Neuropsychiatric Disorders and Pediatric Psychiatry | Published:

Neurobiology of Attention Deficit/Hyperactivity Disorder

Pediatric Research volume 69, pages 69R76R (2011) | Download Citation

Abstract

Attention deficit/hyperactivity disorder (ADHD), a prevalent neurodevelopmental disorder, has been associated with various structural and functional CNS abnormalities but findings about neurobiological mechanisms linking genes to brain phenotypes are just beginning to emerge. Despite the high heritability of the disorder and its main symptom dimensions, common individual genetic variants are likely to account for a small proportion of the phenotype's variance. Recent findings have drawn attention to the involvement of rare genetic variants in the pathophysiology of ADHD, some being shared with other neurodevelopmental disorders. Traditionally, neurobiological research on ADHD has focused on catecholaminergic pathways, the main target of pharmacological treatments. However, more distal and basic neuronal processes in relation with cell architecture and function might also play a role, possibly accounting for the coexistence of both diffuse and specific alterations of brain structure and activation patterns. This article aims to provide an overview of recent findings in the rapidly evolving field of ADHD neurobiology with a focus on novel strategies regarding pathophysiological analyses.

Main

Attention deficit/hyperactivity disorder (ADHD) is a highly prevalent neurodevelopmental condition, characterized by symptoms of inattention and impulsivity/hyperactivity to a degree that is inconsistent with developmental level. ADHD symptoms persist into adulthood in a majority of patients (1) and are associated with functional impairment and increased risk of depression, substance abuse, and antisocial behavior. Clinical presentation is heterogeneous with three subtypes identified according to the most prevalent symptoms (primarily inattentive, primarily hyperactive/impulsive, and combined) and with a relative context-dependence of symptom expression although the condition has a chronic course. ADHD is associated with cognitive impairments in inhibitory control and executive function but neuropsychological profiles of subjects with ADHD, despite significantly differing from controls in group comparisons, also show considerable inter- and intraindividual variability. This clinical heterogeneity is likely to reflect the multiplicity of causal pathways leading to the development of the disorder and of a series of moderating and mediating factors involved in symptom expression. Treatment of ADHD involves pharmacologic and nonpharmacologic strategies. Catecholaminergic systems are the main targets of stimulant and nonstimulant medications used to alleviate ADHD symptoms. Convergent studies support that genetic factors are involved in the liability of ADHD symptoms (OMIM 143465). The last decade's research has pointed out various CNS abnormalities in ADHD patients, confirming the neurobiological basis of the disorder. However, there is still a lack of insight into the mechanisms linking genotypes, neural processes, and cognitive/behavioral symptoms. Recent findings point out that other neurodevelopmental disorders like autism, schizophrenia, and epilepsy share genetic variants with ADHD (2). These developments should encourage the search for relevant intermediate clinical or cognitive phenotypes that are more likely related to the underlying neurobiological mechanisms involved in ADHD symptoms than the categorical diagnosis itself. In particular, traits shared by different neuropsychiatric conditions warrant further attention (3). As neurobiology of ADHD is a rapidly evolving domain of research, this article aims to provide an update of recent findings in genetics, molecular biology, and neuroimaging and a review of the main neurocognitive and biological models of ADHD.

Genetic and Environmental Contributions to ADHD

Family studies have shown that relatives of ADHD patients are at increased risk for the disorder (4). As the familial clustering of ADHD symptoms may be accounted for by both genetic and environmental sources of transmission, twin studies were used to estimate the relative contributions of genes and environment to the phenotypic variance of ADHD in the population. Twin studies provide an estimate of heritability by comparing concordance rates of ADHD diagnosis or traits in monozygotic and dizygotic twins. They have consistently shown that genetic factors explain a large proportion of ADHD variance with pooled data from 20 twin studies providing a mean heritability estimate of 76% in children and adolescents (5). Heritability estimates in adults are lower, 30% (6), a possible consequence of the broader environmental range in adulthood. Adoption studies are another method to test whether genetics contribute to the familial transmission of a disorder. ADHD rates have been found to be greater in biological relatives of ADHD children than in the adoptive families (7). The results of a recent meta-analysis of twin and adoption studies indicated that genetic factors accounted for 71 and 73% of the variance of inattentive and hyperactive symptoms, respectively. Nonadditive genetic effects (e.g. interactions between alleles across and within loci) showed stronger influences on inattention compared with hyperactivity (15 versus 2%), suggesting that specific etiological factors influence each symptom dimension (8).

