Contents

1 Epidemiology and Risk Factors

The etiology of attention-deficit/hyperactivity disorder (ADHD) is unclear. However, it is well accepted that ADHD has both genetic and environmental risk factors [3, 13]. ADHD is likely not a single pathophysiological entity, which suggests complex and multiple etiologies. Multiple genetic and environmental factors may act in concert, which gives rise to a spectrum of neurobiological liability [10] which manifests as a set of ADHD symptoms. Estimates of heritability from many familial and twin studies range from 0.5 to 0.9, average 0.75; which, taken together with a five-fold increased risk in first-degree relatives, strongly implies a genetic component [3, 8, 10, 13, 30]. Environmental risk factors such as obstetric complications, family conflict, and lead exposure have also shown positive, yet small, increases in risk for ADHD.

2 Genetic Risk Factors

No single gene abnormality reliably predicts ADHD, but consistent association between several genes regulating dopamine (DA) transport and signaling have been implicated (these have been the genes most studied by candidate gene association studies because of prevalent DA hypotheses concerning the pathophysiology of ADHD [19, 37] and the mechanisms of the most popular drugs used to treat ADHD [32, 34–36] ). Genome-wide association studies have failed to report any associations that are significant after correction for multiple testing [10]. Cortese et al. [8] estimates that a genome-wide association study would have to use sample sizes between 10,000 to 20,000 subjects in order to accurately detect novel genes involved in ADHD with risk factors similar to those seen in candidate gene association studies. Candidate gene association studies have shown positive, but small correlations with the dopamine receptor D4 gene (DRD4), dopamine receptor D5 gene (DRD5), dopamine transporter gene (SLC6A3), dopamine β-hydroxylase (DβH), synaptosomal-associated protein of 25 kDa gene (SNAP25), serotonin transporter gene (SLC6A4), and the serotonin 1B receptor gene (HTR1B) [3], which is in line with the multifactorial polygenic model in which a plethora of genes each confer a small but real risk to the disorder [8]. It is easy to imagine that combinations of risk alleles impacting dopaminergic signaling could produce an extreme hypodopaminergic state that would lead to poor cognitive function [30].

The SLC6A3 and DRD4 genes show variation amongst the population based on a variable number of tandem repeats where the nucleotide or base pair sequence is repeated a different number of times in different alleles of the gene. A 40 base pair variable tandem nucleotide repeat in the 3′ untranslated region of the human DAT1 gene (SLC6A3 [7]) and a 48 base pair DA D4 receptor 7-repeat allele [17] have both been implicated in ADHD, and have been the most consistently positive across multiple candidate gene association studies [13, 14, 20, 29], which is not always common [6, 9].

Dopamine receptor genes linked to ADHD The DA D4 receptor is prevalently expressed in frontal and subcortical networks that are implicated in the pathophysiology of ADHD [3]. DRD4 association studies have assayed a variant known as the exon-III 7-repeat allele (16 amino acid repeat in the 3rd intracellular loop of the receptor that couples the receptor to pre- or post-synaptic G-protein effectors [30]), which while it shows a positive association with ADHD, may paradoxically be protective, as the DRD4 7-repeat allele produces an in vitro blunted response to dopamine, but subjects with the DRD4 7-repeat allele and ADHD tend to have better clinical and academic outcomes than those with ADHD and the DRD4 4-repeat allele more common in the general population [3, 17, 30]. Candidate gene studies of the DA D5 receptor, which is expressed in the hippocampus, and especially the dentate gyrus [16], have shown positive correlation with ADHD with a repeated sequence near the transcription start site [3].

Although DA D1 and D2 receptors are thought to be the major effectors of stimulant-induced alterations in impulsive, addictive, and compulsive behavior [33], it is unsettled as to whether variants of these full-length genes are associated with ADHD [27].

Dopamine transporter gene linked to ADHD When pooled in meta-analysis, studies of the SLC6A3 10-repeat sequence in the 3′ untranslated region (the 3′ untranslated region of mRNA often contains regulatory sequences that can influence post-transcriptional gene expression) estimate an increased odds ratio of 1.13 for ADHD [3, 7]. It may be possible that different variants of the dopamine transporter (DAT) have an altered sensitivity to endogenous DA. At present, no such variations in the coding sequence of the DAT are known, nor are they separable pharmacologically [27].

Norepinephrine synthesis linked to ADHD Dopamine β-hydroxylase is the main enzyme and rate-limiting step in converting DA to norepinephrine (NE). Meta-analysis of multiple family studies suggest a significant association with ADHD and the 5′ Taq1 polymorphism of the DβH gene [3].

Serotonin signaling linked to ADHD Both the serotonin transporter gene (SLC6A4) and the serotonin 1B receptor gene (HTR1B) have been implicated in ADHD. A functional variant of the SLC6A4 has a meta-analysis adjusted odds ratio of 1.31 for ADHD. Many studies of the HTR1B have also been positive, with a non-functional marker showing an odds ratio of 1.44 [3].

Synaptic transmission linked to ADHD SNAP25 is a neuron-specific protein involved in synaptic vesicle transport, fusion, and release. A meta-analysis of several studies assessing the association between the gene and ADHD found an odds ratio of 1.19. SNAP25 knockout mice also show spontaneous hyperactivity which can be reduced with stimulant drugs [3].

