). Thus there is broad support for a widespread role for impaired function of arousal and adrenalin systems in ADHD and the impulsivity that is characteristic of the disorder. From our current results, we would predict that this could be based in an altered expression or function of the PNMT gene. Considering the potential parallel involvement of 5-HT systems in impulsivity, and the demonstrated role of 5-HT in the control of autonomic function  it would be useful to look for tagging between variants influencing PNMT and 5-HT receptors.
In agreement with our expectations, analyses of the two forms of impulsivity are reflected at least nominally in similar but also in different associations with the genetic markers for monoamine activity. For the 5-HT system, association with synthesis (TPH2) and receptor-mediated mechanisms (HTR1E) may be relevant to both forms of impulsivity. Indeed the same SNP for HTR1E (rs1406946) was nominally associated with both types of impulsiveness in the dominant transmission model. It was over-expressed in the cognitive and under-expressed in the behavioral or aggressive form of impulsivity (table 4). The difference for 5-HT function is one of emphasis, with a number of markers pointing to small effects on synthesis (TPH2 3 SNPs), pre-and post-synaptic receptors (HTR1E, HTR2A, HTR3B: 5 SNPs) and reuptake (SERT: STin2) for cognitive (not behavioral) impulsivity. For cognitive impulsivity 4 SNPs for receptors (apart from HTR1E) were under-expressed in a recessive model, whereas the availability of 5-HT (e.g. TPH2 in a dominant model) was influenced by over-expression of relevant alleles. For the DA system, nominally significant markers were found for both types of impulsivity, but while the emphasis for the behavioral/aggressive form was on DRD4 (one SNP and in particular the 3-repeat allele was over-expressed), cognitive impulsivity was nominally associated with uptake (DAT1: 1 SNP) and the D1 receptor (DRD1: 2 SNPs), which were all under-expressed. Based on their anatomical distributions, this could reflect top-down mesocortical and bottom-up mesolimbic mechanisms of control, respectively .
The 5-HT component implies a potential influence of 5-HT activity in those children with ADHD who show aggressive behavioral and cognitive impulsivity both through its availability (TPH2-mediated synthesis and SERT-mediated uptake), and the efficacy of 5-HT action via the 5-HT2 and 5-HT1 receptor families . Generalizing in this context, activation of the 5-HT1B and 5-HT2A receptors tend to be 'stimulatory', while the 5-HT1A and 5-HT2C sites are more often 'inhibitory' . The 5-HT receptor mediated influence obtains especial significance with regard to the interaction of 5-HT with the DA system considering that ADHD is often considered a 'hypodopaminergic' disorder [69, 70] and the 5-HT and DA systems interact directly and widely through subcortical and cortical regions . Even if the genetic effects reported here are modest, there is intriguing support for our hypothesis of opposing types of interactions of DA and 5-HT in the two forms of impulsivity. Thus, in aggressive behavioral impulsivity a DRD4 SNP was overexpressed while those for HTR1E and TPH were underexpressed. In contrast in cognitive impulsivity SNPs for DRD1 and DAT1 were underexpressed while others for TPH2 and HTR1E were overexpressed.
Corrected significant associations for the 5-HT2A gene have also been reported recently for children and adults with ADHD  and correlations with hyperactive/impulsive symptoms were described for a normal population . However, other groups have seen no association [73, 74]. Unfortunately, little is known about the functional role of 5-HT1E sites that make up a quarter of those binding 5-HT in the forebrain in autoradiographic postmortem studies of cortical and hippocampal regions (CA3-4 >> CA1 ). In contrast, 5-HT3 receptors have been more widely studied, and are abundant in limbic and frontal regions . In contrast to the inhibitory functions attributed to HT1 receptors, stimulation of HT3 sites enhances DA release . Thus the nominal significance of the association of 4 SNPs for stimulatory receptors (HT2A and HT3B) with cognitive impulsivity is consistent with the opposing effects of 5-HT activity on the two forms of impulsiveness proposed in the introduction.
The presence of 3 SNPs for TPH2 with near gene-wide significant associations with cognitive impulsiveness along with the significant relationship for a SERT allele (as also indicated by ) would suggest that markers for the presynaptic availability of 5-HT merit continued attention. The importance of this is illustrated, for example, by the functional consequence of changes in SERT activity as expressed with the short allele. In this instance the binding potential of 5-HT receptors may alter, as demonstrated for the 5-HT1a binding site . In turn changes at this binding site (with inhibitory function) would strongly modulate transmitter release in DA systems. Considering the well-known interactions of these two monoaminergic systems , the potential for tagging between genetic loci should be sought in future studies.