Several environmental factors have been identified as putative risk factors for ADHD. In utero events such as maternal stress during pregnancy (9), prenatal exposure to tobacco, alcohol and other drugs/environmental toxins (10,11), pregnancy/birth complications (11), as well as intrauterine growth retardation and low birth weight/prematurity (12,13) have been associated with ADHD. Early postnatal environmental influences related to ADHD or core ADHD symptoms include neonatal anoxia and seizures, brain injury (11), exposure to lead (14), and polychlorinated biphenyls (15). Psychosocial adversity and high levels of family conflict were also associated with ADHD (16,17). Recent findings have related ADHD to more specific familial issues such as inconsistent parenting after controlling for parental ADHD (17), marital, and children's negative appraisal of family conflict (18). Children having suffered early institutional deprivation for a duration of 6 mo or above show high levels of ADHD-like symptoms, but in this population, inattention/hyperactivity was also strongly linked to attachment disorders (19).

Recent studies have taken into account genetic factors that may contribute to adverse prenatal and later life circumstances (i.e. smoking during pregnancy or stress during pregnancy might be more frequent in mothers with ADHD). A comparison of siblings differing for their exposure to prenatal nicotine showed that the association of smoking during pregnancy on subsequent ADHD in the child was reduced but remained significant by controlling for genetic and environmental confounds (20). A study of pregnant mothers related or unrelated to their child as a result of in vitro fertilization showed that prenatal stress was linked to ADHD only when mothers were related to their child, suggesting that the association may be accounted for by inherited factors (21). A recent twin study focused on ADHD-related conditions (antisocial behavior and substance use disorders in young adults), has provided an important insight into mechanisms of gene-environment influence on externalizing disorders by showing that genetic factors contribute more to the development of behavioral symptoms in a context of high environmental adversity (22), in accordance with a diathesis-stress model. These examples illustrate the importance of genetically informed study designs to further disentangle environmental and genetic contributions to ADHD.

Neuropsychological Endophenotypes

The clinical and etiological complexity of ADHD as well as the small proportion of variance in ADHD symptoms explained by candidate genes has encouraged the search for endophenotypes, heritable traits thought to be more proximal to the genetic etiology of the disorder. Cognitive deficits have been consistently identified in ADHD and are potential markers for the neural dysfunctions of the disorder. Compared with controls, subjects with ADHD show deficits in executive functions, especially in tasks involving executive control (response inhibition, working memory) (23), have variable response speed (24), show delay aversion (25), and variability in motor timing (26). Cognitive deficits in ADHD have shown to persist over time, even in subjects showing remission of behavioral symptoms (27). Unaffected co-twins of ADHD performed worse than controls in a majority of neuropsychological tasks. Results showed differences in response variability, inhibitory control, and processing speed despite controlling for subclinical ADHD, suggesting that these variables meet criteria for neuropsychological endophenotypes (28). Using neuropsychological tests having previously showed significant heritability in a genome wide linkage analysis of ADHD, Rommelse et al. (29) found two significant genome-wide linkage signals, one for Motor Timing task on chromosome 2q21.1 (LOD score: 3.944) and one for Digit Span test on 13q12.11 (LOD score: 3.959). The examination of neuropsychological endophenotypes is a promising method to identify more homogenous subgroups of patients, increasing the possibility to detect small genetic effects and specific neurobiological mechanisms involved in the etiology of ADHD.

Molecular Genetics of ADHD

Whole genome linkage studies.

Linkage studies in families with multiple affected individuals screen the genome with genetic markers. Co-segregation of markers with the disorder indicates that a particular region is likely to contain risk genes for ADHD. The LOD is an estimate of the strength of linkage and is considered significant above 3 and suggestive for linkage between 2 and 3. In the whole genome linkage studies published to date, few regions were identified in more than one study but no locus was identified in all of them. A meta-analysis of seven linkage studies identified a genome wide significant finding in the chromosome region from 16q23.1 to the q terminal (30) but no gene within this region had been previously identified in the candidate gene approaches. As linkage studies are predominantly suited to identify genetic factors of strong effect (>10% of the variance), this approach may not be able to capture small effects of specific genes.

Candidate gene association studies.

Candidate gene association studies select genes on the basis of their possible implication in the pathophysiology of the disorder. Case-control association studies compare frequencies of genetic variants in controls and affected probands, whereas familial association studies search of an excess of transmission from parents to offspring.

Most of medications used for the treatment for ADHD increase the availability of catecholamines in the synaptic cleft; therefore genetic association studies examining putative risk genes have mainly focused on genes of the dopamine (DA) and norepinephrine (NE) neurotransmitter systems. In general, genetic markers encompassing the candidate gene that are screened for association, are usually of two types: single nucleotide polymorphisms (SNPs), one nucleotide position with a bi-allelic variation, and variable nucleotide tandem repeats, a repeated sequence of nucleotides with multiallelic variation. Table 1 summarizes main findings of association studies with positive meta-analyses (5,3136). The most consistent evidence for a genetic association to the ADHD phenotype has been shown for markers in DA receptor D4 (DRD4), DA receptor D5 (DRD5), DA transporter (SLC6A3/DAT1), serotonin receptor 1B (HTR1B), serotonin transporter (SLC6A4/5HTT), and synaptosomal-associated protein 25 (SNAP-25) genes. The catechol-O-methyltransferase val/val genotype, although not significantly associated to the global ADHD phenotype, has been linked to conduct disorder symptoms in patients with ADHD in several independent samples (37). This finding suggests that the examination of refined phenotypes is a fruitful strategy to identify vulnerability genes of small effect in candidate gene studies of a complex condition such as ADHD.