Negative candidate gene results Candidate gene association studies have also been done on several genes that have provided negative or equivocal results. Two genes involved in monoamine degredation, catechol-O-methyl-transferase (COMT) and monoamine oxidase (MAO), have shown negative results, as well as the norepinephrine transporter gene (SLC6A2) and the norepinephrine 1C, 2A, and 2C receptors [3].

3 Environmental Risk Factors

Environmental factors play a critical role in the etiology of ADHD. One of the best evidences supporting this point comes from the genetic twin studies, which show that the risk of ADHD in monozygotic twins is much lower than 100 % [8]. Many studies have indicated that complications during pregnancy and delivery could be associated with childhood ADHD. The complications that are associated with later ADHD tend to include chronic exposures to the fetus, and complications that lead to hypoxia rather than acute events [3].

Prenatal risk factors Maternal alcohol use during pregnancy leads to behavioral, cognitive, and learning problems that could present as ADHD. Prenatal alcohol exposure is known to induce brain structural anomalies, and children exposed to prenatal alcohol are more hyperactive, disruptive, impulsive, and are at increased risk of a range of psychiatric disorders [10]. Studies of ADHD children show an increased likelihood of having been exposed to alcohol as a fetus [3].

There is also a well documented, almost 3-fold increased risk for the disorder in children whose mothers smoked during pregnancy [3, 24]. Exposure of the fetus to nicotine can damage the development of the brain at critical time points as nicotinic receptors modulate dopaminergic activity [11, 12, 31], and animal studies have also shown a correlation between chronic nicotine exposure of pregnant dams and hyperactive offspring [3].

Perinatal risk factors Low birthweight (< 2500g) and premature birth (< 37weeks gestation) increase the risk for ADHD [2, 3, 18, 22]. Very low birthweight children show a 2-fold increase in the proportion of those with ADHD vs. average birthweight counterparts [10]. Interestingly, prenatal tobacco exposure can result in both low birthweight and preterm birth [15]. In a huge study from the Danish longitudinal birth registers, Linnet et al. [21] found a rate ratio for hyperkinetic disorder (the International Statistical Classification of Diseases and Related Health Problems (ICD) analogue of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)’s ADHD) of 1.7 for 34 to 37 weeks gestation and rate ratio 2.7 for less than 34 weeks gestation. Likewise, low birth weight for children born at term gave a rate ratio of 1.9 for birthweight of 1500 g to 2499 g and 1.5 for birthweight 2500 g to 2999 g [21]. In a similar study, Mick et al. [23] reported that ADHD cases were 3.1 times more likely than controls to be born under 2500 g.

Postnatal and childhood risk factors Malnutrition and dietary deficiency have been proposed, and iron deficiency has been implicated in some cases of ADHD, however further evidence is necessary to firmly establish a role [10].

Lead exposure Lead exposure has been implicated in the pathophysiology of ADHD, although most children with ADHD do not show lead contamination and many children with high lead exposure do not become affected with the disorder [3]. Nigg et al. [26] suggests that low-level lead exposure, below the US Environmental Protection Agency (EPA) limits, may represent a hidden major effect on ADHD incidence. A population sample, Braun et al. [4] reported that very low levels of lead were associated with ADHD, even with lead exposures below 5 μg/dL, which highlights the importance of a gene–environment interaction model, as these levels of lead exposure are common in the US population [5].

4 Gene–Environment Interactions

Molecular genetics supports the association of ADHD with several DA signaling related genes, and environmental effects suggests increased risks for ADHD related to maternal smoking, exposure to low levels of lead, premature birth or low birth weight, and other factors that alter fetal development with lasting or possibly permanent effects on attention and behavior [30]. It is noteworthy that individual genes or environmental risk factors carry quite modest risk, and also that some of the environmental risk factors associated with ADHD (e.g. low lead exposure) are quite common in the general population [30]. More complex models of the etiology of ADHD which incorporate gene–environment interactions are being studied. However, the multitude of possible etiologies of gene–environment combinations add complexity, and would require enormous sample sizes for adequate evaluation [30]. Neuman et al. [25] demonstrated that smoking during pregnancy is associated with the ADHD combined subtype in children with the ‘susceptible’ DRD4 and dopamine transporter gene (SLC6A3) gene variants. Also, a significant interaction between SLC6A3 genotype and prenatal smoke exposure was found in males: Men with prenatal smoke exposure and homozygous for the SLC6A3 10-repeat allele had higher hyperactivity/impulsivity than males from all other groups [1]. Through unknown mechanisms, abnormal DAT density is a common feature among subjects with ADHD [28].

Acronyms

ADHD

attention-deficit/hyperactivity disorder

CDC

Center for Disease Control and Prevention

COMT

catechol-O-methyl-transferase

DAT

dopamine transporter

DA

dopamine

DbH

dopamine β-hydroxylase

DRD4

dopamine receptor D4 gene

DRD5

dopamine receptor D5 gene

DSM-IV

Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition

EPA

US Environmental Protection Agency

HTR1B

serotonin 1B receptor gene

ICD

International Statistical Classification of Diseases and Related Health Problems

MAO

monoamine oxidase

NE

norepinephrine

SLC6A2

norepinephrine transporter gene

SLC6A3

dopamine transporter gene

SLC6A4

serotonin transporter gene

SNAP25

synaptosomal-associated protein of 25 kDa gene

References