Lastly, we studied SNPs representing 3 other genes (BDNF, FADS2, NURR1/NR4A2) on the grounds that their activity could influence neurotransmission including that based on 5-HT, and that some associations with ADHD have been reported . Brain derived neurotrophic factor (BDNF) facilitates the development of the release mechanisms for several neurotransmitters. It is known to have age-dependent effects on 5-HT transporter function . In BDNF-knockout mice this led to reduced 5-HT metabolism  and aggressive impulsive behavior . A nominal association with both forms of impulsiveness emerged from the present analysis, that may reflect a small effect on the development of monoamine systems in general for cases of ADHD that particularly reflect an etiology of delayed maturation . However, there is not much support for an association of BDNF markers with the diagnosis of ADHD . NURR1/NR4A2 is an orphan nuclear receptor and transcription factor crucial to the genetic control of development of DA neurons [85, 86]. The expression of NURR1/NR4A2 is essential for the induction of several markers of DA activity (e.g. tyrosine hydroxylase). However, there was no evidence here for the altered expression or function of NURR1/NR4A2. Finally, fatty-acid desaturase gene-2 (FADS2) is involved in regulating membrane synthesis and function and at least one polymorphism has been closely associated with ADHD . The ratio of omega-3 to omega-6 unsaturated fatty acids in neural membranes certainly influences their fluidity and the ability of neurons to conduct efficiently: this is a problem for ADHD with documented white matter anomalies  and potentially for the function of oligodendrocytes responsible for membrane synthesis . But we found no evidence that the FADS2 markers investigated were associated with the types of impulsivity studied here.
Limitations of the study
The design of the study involved recruiting children and adolescents who showed to a greater or lesser extent the features of impulsivity we sought. Alternative approaches could contrast children with and without these features, and compare pre-, post-pubertal and young adult subjects to investigate putative developmental changes in gene expression. A comparison of groups with high comorbidity for externalizing or internalizing symptoms would be instructive both for the integrity of our concepts of impulsivity in affect and cognition, as well as for identifying the grounds for separating subgroups of ADHD with 'comorbid features'. We would also point out the severe limitations of interpreting symptoms based on lay responses to questionnaires. It is important that the preliminary work described here be extended to neuropsychological testing that would contrast not only provoked aggression with impulsive decision making, but incorporate the role of reinforcement (e.g. delayed gratification).
There are also several limitations with regard to the sample and genotyping. Although this sample is reasonably sized for moderate genetic effects, the number of individuals could be larger to detect the modest genetic effects that one would expect to observe here. In addition, individuals enrolled in the IMAGE study are from several different places throughout Europe, including Spain and Israel. Although the FBAT statistic is robust to population stratification, the PBAT screening algorithm can be affected by this. Finally, current genome-wide scans are suggesting many genes that one could not have suspected of being of interest a short time ago. Therefore some candidate genes that may now seem important were not included in this analysis.
ADHD is a highly heterogeneous disorder: it has been argued that there are potentially multiple variants of the condition with different etiological bases, pathophysiological signatures and neuropsychological and behavioral markers . Consequently, it has been suggested that one of the key goals for ADHD research should be to parse that heterogeneity, to create more neurobiologically homogeneous sub-groupings so as to provide more refined diagnostic criteria and more specific treatment targets . One manifestation of such a strategy is the search for endophenotypes, for pathophysiologic markers that mediate the pathways from genetic and environmental risk to disorder . From this perspective the current differentiation between two types of impulsiveness on the basis of their associated genes and their behavioral characteristics both highlight these constructs as putative endophenotypes for ADHD and encourage further research to explore the possibility that two 'subtypes' of ADHD might exist marked by different types of impulsiveness. The one has a strong basis in motivation and emotion with expression dependent on a degree of motor disinhibition (aggressive-behavioral impulsivity), and the other reflects poor executive control of endogenous attention-related processes that can underlie risky decision-making in several functional domains (cognitive impulsivity).