Table 1: Main findings of genetic association studies

Genome-wide association studies.

Genome-wide association study (GWAS) studies, by testing >100,000 SNPs distributed across the genome for association with a disorder, offer a hypothesis-free approach to identify genetic variants in complex diseases. These studies have been successful for a variety of neurodevelopmental and neurodegenerative diseases such as autism, schizophrenia, and Alzheimer. However, most of associated SNPs have a small effect size and the proportion of heritability explained is at best modest (38). GWAS studies have only recently been used in ADHD and none of these first studies showed robust SNP associations in the primary analyses (3941). This suggests that a variety of alleles may be associated with ADHD but each of them with a small effect size requiring further association studies with sufficient statistical power through increased sample size or identification of more homogenous intermediate phenotypes. Although the findings of the first ADHD-GWAS studies were not significant at the genome-wide level, analysis of high ranking SNPs yielded evidence for genes involved in basic neurobiological processes such as cell architecture and communication (42). If confirmed, these findings may extend future research from neurotransmitter systems to brain development, maturation, neuronal migration, and plasticity.

Search for copy number variants.

Strong evidence suggests that rare mutations of large effect may be responsible for a substantial proportion of the heritability of complex diseases (43). Recent studies scanned the genomes of United States, British, and Icelandic patients with ADHD for deleted or duplicated regions, known as copy number variants (2,44). It may be expected that a copy number variant on one allele can directly affect the dosage of contained genes by minus 50% (deletion) or plus 50% (duplication). Such a dosage effect can be hypothesized as causal in human diseases. Importantly, both repertoires recently identified in ADHD are significantly enriched for genes known to be important for psychological and neurological functions, including learning, behavior, synaptic transmission, and CNS development. Furthermore, they overlap with repertoires previously identified in autism (45), schizophrenia (46), and epilepsy (47).

Gene-environment interactions.

Gene-environment interactions (GxE) operate in two ways: 1) a genetic factor may enhance or diminish the impact of a particular environment and 2) an environmental factor may activate a genetic effect. GxE may account for a significant proportion of the clinical heterogeneity of ADHD by increasing phenotypic variance beyond main effects of genes and environment (48). GxE has been reported between various genetic variants and environmental factors such as maternal smoking and maternal alcohol use during pregnancy, LBW, season of birth, and psychosocial adversity (49). Some of these GxE findings failed to be replicated but globally, results appear to be more consistent for psychosocial factors compared with prenatal/early environmental factors (49) and compatible with a diathesis-stress model according to which genetic factors have more impact on ADHD in at-risk environments (50).

Pharmacological Treatments and Neurobiology of ADHD

Pharmacological treatments of ADHD all optimize catecholamine signaling in the prefrontal cortex. Mechanisms of action of stimulants [methylphenidate (MPH) and amphetamines] include blockade of the DA SLC6A3/DAT and NE transporters SLC6A2/NET, inhibition of monoamine oxidase and enhanced release of catecholamines (51). Stimulants mainly act on DA D1 receptors in the prefrontal cortex and on D2 receptors in the striatum. Atomoxetine, a nonstimulant drug used in ADHD, blocks the NE transporter and increases levels of both NA and DA in the prefrontal cortex. Guanfacine, another nonstimulant drug acts at postsynaptic alpha-2A receptors to enhance NE transmission. Therapeutic effects of DA stimulation is thought to involve a weakening of inappropriate network connections (i.e. producing a decrease of “noise”) whereas enhanced NE transmission may function by strengthening appropriate connections (i.e. producing an increase of “signal”) (52). Current knowledge about the neurobiological mechanisms of pharmacological treatments of ADHD suggest that despite some overlap, medications show differential effects with stimulants having broad effects on attention deficits and motor symptoms and nonstimulants likely to have a more specific action in the prefrontal cortex. Recent developments in therapeutic research have extended the range of medications for the treatment of ADHD. Further research is likely to improve targeting treatments to individual symptom patterns, developmental level, and possibly to brain maturation status.

