Attention deficit hyperactivity disorder (ADHD) is the most commonly diagnosed neurodevelopmental disorder of childhood. For decades, neuroscientists and psychiatrists alike have been searching for the aetiology of ADHD. This quest has been informed by the belief that if we can find the causes of the disorder we may be able to improve our unders­tanding of ADHD’s psychopathology and discover more accurate therapeutic models or even prevent the onset of this condition. Two potential sour­ces of aetiology have featured particularly prominently in the available literature: the DNA variants coded in our genome and shared and non-shared environment factors that impact the developing brain.

To fully understand the aetiology of ADHD, we must consider how genes and environment work together to cause the disorder, since the DNA variants that increase risk for ADHD do not do so in a vacuum.

GENETIC RISK FACTORS

Decades of research show that genes play a vital role in the aetiology of attention deficit hyperactivity disorder (ADHD) and its comorbidity with other disorders. Several studies of families have demonstrated that the siblings and parents of children with ADHD are at increased risk for the disorder. This has great implications for clinicians treating ADHD children, since it implies that many of the parents of those children will also have ADHD, which could make it difficult for them to carry out instructions about how to implement medical or psychosocial treatments for their children.

As an example, a study of 894 ADHD probands and 1135 of their siblings aged 5 to 17 years old found a nine-fold increased risk of ADHD in siblings of ADHD probands compared with siblings of controls. Adoption studies suggest that the familial factors of ADHD are attributable to genetic factors rather than shared environmental factors with the most recent one reporting rates of ADHD to be greater among biological relatives of non-adopted ADHD children than adoptive relatives of adopted ADHD children. The adoptive relatives had a risk for ADHD comparable to the risk in relatives of control children. A similar heritability estimate of around 80% was seen in a study of monozygotic and dizygotic twins, full siblings, and maternal and paternal half-siblings.

Heritability has been proven to be similar in males and females and for the inattentive and hyperactive-impulsive components of ADHD. Twin studies have also been able to test if ADHD is best described as a categorical disorder or a continuous trait in the population. A study of 16,366 Swedish twins found a strong genetic association between the extreme and the sub-threshold variation of DSM-IV ADHD symptoms.

These studies suggest that ADHD is best described as a quan­titative trait that ranges from non-existent and mild to moderate and severe. Under this model, the diagnosis of ADHD is the extreme of a trait that occurs in all indi­viduals. Such data has clinical implications for how one should subthreshold cases of ADHD that are referred to clinical settings.

INCREASED RISK OF COMORBIDITIES

Multivariate twin and sibling studies have found a general genetic factor that influences ADHD and a broad spectrum of neuropsychiatric conditions. Both clinical and epidemiological studies have documented that children and adults with ADHD are at increased risk for antisocial disorders, autism spectrum di­sorders (ASDs), anxiety disorders, mood disorders and substance abuse disorders. Except for some anxiety disorders, each of these disorders clusters together with ADHD in families.

The fact that ADHD shares gene­tic causes with other psychiatric disorders is extremely important for clinicians to understand. This kind of data argues against the idea that when two disorders co-occur, only the primary disorder should be treated. Instead, current practice suggests that all disorders be treated sequentially starting with the most serious condition.

A recent study correlated ADHD’s poly­genic risk with 220 disorders and traits. That work, along with other studies, has confirmed reports from family and twin studies suggesting that ADHD shares ge­netic risk with conduct disorder, major depression and bipolar disorder. Thus, the pervasive psychiatric comorbidity observed in ADHD patients is due, at least in part, to sharing the genetic risk factors comprising ADHD’s genetic risk score. In addition to these expected associations, it has been discovered that the genetic risk for ADHD was correlated with the genetic risk for other traits. Posi­tive correlations were observed for obesity and smoking and negative correlations were observed for years of education, university completion, intelligence quotient and subjective well-being.

ADHD risk score has also been positively correlated with:

  • having a large family
  • having children at a young age
  • a younger age of death of the respondent’s mother and father.