In particular, this study has taken an exploratory look at whether some SNPs from genes related to 5-HT function are associated with symptom ratings that reflect aggressive behavioral and cognitive impulsivity. Clearly different results could emerge from the study of other genes/SNPs as they become available. These SNPs cover genes for only four of the 22 types 5-HT receptor identified. There are indications that other receptors could be involved (e.g. 5-HT1D, 5-HT4, 5-HT6, 5-HT7: [71, 93]. Complementary to the present study, one using cognitive impulsivity measures from neuropsychological tests (e.g. continuous performance and flanker tasks) would be necessary before one could draw firm conclusions about the influence of heritable features of the 5-HT system on cognitive decision-making processes.
Nonetheless, based on ratings of impulsive symptoms, in the first instance this study strongly implicates genetic influences in ADHD on the synthesis of adrenalin and by implication on the degree of arousal influencing the organization and expression of behavior. In the second instance we report a genetic influence on the expression of SERT, along with potential, small effects of TPH2, 5-HT1E, 5-HT2A, DAT1, DA D1 and D4 receptors prominently expressed in limbic and association cortices and implicated in the initiation of impulsive processes and their expression by young people with ADHD. These features of 3 monoamine systems and two types of impulsivity may be regarded as 'intermediate phenotypes' for the psychopathology of combined-type ADHD. The usefulness of the FBAT-PC approach in the context of dissecting impulsivity in ADHD has been demonstrated, and warrants further, closer study using measures of impulsivity defined by neuropsychological task performance.
The IMAGE project is a Multisite, international effort supported by National Institutes of Health (NIH) Grant R01MH62873 to Stephen V. Faraone. Additional sources of financial support for data collection reported in this paper included the Medical Research Council (London; Kuntsi); Economic and Social Research Council, Southampton Primary Care Trust, HOPE and the University of Southampton (Southampton; Sounga-Barke and Thompson); Catherijne Foundation and the Radboud University Medical Centre (Nijmegen; Buitelaar). Chief Investigators (CIs) at each site were Marieke Altink, Wai Chen, Hanna Christiansen, Rafaela Marco, Ueli C. Mueller, Fernando Mulas, Aisling Mulligan, Nanda Rommelse, Lamprini Psychogiou and Henrik Uebel. There are no further financial disclosures to report. We sincerely thank all the families who kindly participated in this research.
- Moeller FG, Barratt ES, Dougherty DM, Schmitz JM, Swann AC: Psychiatric aspects of impulsivity. Am J Psychiat. 2001, 158: 1783-1793.View ArticlePubMed
- Taylor EA, Sergeant JA, Doepfner M, Gunning B, Overmeyer S, Möbius H-J: Clinical guidelines for hyperkinetic disorder. Eur Child Adolesc Psychiat. 1998, 7: 184-200.View Article
- Sonuga-Barke EJS: The dual pathway model of AD/HD: an elaboration of neuro-developmental characteristics. Neurosci Biobehav Rev. 2003, 27: 593-604.View ArticlePubMed
- Oades RD: The role of the serotonin system in ADHD: treatment implications. Expert Rev Neurother. 2007, 7 (10): 1357-1374.View ArticlePubMed
- Faraone SV, Perlis RH, Doyle AE, Smoller JW, Goralnick JJ, Holmgren MA: Molecular Genetics of Attention Deficit Hyperactivity Disorder. Biol Psychiat. 2005, 57: 1313-1323.View ArticlePubMed
- Winstanley CA, Eagle DM, Robbins TW: Behavioral models of impulsivity in relation to ADHD: Translation between clinical and preclinical studies. Clin Psychol Rev. 2006, 26: 379-395.PubMed CentralView ArticlePubMed