Improving adjustment of treatments to individual needs is also the aim of pharmacogenetic approaches. Pharmacogenetic studies search for genetic factors involved in the pharmacodynamics and pharmacokinetics of drugs that could explain the interindividual variability of treatment response or tolerance. A meta-analysis of SLC6A3/DAT1 pharmacogenetic studies on a total of 475 subjects showed a significant association between the 10 and 10 genotype of the 40-bp variable nucleotide tandem repeats and low rates of MPH response (53). Recently, a variant of the carboxylesterase 1, the principal enzyme that metabolizes MPH, was found associated with dosages needed to obtain treatment response; heterozygote patients (Gly/Glu) needed lower doses for optimal treatment effects compared with homozygotes (Gly/Gly) (54). To date, only one GWAS was performed on MPH treatment response but failed to identify markers meeting criteria for statistical significance for GWAS (55). Two studies screened the pharmacogenetic effect of on cytochrome P450 2D6 (CYP2D6) and SLC6A2/NET1 genes. The first showed that specific alleles of the CYP2D6 gene involved in rapid or poor metabolism were associated with a lower or a greater reduction in ADHD symptoms, respectively (56). The second study on two cohorts of patients, identified polymorphisms in the SLC6A2/NET1 gene in the clinical response of atomoxetine in ADHD (57). Coupled analyses of clinical response to pharmacological interventions, pharmacogenetics, and brain functioning imaging, as proposed by Szobot et al. (58) are likely to further improve knowledge about ADHD and its treatment.

Brain Phenotypes in ADHD

Insights from neuroimaging.

A variety of brain subregions including frontal and parietal cortexes, basal ganglia, cerebellum, hippocampus, and corpus callosum were found impacted in ADHD (59). These regions have been involved in the functional networks related to ADHD (Fig. 1). A detailed review of these networks indicates that diffuse and more specific alterations in brain structures and neural networks are possibly combined in ADHD and lead to organized brain phenotypes (60). For example, a study of functional MRI in children and adolescents with ADHD showed decreased connectivity in a fronto-striato-parieto-cerebellar network. This connectivity was normalized by MPH except in the parieto-cerebrellar functional circuit (61). New techniques such as diffusion tensor imaging using the direction of diffusion of water molecules to infer the orientation of white matter tracts in the brain have shown preliminary evidence for dysfunctions in anatomical connections in ADHD (62).

Figure 1
Figure 1

Schematic representation of functional circuits involved in the pathophysiology of ADHD. Here are summarized the attentional network (green), the fronto-striatal network (yellow), the executive function network (black), the fronto-cerebellar network (red), and the reward network (blue).

Over the past 2 decades, MRI allowed to study developmental trajectories of brain morphometry in patients with ADHD compared with controls. These longitudinal studies have shown a developmental delay of cortical thickness in ADHD, with greatest differences between ADHD and controls in maturation of the middle prefrontal cortex. Interestingly, normalization of volumes in different brain regions such as the parietal cortex and the hippocampus parallel clinical improvement of symptoms, whereas progressive volume loss of cerebellar regions and hippocampus were associated with persistent symptoms (59).

Imaging studies are also beginning to study familial patterns of brain structure and function. Brain endophenotypes refer to brain characteristics shared by ADHD patients and their siblings and likely to be involved in the liability to the disorder. Activation pattern of the ventral prefrontal cortex and reduced striatal activity have been identified as possible brain endophenotype candidates (63,64).

Neurocognitive models of ADHD.

The dual pathway model of ADHD (25,65) links inattention and deficits in executive functions to impairments in prefrontal-striatal circuits whereas hyperactivity may be consecutive to dysfunctions of reward response and motivation, related to a frontal-limbic system. Multiple pathways to ADHD symptoms are also pointed out in another model suggesting that a poor adjustment of behavior to environmental cues may arise from deficient signaling of the prefrontal cortex by subcortical and posterior systems (i.e. a failure to detect discrepancies between current and expected context because of a failure in bottom-up mechanisms) or from an intact signaling but inefficient top-down control (66,67).

From genes to brain structure and function.

Striatal activation patterns have been linked to DAT1 genotype through higher levels of DAT expression in carriers of the 10-R allele (64). Gene effects have also been shown on brain structure with DRD4 and DAT1 genotypes influencing the volume of the prefrontal cortex and the volume of the caudate nucleus, respectively (68). Neuroimaging methods may not only contribute to further document gene effects on brain function and structure but also provide insight into environmental or GxE effects in the near future (69).

Recent genetic findings suggest that a variety of genes could have, via their rare variants, a similar impact on protein complexes. Modifications of proteins in neuronal structures such as the dendritic spine could account for an intermediate phenotype (i.e. changes in dendritic spine morphology) leading to an abnormal synaptic transmission. Such molecular and subcellular phenotypes can be common to a variety of distinct rare variants (Fig. 2). A key issue for future research is to understand how a diversity of neuropsychiatric phenotypes can be generated by overlapping genotypes.