The latter finding could be due to ADHD’s shared genetic risk for obesity, co­ronary artery disease and lung cancer.

The efficiency of indirect dopamine agonists in reducing the symptoms of ADHD led to the development of the ‘dopamine hypothesis’ of ADHD, which postulated that dysregulated dopamine signalling is central to the pathophysiology of ADHD. Putative disruption of other monoamines such as noradrenaline and serotonin in ADHD has also been proposed. Accordingly, genetic markers mapped to these monoamine pathways have historically been pursued as candidate genes for ADHD.

GENOME-WIDE ASSOCIATION STUDIES

In a genome-wide association study (GWAS) of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, it was found that associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. A strong concordance between GWAS and quantitative population measures of ADHD symptoms supports the position that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.

Although GWAS had been developed to assay common variants, this method can also detect large, rare copy number variants (CNVs). CNVs delete or duplica­te a large section of DNA that might contain part of a single gene or several genes in their entirety. Because many of these create large genomic lesions, they seem to have clear consequences for gene functioning. Most studies of CNVs in ADHD have found an increased burden among patients with ADHD compared with con­trols. It has been reported that dele­tions and duplications are equally over-represented in ADHD samples. The CNVs found in ADHD studies showed some overlap with the CNVs found in studies of schizophrenia and ASDs.

Given the above, there can be no doubt now that people with ADHD carry DNA variants that ope­rate via unknown mechanisms to cause inattention, hyperactivity and impulsivity. Most of these variants are fairly common such that everyone carries some genetic risk for ADHD. This creates a polygenic genetic architecture and supports the idea that the risk for ADHD, and its expression in symptoms, is a continuously varying trait in the population. This means that people who present with subthreshold symptoms may carry some biological risk for ADHD even though they don’t meet the full diagnostic criteria for the disorder.

While gene discovery for ADHD has succeeded, it has left us with unexpected results. None of the genome-wide significant findings had been predicted a priori and a set of ADHD candidate genes, implicated primarily by the disorder’s neuropharmacology, did not reach statistical significance. These findings challenge the idea that the core of ADHD’s pathophysiology rests within the machinery of catecholaminergic transmission. Instead, it is possible that catecholaminergic dysregulation is a secondary compensation to ADHD’s primary aetiology.

ENVIRONMENTAL RISK FACTORS

The convincing evidence for genes as risk factors for ADHD does not, however, exclude the environment as a source of aetiology. The fact that twin estimates of heritability are less than 100% asserts quite strongly that environmental factors must be involved. ADHD’s heritability is high, and that estimate encompasses gene by environment interaction. Thus, it is possible that such interactions will account for much of ADHD’s aetiology. Environmental risk factors likely work through epigenetic mechanisms, which have barely been studied in ADHD.

The importance of the environment can also be seen in the fact that, as for other complex genetic disorders, much of ADHD’s heritability is explained by SNPs in regulatory regions rather than coding regions. Our genome comes into existence prior to our birth. So, when scientists discover an association between ADHD and a DNA va­riant, it is clear that having ADHD cannot cause one to have a specific DNA va­riant but that having a DNA variant could logically increase risk for ADHD. Stu­dies of the environment are less clear-cut.

For example, if a study documents that poverty is associated with ADHD, that could mean that poor nutrition, stress and other concomitants of poverty increase the risk for ADHD. But it is also possible that having ADHD leads to lower levels of education, poorer job performance and thereby increases the risk for parents with high genetic risk for ADHD to live in poverty. Thus, one must always keep in mind the potential for such ‘reverse causa­tion’ when evaluating environmental risk factors and evaluate whether these have been considered by the relevant studies.

Figure 1: Model of the aetiology of ADHD (Rohde et al, 2109)

However, it has been demonstrated that when one member of an identical twin pair has ADHD, the risk to the co-twin is only about 50%. Thus, environmental risk factor must contribute to the aetiology of ADHD. Some environmental risks are due to exposures to toxins, lack of nutrients or trauma. Many studies have examined the effects of iron and zinc on ADHD be­cause both of these elements are essential for producing norepinephrine and do­pamine in the brain. It has been reported that measures of iron deficiency were associated with ADHD. They also found that ADHD was associated with low levels of zinc in the blood. Among the many toxins studied in ADHD patients, the strongest evidence implicates lead contamination.