- Daruna JH, Barnes PA: A neurodevelopmental view of impulsivity. The impulsive client: theory research and treatment. Edited by: McCown WG, Johnson JL, Shure MB. 1993, Washington, DC: The American Psychological Association
- Coccaro EF, Kavoussi RJ, Sheline YI, Berman ME, Csernansky JG: Impulsive aggression in personality disorder correlates with platelet 5-HT2A receptor binding. Neuropsychopharmacology. 1997, 16 (3): 211-216.View ArticlePubMed
- Parsey RV, Oquendo MA, Simpson NR, Ogden RT, Van Heertum R, Arango V: Effects of sex, age, and aggressive traits in man on brain serotonin 5-HT(1A) receptor binding potential measured by PET using [C-11]WAY-100635. Brain Res. 2002, 954: 173-182.View ArticlePubMed
- Carver CS, Miller CJ: Relations of serotonin function to personality: current views and a key methodological issue. Psychiatry Res. 2006, 144 (1): 1-15.View ArticlePubMed
- Halperin JM, Sharma V, Siever LJ, Schwartz ST, Matier K, Wornell G: Serotonergic function in aggressive and nonaggressive boys with attention deficit hyperactivity disorder. Am J Psychiat. 1994, 151: 243-248.View ArticlePubMed
- Pine DS, Coplan JD, Wasserman GA, Miller LS, Fried JE, Davies M: Neuroendocrine response to fenfluramine challenge in boys. Associations with aggressive behavior and adverse rearing. Arch Gen Psychiat. 1997, 54: 839-846.View ArticlePubMed
- Schulz KP, Newcorn JH, McKay KE, Himelstein J, Koda VH, Siever LJ: Relationship between central serotonergic function and aggression in prepubertal boys: effect of age and attention-deficit/hyperactivity disorder. Psychiatry Res. 2001, 101 (1): 1-10.View ArticlePubMed
- Kruesi MJP, Hibbs ED, Zahn TP, Keysor CC, Hamburger SD, Bartko JJ: A 2-year prospective follow-up study of children and adolescents with disruptive behavior disorders. Arch Gen Psychiat. 1992, 49: 429-435.View ArticlePubMed
- Clarke RA, Murphy DL, Constantino JN: Serotonin and externalizing behavior in young children. Psychiatry Res. 1999, 86 (1): 29-40.View ArticlePubMed
- van Goozen SHM, Matthys W, Cohen-Kettenis PT, Westenberg H, van Engeland H: Plasma monoamine metabolites and aggression: two studies of normal and oppositional defiant disorder children. Eur Neuropsychopharmacol. 1999, 9: 141-147.View ArticlePubMed
- Armenteros JL, Lewis JE: Citalopram treatment for impulsive aggression in children and adolescents: an open pilot study. J Am Acad Child Adolesc Psychiatry. 2002, 41 (5): 522-529.View ArticlePubMed
- Stadler C, Zepf FD, Demisch L, Schmitt M, Landgraf M, Poustka F: Influence of Rapid Tryptophan Depletion on Laboratory-Provoked Aggression in Children with ADHD. Neuropsychobiology. 2007, 56 (2-3): 104-110.View ArticlePubMed
- Flory JD, Newcorn JH, Miller C, Harty S, Halperin JM: Serotonergic function in children with attention – deficit hyperactivity disorder Relationship to later antisocial personality disorder. Br J Psychiatry. 2007, 190: 410-414.View ArticlePubMed
- Evenden JL: Varieties of impulsivity. Psychopharmacology (Berl). 1999, 146 (4): 348-361.View Article
- Robinson ESJ, Eagle DM, Mar AC, Bari A, Banerjee G, Jiang X: Similar Effects of the Selective Noradrenaline Reuptake Inhibitor Atomoxetine on Three Distinct Forms of Impulsivity in the Rat. Neuropsychopharmacology. 2008, 33 (5): 1028-1037.View ArticlePubMed
- Posner MI, Rothbart MK: Attention, self-regulation and consciousness. Philos Trans R Soc Lond B Biol Sci. 1998, 353 (1377): 1915-1927.PubMed CentralView ArticlePubMed
- Sonuga-Barke EJS, Dalen L, Remington B: Do Executive Deficits and Delay Aversion Make Independent Contributions to Preschool Attention-Deficit/Hyperactivity Disorder Symptoms?. J Am Acad Child Adolesc Psychiatry. 2003, 42 (11): 1335-1342.View ArticlePubMed