Figure 2
Figure 2

A same intermediate phenotype can be generated by variants identified in many genes. The figure illustrates how a variety of genes could have a similar impact on protein complexes neuronal structures such as the dendritic spine. Similar changes in dendritic spine morphology could constitute an intermediate phenotype involved in abnormal synaptic transmission.

Novel strategies for pathophysiological analyses of ADHD.

Animal models are one of the most promising approaches to study molecular pathophysiology of ADHD. If models that may recapitulate the full phenotypic spectrum of a psychiatric disorder are currently out of reach, creation of phenotypic components is feasible (70). Table 2 illustrates the main animal models related to ADHD (7175).

Table 2: Principal animal models related to ADHD

New perspectives are expected from using top-down and bottom-up cognitive paradigms in experiments with primates. Such paradigms can be transposed to rodents allowing experimental analysis of the role of the prefrontal cortex in decision making using models attainable to genetic modifications (76). Such approaches can be instrumental in a near future to dissect molecular mechanisms involved in executive function networks and their defects in ADHD.

Another promising development relates to models mimicking human mutation and chromosomal rearrangements that have been recently generated for both autism spectrum disorders (ASDs) and schizophrenia. For ASDs, one of the neuroligin-3 mutations identified in patients with ASDS was introduced into mice. The mutant mice showed impaired social interactions but enhanced spatial learning abilities. Unexpectedly, these behavioral changes were accompanied by an increase in inhibitory synaptic transmission with no apparent effect on excitatory synapses. Chromosomal engineering was used by to generate a large duplication in chromosome 15q11-13 seen in ASDs (77). Mice with a paternal duplication display poor social interaction, behavioral inflexibility, abnormal ultrasonic vocalizations, and correlates of anxiety. Furthermore, abnormal serotonin neurotransmission was reported.

For schizophrenia, a mouse model mimicking disrupted-in-schizophrenia 1 (DISC1) translation was generated by Kvajo et al. (78). A balanced chromosomal translocation segregating with schizophrenia and affective disorders in a large Scottish family (79) implicated DISC1 as a susceptibility gene for major mental illness. Kvajo et al. (78) used a disease-oriented approach to generate mutant mice carrying a truncating lesion in the endogenous DISC1 orthologue that models the only well-defined DISC1 schizophrenia risk allele. This approach preserves the endogenous spatial and temporal expression pattern of the gene, thus preventing the induction of neomorphic phenotypic features. A comprehensive analysis of these mice implicates malfunction of neural circuits within the hippocampus, including synaptic plasticity changes, and medial prefrontal cortex contributing to the genetic risk conferred by the DISC1 gene.

Conclusion

ADHD being a prevalent and chronically impairing condition, a better knowledge of neurobiological mechanisms underlying symptoms and cognitive characteristics is likely to help in optimizing current treatment options and developing novel medications and behavioral/cognitive strategies. Major advances have been made in several domains of neurobiological research.

  • Improved insight into the interplay of genetic and environmental factors in the development of ADHD through genetically informed studies of risk factors.

  • Identification of valid neuropsychological endophenotypes contributing to the definition of more homogeneous subgroups of patients to improve the power of genetic studies and facilitate the access to the neural basis of cognitive impairments.

  • Molecular genetic studies have shown the implication of common genetic variants but their small effects on the variance of the ADHD phenotype calls for improvements in research strategies (reduce heterogeneity, increase sample sizes). Low-frequency variants have also been associated with ADHD and indicate that some genetic factors may be shared across a number of neurodevelopmental disorders.

  • The ongoing studies about mechanisms of action of pharmacological treatments and the development of pharmacogenetic studies will carry opportunities for individually and developmentally tailored treatments for ADHD symptoms.

  • Imaging studies have documented alterations in brain structures and functional networks, suggesting that ADHD involves both cortical dysfunction and abnormal connectivity. Several brain structures show maturational delays in anatomic brain developmental studies and brain development patterns that have been correlated with clinical and functional outcome. Similarly, recent models based on imaging and neuropsychological data have proposed links between main symptom dimensions of ADHD and impairments in specific brain circuits.

Our overview of recent trends in neurobiology of ADHD shows promising domains of research including further exploration of refined phenotypes, treatment response/outcome patterns, impact and mechanisms of action of environmental factors, and search for both common and rare genetic variants with samples and methods appropriate to the study of complex diseases. Development of new techniques of brain imaging such as DTI and functional MRI has provided preliminary evidence for functional and anatomical abnormalities in patients with ADHD.

Recent findings in molecular genetics indicate that, although it is important to improve knowledge about brain macrostructure, a move toward studies exploring basic mechanisms involved in brain microstructure is warranted. In this regard, identification of the functional changes contributing to ADHD (through changes in the protein's code or changes in gene transcription) is another crucial issue for future research.