- Tseng MH, Henderson A, Chow SMK, Yao G: Relationship between motor proficiency, attention, impulse, and activity in children with ADHD. Dev Med Child Neurol. 2004, 46: 381-388.View ArticlePubMed
- Hervey AS, Epstein JN, Curry JF: Neuropsychology of Adults With Attention-Deficit/Hyperactivity Disorder: A Meta-Analytic Review. Neuropsychology. 2004, 18: 485-503.View ArticlePubMed
- Oades RD: The Roles of Norepinephrine and Serotonin in ADHD. Attention Deficit Hyperactivity Disorder: From Genes to Animal Models to Patients. Edited by: Gozal D, Molfese DL. 2005, Tootawa, N.Y.: Humana Press, 97-130.View Article
- Oades RD, Slusarek M, Velling S, Bondy B: Serotonin platelet-transporter measures in childhood attention-deficit/hyperactivity disorder (ADHD): clinical versus experimental measures of impulsivity. World J Biol Psychiatry. 2002, 3: 96-100.View ArticlePubMed
- Unis AS, Cook EH, Vincent JG, Gjerde DK, Perry BD, Mason C: Platelet serotonin measures in adolescents with conduct disorder. Biol Psychiat. 1997, 42: 553-559.View ArticlePubMed
- Rubia K, Smith AB, Taylor EA: Performance of Children with Attention Deficit Hyperactivity Disorder (ADHD) on a Test Battery of Impulsiveness. Child Neuropsychol. 2007, 13: 276-304.View ArticlePubMed
- Rubia K, Taylor EA, Smith AB, Oksannen H, Overmeyer S, Newman S: Neuropsychological analyses of impulsiveness in childhood hyperactivity. Br J Psychiatry. 2001, 179: 138-143.View ArticlePubMed
- Rubia K, Lee F, Cleare AJ, Tunstall N, Fu CHY, Brammer MJ: Tryptophan depletion reduces right inferior prefrontal activation during no-go trials in fast, event-related fMRI. Psychopharmacol. 2004, 179: 791-803.View Article
- Oades RD: Dopamine-serotonin interactions in attention-deficit hyperactivity disorder (ADHD). Prog Brain Res. Edited by: Di Giovanni G, Di Matteo V, Esposito E. 2008, 172: 543-565.View ArticlePubMed
- Brookes K-J, Xu X, Chen W, Zhou K, Neale BM, Lowe N: Analysis of 51 candidate genes in DSM-IV combined subtype attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes. Mol Psychiat. 2006, 11: 934-953.View Article
- Chen W, Taylor EA: Parental Account of Children's Symptoms (PACS), ADHD phenotypes and its application to molecular genetic studies. Attention-Deficit/Hyperactivity Disorder and the Hyperkinetic Syndrome: Current Ideas and Ways Forward. Edited by: Oades RD. 2006, Hauppauge, NY 11788: Nova Science Publishing Inc, 3-20.
- Christiansen H, Chen W, Oades RD, Asherson P, Taylor EA, Lasky-Su J: Co-transmission of Conduct Problems with Attention Deficit Hyperactivity Disorder: familial evidence for a distinct disorder. J Neural Transm. 2008, 115: 163-175.View ArticlePubMed
- Taylor EA, Sandberg S, Thorley G, Giles S: The epidemiology of childhood hyperactivity. 1991, Oxford, UK: Oxford University Press
- Conners CK: Manual for Conners' rating scales, Revised edn. 2002, N.Tonoawanda, NY: Multi-Health Systems Inc
- Goodman R: The strengths and difficulties questionnaire: a research note. J Child Psychol Psychiat. 1997, 38: 581-586.View ArticlePubMed
- Woerner W, Becker A, Rothenberger A: Normative data and scale properties of the German parent SDQ. Eur Child Adolesc Psychiatry. 2004, 13 Suppl 2: II3-II10.PubMed
- Oades RD: Function and dysfunction of monoamine interactions in children and adolescents with AD/HD. EXS. Edited by: Levin ED. 2006, Basel: Birkhäuser Verlag, 98: 207-244.
- Friedel S, Heiser P, Dempfle A, Konrad K, Hebebrand J: Molecular Genetic Aspects of Attention-Deficit/Hyperactivity Disorder. Attention-Deficit/Hyperactivity Disorder and the Hyperkinetic Syndrome: Current Ideas and Ways Forward. Edited by: Oades RD. 2006, Hauppauge, New York: Nova Science Publishers, Inc, 35-59.