References

  1. 1.

    1998 Attention-deficit/hyperactivity disorder: a life-span perspective. J Clin Psychiatry 59: 4–16

  2. 2.

    , , , , , , , , , , , , , 2010 Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis. Lancet 376: 1401–1408

  3. 3.

    2010 Neuropsychiatric connexions of ADHD genes. Lancet 376: 1367–1368

  4. 4.

    , 1994 Is attention deficit hyperactivity disorder familial?. Harv Rev Psychiatry 1: 271–287

  5. 5.

    , , , , , , 2005 Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry 57: 1313–1323

  6. 6.

    , , , , , , , , , , 2010 Genetic epidemiology of attention deficit hyperactivity disorder (ADHD index) in adults. PLoS One 5: e10621

  7. 7.

    , , , , 2000 Adoptive and biological families of children and adolescents with ADHD. J Am Acad Child Adolesc Psychiatry 39: 1432–1437

  8. 8.

    , 2010 Genetic and environmental influences on ADHD symptom dimensions of inattention and hyperactivity: a meta-analysis. J Abnorm Psychol 119: 1–17

  9. 9.

    , , 2007 Antenatal maternal stress and long-term effects on child neurodevelopment: how and why?. J Child Psychol Psychiatry 48: 245–261

  10. 10.

    , , , , , 2007 Exposure to hexachlorobenzene during pregnancy and children's social behavior at 4 years of age. Environ Health Perspect 115: 447–450

  11. 11.

    , , , , , , , , , 2007 Environmental influences that affect attention deficit/hyperactivity disorder: study of a genetic isolate. Eur Child Adolesc Psychiatry 16: 337–346

  12. 12.

    , , , , , , , , , , 2008 Very low birth weight and behavioral symptoms of attention deficit hyperactivity disorder in young adulthood: the Helsinki study of very-low-birth-weight adults. Am J Psychiatry 165: 1345–1353

  13. 13.

    , , , , 2002 Cognitive and behavioral outcomes of school-aged children who were born preterm: a meta-analysis. JAMA 288: 728–737

  14. 14.

    , , , , , , , 2010 Environmental exposure to lead, but not other neurotoxic metals, relates to core elements of ADHD in Romanian children: performance and questionnaire data. Environ Res 110: 476–483

  15. 15.

    , 2003 Prenatal exposure to polychlorinated biphenyls and attention at school age. J Pediatr 143: 780–788

  16. 16.

    , , , , , , , , 1995 Family-environment risk factors for attention-deficit hyperactivity disorder. A test of Rutter's indicators of adversity. Arch Gen Psychiatry 52: 464–470

  17. 17.

    , 2009 Parenting practices and attention-deficit/hyperactivity disorder: new findings suggest partial specificity of effects. J Am Acad Child Adolesc Psychiatry 48: 146–154

  18. 18.

    , , , , 2005 Family adversity in DSM-IV ADHD combined and inattentive subtypes and associated disruptive behavior problems. J Am Acad Child Adolesc Psychiatry 44: 690–698

  19. 19.

    , 2010 X. Conclusions: overview of findings from the era study, inferences, and research implications. Monogr Soc Res Child Dev 75: 212–229

  20. 20.

    , , , , , , 2008 Smoking during pregnancy and offspring externalizing problems: an exploration of genetic and environmental confounds. Dev Psychopathol 20: 139–164

  21. 21.

    , 2010 Estimating the relative contributions of maternal genetic, paternal genetic and intrauterine factors to offspring birth weight and head circumference. Early Hum Dev 86: 425–432

  22. 22.

    , , , , 2009 Environmental adversity and increasing genetic risk for externalizing disorders. Arch Gen Psychiatry 66: 640–648

  23. 23.

    1997 Behavioral inhibition, sustained attention, and executive functions: constructing a unifying theory of ADHD. Psychol Bull 121: 65–94

  24. 24.

    , , , , 2003 The top and the bottom of ADHD: a neuropsychological perspective. Neurosci Biobehav Rev 27: 583–592

  25. 25.

    2003 The dual pathway model of AD/HD: an elaboration of neuro-developmental characteristics. Neurosci Biobehav Rev 27: 593–604

  26. 26.

    , , , , , , 2008 Speed, variability, and timing of motor output in ADHD: which measures are useful for endophenotypic research?. Behav Genet 38: 121–132

  27. 27.

    , , , , , , , 2009 Are cognitive deficits in attention deficit/hyperactivity disorder related to the course of the disorder? A prospective controlled follow-up study of grown up boys with persistent and remitting course. Psychiatry Res 170: 177–182

  28. 28.

    , , , 2007 Testing for neuropsychological endophenotypes in siblings discordant for attention-deficit/hyperactivity disorder. Biol Psychiatry 62: 991–998

  29. 29.

    , , , , , , , , , , 2008 Neuropsychological endophenotype approach to genome-wide linkage analysis identifies susceptibility loci for ADHD on 2q21.1 and 13q12.11. Am J Hum Genet 83: 99–105

  30. 30.

    , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 2008 Meta-analysis of genome-wide linkage scans of attention deficit hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet 147B: 1392–1398

  31. 31.

    , , , 2006 Meta-analysis shows significant association between dopamine system genes and attention deficit hyperactivity disorder (ADHD). Hum Mol Genet 15: 2276–2284

  32. 32.

    , , 2009 Candidate gene studies of ADHD: a meta-analytic review. Hum Genet 126: 51–90

  33. 33.

    , , , , , , , 2006 Association between the 5HT1B receptor gene (HTR1B) and the inattentive subtype of ADHD. Biol Psychiatry 59: 460–467

  34. 34.

    , 2008 Genetics of attention deficit hyperactivity disorder. Child Adolesc Psychiatr Clin N Am 17: 261–284

  35. 35.

    , 2006 Meta-analysis of association between a catechol-O-methyltransferase gene polymorphism and attention deficit hyperactivity disorder. Behav Genet 36: 651–659

  36. 36.

    , , , , , 2007 A meta-analysis of association studies between the 10-repeat allele of a VNTR polymorphism in the 3′-UTR of dopamine transporter gene and attention deficit hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet 144B: 541–550

  37. 37.

    , , , , , , , , , , , 2008 A replicated molecular genetic basis for subtyping antisocial behavior in children with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 65: 203–210

  38. 38.

    , , , , , , , , , , , , , , , , , , , , , , , , , , 2009 Finding the missing heritability of complex diseases. Nature 461: 747–753

  39. 39.

    , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 2010 Case-control genome-wide association study of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 49: 906–920

  40. 40.

    , , , , , , , , , , , , , , , , , 2010 Family-based genome-wide association scan of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 898–905. e3

  41. 41.

    , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 2010 Meta-analysis of genome-wide association studies of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 49: 884–897

  42. 42.

    , , 2009 Genome-wide association studies in ADHD. Hum Genet 126: 13–50

  43. 43.

    , 2010 Genetic heterogeneity in human disease. Cell 141: 210–217

  44. 44.

    , , , , , , , , , , , , , , , , , , , , 2010 Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes. Mol Psychiatry 15: 637–646

  45. 45.

    , , 2009 Rare structural variants in schizophrenia: one disorder, multiple mutations; one mutation, multiple disorders. Trends Genet 25: 528–535

  46. 46.

    , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 2008 Large recurrent microdeletions associated with schizophrenia. Nature 455: 232–236

  47. 47.

    , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 2010 Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes. Am J Hum Genet 86: 707–718

  48. 48.

    , 2009 The genetics of attention-deficit/hyperactivity disorder. Expert Rev Neurother 9: 1547–1565

  49. 49.

    , , 2010 Measured gene-by-environment interaction in relation to attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 49: 863–873

  50. 50.

    , , , , , , , , 2009 Gene X environment interactions in reading disability and attention-deficit/hyperactivity disorder. Dev Psychol 45: 77–89

  51. 51.

    1998 Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit hyperactivity disorder: a review and integration. Behav Brain Res 94: 127–152

  52. 52.

    2009 The emerging neurobiology of attention deficit hyperactivity disorder: the key role of the prefrontal association cortex. J Pediatr 154: I–S43

  53. 53.

    , , , , , , , 2008 Pharmacogenetics of methylphenidate response in attention deficit/hyperactivity disorder: association with the dopamine transporter gene (SLC6A3). Am J Med Genet B Neuropsychiatr Genet 147B: 1425–1430

  54. 54.

    , , , , 2009 Carboxylesterase 1 gene polymorphism and methylphenidate response in ADHD. Neuropharmacology 57: 731–733

  55. 55.

    , , , , 2008 Genome-wide association study of response to methylphenidate in 187 children with attention-deficit/hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet 147B: 1412–1418

  56. 56.

    , , , , , 2007 CYP2D6 and clinical response to atomoxetine in children and adolescents with ADHD. J Am Acad Child Adolesc Psychiatry 46: 242–251

  57. 57.

    , , , , , , , , , 2009 A haplotype of the norepinephrine transporter (Net) gene Slc6a2 is associated with clinical response to atomoxetine in attention-deficit hyperactivity disorder (ADHD). Neuropsychopharmacology 34: 2135–2142

  58. 58.

    , , , , , , , , , 2011 Molecular imaging genetics of methylphenidate response in ADHD and substance use comorbidity. Synapse 65: 154–159

  59. 59.

    , 2010 Structural MRI of pediatric brain development: what have we learned and where are we going?. Neuron 67: 728–734

  60. 60.