- Freeman B, Smith N, Curtis C, Huckett L, Mill J, Craig I: DNA from buccal swabs recruited by mail: evaluation of storage effects on long term stability and suitability for multiplex polymerase chain reaction genotyping. Behav Genet. 2003, 33: 67-72.View ArticlePubMed
- Brookes K-J, Xu X, Chen CK, Huang YS, Wu YY, Asherson P: No evidence for the association of DRD4 with ADHD in a Taiwanese population within-family study. BMC Med Genet. 2005, 6: 31-PubMed CentralView ArticlePubMed
- Xu X, Mill J, Chen CK, Brookes K-J, Taylor EA, Asherson P: Family-based association study of serotonin transporter gene polymorphisms in attention deficit hyperactivity disorder: no evidence for association in UK and Taiwanese samples. Am J Med Genet B Neuropsychiatr Genet. 2005, 139B (1): 11-13.View ArticlePubMed
- Asherson P, Brookes K-J, Franke B, Chen W, Gill M, Ebstein RP: Confirmation that a specific haplotype of the dopamine transporter gene is associated with combined type ADHD. Am J Psychiat. 2007, 164: 674-677.View ArticlePubMed
- Peralta V, Cuesta MJ: Dimensional structure of psychotic symptoms: an item-level analysis of SAPS and SANS symptoms in psychotic disorders. Schizophr Res. 1999, 38: 13-26.View ArticlePubMed
- Muris P, Meesters C: The validity of attention deficit hyperactivity disorder and hyperkinetic disorder symptom domains in nonclinical Dutch children. J Clin Child Adolesc Psychol. 2003, 32: 460-466.View ArticlePubMed
- Lange C, DeMeo D, Silverman EK, Weiss ST, Laird NM: PBAT: tools for family-based association studies. Am J Hum Genet. 2004, 74: 367-369.PubMed CentralView ArticlePubMed
- Lange C, van Steen K, Andrew T, Lyon H, DeMeo DL, Raby B: A family-based association test for repeatedly measured quantitative traits adjusting for unknown environmental and/or polygenic effects. Stat Appl Genet Mol Biol. 2004, 3: 17-
- Lasky-Su J, Lyon HN, Emilsson V, Heid IM, Molony C, Raby BA: On the replication of genetic associations: timing can be everything!. Am J Hum Genet. 2008, 82 (4): 849-858.PubMed CentralView ArticlePubMed
- Lasky-Su J, Banaschewski T, Buitelaar JK, Franke B, Brookes K-J, Sonuga-Barke EJS: Partial replication of a DRD4 association in ADHD individuals using a statistically derived quantitative trait for ADHD in a family-based association test. Biol Psychiat. 2007, 62: 985-990.View ArticlePubMed
- Benjamini Y, Hochberg Y: Controlling the false discovery rate: A practical and powerful approch to multiple testing. J Roy Stat Soc. 1995, 57: 289-300.
- Psychogiou L, Thompson M, Christiansen H, Chen W, Buitelaar JK, Banaschewski T: Parental expressed emotion and comorbid disorders in children with ADHD: Effects by parent gender and cultural setting. J Abnorm Child Psychol. 2008,
- Mezey E, Kiss JZ, Skirboll LR, Goldstein M, Axelrod J: Increase of corticotropin-releasing factor staining in rat paraventricular nucleus neurones by depletion of hypothalamic adrenaline. Nature. 1984, 310: 140-141.View ArticlePubMed
- Sergeant JA, Oosterlaan J, Meere van der JJ: Information processing in attention-deficit/hyperactivity disorder. Handbook of disruptive behavior disorders. Edited by: Quay HC, Hogan AE. 1999, New York: Plenum Press, 75-104.View Article
- Klinteberg BA, Magnusson D: Aggressiveness and hyperactive behavior as related to adrenaline excretion. Special issue; personality and aggression. Eur J Personal. 1989, 3: 81-93.View Article
- Hanna GL, Ornitz EM, Hariharan M: Urinary epinephrine excretion during intelligence testing in attention-deficit hyperactivity disorder and normal boys. Biol Psychiat. 1996, 40: 553-555.View ArticlePubMed
- Pliszka SR, Maas JW, Javors MA, Rogeness GA, Baker J: Urinary catecholamines in attention-deficit hyperactivity disorder with and without comorbid anxiety. J Am Acad Child Adolesc Psychiatry. 1994, 33 (8): 1165-1173.View ArticlePubMed
- Ionescu G, Kiehl R, Eckert S, Zimmerman T: Abnormal plasma catecholamines in hyperkinetic children. Biol Psychiat. 1990, 28: 547-551.View ArticlePubMed
- Oades RD, Daniels R, Rascher W: Plasma neuropeptide Y levels, monoamine metabolism, electrolyte excretion, and drinking behavior in children with attention-deficit hyperactivity-disorder (ADHD). Psychiatry Res. 1998, 80 (2): 177-186.View ArticlePubMed
- Konrad K: Catecholamines and attentional function in children with ADHD. Attention-Deficit/Hyperactivity Disorder and the Hyperkinetic Syndrome: Current Ideas and Ways Forward. Edited by: Oades RD. 2006, Hauppauge, New York: Nova Science Publishers Inc, 155-169.