    , , , 2009 Towards conceptualizing a neural systems-based anatomy of attention-deficit/hyperactivity disorder. Dev Neurosci 31: 36–49

  61. 61.

    , , , , , 2010 Disorder-specific dysfunction in right inferior prefrontal cortex during two inhibition tasks in boys with attention-deficit hyperactivity disorder compared to boys with obsessive-compulsive disorder. Hum Brain Mapp 31: 287–299

  62. 62.

    , 2010 Is the ADHD brain wired differently? A review on structural and functional connectivity in attention deficit hyperactivity disorder. Hum Brain Mapp 31: 904–916

  63. 63.

    , , , , 2006 Activation in ventral prefrontal cortex is sensitive to genetic vulnerability for attention-deficit hyperactivity disorder. Biol Psychiatry 60: 1062–1070

  64. 64.

    , , , , , , 2008 Dopamine transporter genotype conveys familial risk of attention-deficit/hyperactivity disorder through striatal activation. J Am Acad Child Adolesc Psychiatry 47: 61–67

  65. 65.

    2005 Causal models of attention-deficit/hyperactivity disorder: from common simple deficits to multiple developmental pathways. Biol Psychiatry 57: 1231–1238

  66. 66.

    , 2005 An integrative theory of attention-deficit/ hyperactivity disorder based on the cognitive and affective neurosciences. Dev Psychopathol 17: 785–806

  67. 67.

    , , 2007 New potential leads in the biology and treatment of attention deficit-hyperactivity disorder. Curr Opin Neurol 20: 119–124

  68. 68.

    , , , , , , , , , , 2005 Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder, their unaffected siblings, and controls. Mol Psychiatry 10: 678–685

  69. 69.

    , , 2009 Understanding genes, environment and their interaction in attention-deficit hyperactivity disorder: is there a role for neuroimaging?. Neuroscience 164: 230–240

  70. 70.

    , 2006 Modeling madness in mice: one piece at a time. Neuron 52: 179–196

  71. 71.

    2000 Behavioral validation of the spontaneously hypertensive rat (SHR) as an animal model of attention-deficit/hyperactivity disorder (AD/HD). Neurosci Biobehav Rev 24: 31–39

  72. 72.

    , , 1995 Coloboma hyperactive mutant exhibits delayed neurobehavioral developmental milestones. Brain Res Dev Brain Res 89: 264–269

  73. 73.

    , 2000 An animal model of attention deficit hyperactivity disorder. Mol Med Today 6: 43–44

  74. 74.

    , , , , 2008 Chronic nicotine exposure has dissociable behavioural effects on control and beta2−/− mice. Behav Genet 38: 503–514

  75. 75.

    , , , , 2008 A mouse model of fragile X syndrome exhibits heightened arousal and/or emotion following errors or reversal of contingencies. Dev Psychobiol 50: 473–485

  76. 76.

    , , , , 2010 Distinct roles of rodent orbitofrontal and medial prefrontal cortex in decision making. Neuron 66: 449–460

  77. 77.

    , , , , , , , , , , , , , , , , , , 2009 Abnormal behavior in a chromosome-engineered mouse model for human 15q11-13 duplication seen in autism. Cell 137: 1235–1246

  78. 78.

    , , , , , , , 2008 A mutation in mouse Disc1 that models a schizophrenia risk allele leads to specific alterations in neuronal architecture and cognition. Proc Natl Acad Sci U S A 105: 7076–7081

  79. 79.

    , , , , , , , , , , 2000 Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet 9: 1415–1423

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Author information

Affiliations

  1. INSERM U894 Centre Psychiatrie et Neurosciences, Paris 75014, France

    • Diane Purper-Ouakil
    • , Nicolas Ramoz
    •  & Michel Simonneau
  2. Service de Psychopathologie de l'Enfant et de l'Adolescent, Hôpital Robert Debré, Paris 75019, France

    • Diane Purper-Ouakil
  3. Centre National de Génotypage CP 5721, Evry cedex 91057, France

    • Aude-Marie Lepagnol-Bestel
  4. Centre of Psychiatry and Neuroscience, Hôpital Sainte-Anne, Paris 75014, France

    • Philip Gorwood

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Corresponding author

Correspondence to Diane Purper-Ouakil.

Glossary

ADHD

attention deficit/hyperactivity disorder

ASD

autism spectrum disorder

DISC 1

disrupted-in-schizophrenia gene

GWAS

genome-wide association study

GxE

gene-environment interaction

MPH

methylphenidate

SLC6A3/DAT1

dopamine transporter gene

SLC6A2/NET1

norepinephrine transporter gene

SNP

single-nucleotide polymorphism

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DOI

https://doi.org/10.1203/PDR.0b013e318212b40f

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