- Tennes K, Kreye M, Avitable N, Wells R: Behavioral correlates of excreted catecholamines and cortisol in second grade children. J Am Acad Child Psychiatry. 1986, 25 (6): 764-770.View ArticlePubMed
- Elia J, Borcherding BG, Potter WZ, Mefford IN, Rapoport JL, Keysor CS: Stimulant drug treatment of hyperactivity: biochemical correlates. Clin Pharmacol Ther. 1990, 48: 57-66.View ArticlePubMed
- Lawrence CA, Barry RJ, Clarke AR, Johnstone SJ, McCarthy R, Selikowitz M: Methylphenidate effects in attention deficit/hyperactivity disorder: electrodermal and ERP measures during a continuous performance task. Psychopharmacology (Berl). 2005, 183 (1): 81-91.View Article
- Nosjean A, Hamon M, Darmon M: 5-HT2A receptors are expressed by catecholaminergic neurons in the rat nucleus tractus solitarii. Neuroreport. 2002, 13 (17): 2365-2369.View ArticlePubMed
- Viggiano D, Ruocco LA, Sadile AG: Dopamine phenotype and behaviour in animal models: its relation to attention deficit hyperactivity disorder. Neurosci Biobehav Rev. 2003, 27: 623-637.View ArticlePubMed
- Millan MJ, Newman-Tancredi A, Audinot V, Cussac D, Lejeune F, Nicolas J-P: Agonist and antagonist actions of yohimbine as compared to fluparoxan at alpha-2 adrenergic receptors (AR)s, serotonin (5-HT)1A. 5-HT1B, 5-HT1D and dopamine D2 and D3 receptors. Significance for the modulation of frontocortical monoaminergic trasnmsission and depressive states. Synapse. 2000, 35: 79-95.View ArticlePubMed
- Martin P, Waters N, Schmidt CJ, Carlsson A, Carlsson ML: Rodent data and general hypothesis: antipsychotic action exerted through 5-HT2A receptor antagonism is dependent on increased serotonergic tone. J Neural Transm. 1998, 105: 365-396.View ArticlePubMed
- Oades RD: Dopamine may be 'hyper' with respect to noradrenaline metabolism, but 'hypo' with respect to serotonin metabolism in children with ADHD. Behav Brain Res. 2002, 130: 97-101.View ArticlePubMed
- Volkow ND, Wang G-J, Newcorn JH, Telang FW, Solanto MV, Fowler JS: Depressed Dopamine Activity in Caudate and Preliminary Evidence of Limbic Involvement in Adults With Attention-Deficit/Hyperactivity Disorder. Arch Gen Psychiat. 2007, 64: 932-940.View ArticlePubMed
- Ribases M, Ramos-Quiroga JA, Hervas A, Bosch R, Bielsa A, Gastaminza X: Exploration of 19 serotoninergic candidate genes in adults and children with attention-deficit/hyperactivity disorder identifies association for 5HT2A, DDC and MAOB. Mol Psychiatry. 2007
- 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.View ArticlePubMed
- Guimaraes APM, Zeni C, Polanczyk GV, Genro JP, Roman T, Rohde LA: Serotonin Genes and Attention Deficit/Hyperactivity Disorder in a Brazilian Sample: Preferential Transmission of the HTR2A 452His Allele to Affected Boys. Am J Med Genet B Neuropsychiatr Genet. 2007, 144B (1): 69-73.View ArticlePubMed
- Heiser P, Dempfle A, Friedel S, Konrad K, Hinney A, Kiefl H: Family-based association study of serotonergic candidate genes and attention-deficit/hyperactivity disorder in a German sample. J Neural Transm. 2007, 114: 513-521.View ArticlePubMed
- Barone P, Jordan D, Atger F, Kopp N, Fillion G: Quantitative autoradiography of 5-HT1D and 5-HT1E binding sites labelled by [3H]5-HT, in frontal cortex and the hippocampal region of the human brain. Brain Res. 1994, 638: 85-94.View ArticlePubMed
- Swerdlow NR: Serotonin, obsessive-compulsive disorder and the basal ganglia. Int Rev Psychiat. 1995, 7: 115-129.View Article
- Iyer RN, Bradberry CW: Serotonin-mediated increase in prefrontal cortex dopamine release: pharmacological characterization. J Pharmacol Exp Ther. 1996, 277: 40-47.PubMed
- Banerjee E, Sinha S, Chatterjee A, Gangopdhyay PK, Singh M, Nandogopal K: A family-based study of Indian subjects from Kolkata reveals allelic association of the serotonin transporter intron-2 (STin2) polymorphism and attention-deficit-hyperactivity disorder (ADHD). Am J Med Genet B Neuropsychiatr Genet. 2006, 141B (4): 361-366.View ArticlePubMed
- David SP, Murthy NV, Rabiner EA, Munafo MR, Johnstone EC, Jacob R: A Functional Genetic Variation of the Serotonin (5-HT) Transporter Affects 5-HT1A Receptor Binding in Humans. J Neurosci. 2005, 25: 2586-2590.PubMed CentralView ArticlePubMed
- Daws LC, Munn JL, Valdez MF, Frosto-Burke T, Hensler JG: Serotonin transporter function, but not expression, is dependent on brain-derived neurotrophic factor (BDNF): in vivo studies in BDNF-deficient mice. J Neurochem. 2007, 101: 641-651.View ArticlePubMed
- Ren-Patterson RF, Cochran LW, Holmes A, Sherrill S, Huang S-J, Tolliver T: Loss of brain-derived neurotrophic factor gene allele exacerbates brain monoamine deficiencies and increases stress abnormalities of serotonin transporter knockout mice. J Neurosci Res. 2005, 79: 756-771.View ArticlePubMed
- Lyons WE, Mamounas LA, Ricaurte GA, Coppola V, Reid SW, Bora SH: Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonin abnormalities. Proc Natl Acad Sci U S A. 1999, 96 (26): 15239-15244.PubMed CentralView ArticlePubMed
- Shaw P, Eckstrand K, Sharp W, Blumenthal J, Lerch JP, Greenstein D: Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation. Proc Natl Acad Sci U S A. 2007, 104 (49): 19649-19654.PubMed CentralView ArticlePubMed
- Schimmelmann BG, Friedel S, Dempfle A, Warnke A, Lesch KP, Walitza S: No evidence for preferential transmission of common valine allele of the Val66Met polymorphism of the brain-derived neurotrophic factor gene (BDNF) in ADHD. J Neural Transm. 2007, 114: 523-526.View ArticlePubMed
- Simeone A: Genetic control of dopaminergic differentiation. Trends Neurosci. 2005, 28: 62-65.View ArticlePubMed
- Smits SM, Ponnio T, Conneely OM, Burbach JPH, Smidt MP: Involvement of Nurr1 in specifying the neurotransmitter identity of ventral midbrain dopaminergic neurons. Eur J Neurosci. 2003, 18: 1731-1738.View ArticlePubMed
- Brookes K-J, Chen W, Xu X, Taylor EA, Asherson P: Association of Fatty Acid Desaturase Genes with Attention-Deficit/Hyperactivity Disorder. Biol Psychiat. 2006, 60: 1053-1061.View ArticlePubMed
- McAlonan GM, Cheung V, Cheung C, Chua SE, Murphy DGM, Suckling J: Mapping brain structure in attention deficit-hyperactivity disorder: A voxel-based MRI study of regional grey and white matter volume. Psychiatry Res. 2007, 154 (2): 171-180.View ArticlePubMed
- Russell VA, Oades RD, Tannock R, Auerbach J, Killeen PR, Johansen EB: Response variability in attention-deficit/hyperactivity disorder: a neuronal and glial energetics hypothesis. Behav Brain Funct. 2006, 2: 30-PubMed CentralView ArticlePubMed
- Nigg JT: Temperament and developmental psychopathology. J Child Psychol Psychiat. 2006, 47: 395-422.View ArticlePubMed
- Sonuga-Barke EJS, Sergeant JA, Nigg JT, Willcutt EG: Executive Dysfunction and Delay Aversion in ADHD: Nosologic and Diagnostic Implications. Child Adolesc Psychiatr Clin N Am. 2008, 17 (2): 367-384.View ArticlePubMed
- Coghill DR, Nigg JT, Rothenberger A, Sonuga-Barke EJS, Tannock R: Whither causal models in the neuroscience of ADHD?. Dev Sci. 2005, 8: 105-114.View ArticlePubMed
- Li J, Wang Y, Zhou R, Wang B, Zhang H, Yang L: Association of attention-deficit/hyperactivity disorder with serotonin 4 receptor gene polymorphisms in Han Chinese subjects. Neurosci Lett. 2006, 401: 6-9.View ArticlePubMed
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.