Many studies have tested the idea that pregnancy and delivery complications (PDCs) might cause ADHD by harming the brain at early stages of its develop­ment. Although the literature presents conflicting results, it tends to support the idea that PDCs are risk factors for ADHD. Among the most investigated PDCs, prematurity and low birth-weight are the most studied. A recent meta-analysis of the literature on the association between both very-premature and/or very low­-weight babies and ADHD showed a 3 times increased risk for those infants to have ADHD in the future. However, it is important to note that prematurity and low-birth weight are also risk factors to other mental disorders.

Maternal smoking during pregnancy has been widely studied as a risk factor for ADHD. It is well documented that smoking during pregnancy places the foetus at risk for birth complications, including low birth weight, which has been asso­ciated with ADHD. Maternal smoking also places the foetus at risk for a hypoxia, which has been associated with ADHD. People who experience mild traumatic brain injuries (mTBIs) are at risk for developing ADHD. This was the conclusion of a meta-analysis which showed that mTBI associated with ADHD.15 Another well-documented environmental risk factor is severe institutional deprivation in early childhood. We know this from studies of children who spent the early years of life in Romanian orphanages that offered poor nutrition and nearly no human contact. Many of these children deve­loped ADHD later in life.

Additional environmental risk factors for ADHD that have been confirmed by meta-a­nalyses include:

  • preterm birth
  • prenatal exposure to maternal smoking
  • prenatal methylmercury exposure from maternal fish consumption
  • exposure to lead
  • perinatal vitamin D deficiency.

GENES AND ENVIRONMENT COLLABORATE

To fully understand the aetiology of ADHD, we must consider how genes and environment work together to cause the disorder. The DNA variants that increase risk for ADHD do not do so in a vacuum. They reside in cells where they build proteins in response to cellular signals. The environment may generate these signals. Gene by environment interaction occurs when mutant genes only cause disease in the presence of specific signals from the environment.

According to a GWAS of ADHD, 30% of ADHD’s heritability could be explained by the disor­ders polygenic architecture. Some of the other 70% will be accounted for by rare variants but it is likely that a good fraction of heritability will be explained by gene by environment interactions. Unfortunately, these are very difficult to study, as there are many relevant environmental risk factors to study.

Substantial data from epidemiologic studies implicates the environment in the aetiology of ADHD. These data implicate biological assaults on the developing brain such as exposures to toxins, maternal smoking, anoxic birth complications, mild traumatic brain injury and institutional deprivation. Psychosocial stresses such as marital distress, family dysfunction and low social class have also been implicated by epidemiologic studies. Although we expect that gene by environ­ment interaction and epigenetic effects mediate these environmental risks, these areas of research are not sufficiently mature to offer conclusive findings about the aetiology of ADHD.

Given that ADHD has been shown to be polygenic and that many environmen­tal risk factors have been discovered, the multifactorial model of ADHD seems more consistent with the data than an etiologic heterogeneity model. Apart from rare cases caused by gross abnormalities of chromosomes, CNVs or SNVs, we do not expect ADHD to be easily subdivided into separate aetiologic entities.

PHARMACOLOGICAL THERAPY WITH ATOMOXETINE

Atomoxetine (ATX) is a potent inhibitor of the presynaptic norepinephrine transporter, with minimal affinity for other noradrenergic receptors or for other neurotransmitter transporters or receptors. Atomoxetine’s clinical profile seems to differ from that of stimulants. Several reports have provided evidence that atomoxetine is superior to placebo in reducing symptoms of ADHD in children and adults.

In a study among children and adolescents aged 8 to 18, atomoxetine was superior to placebo in reducing ADHD symptoms and in improving social and family functioning symptoms. Atomoxetine was associated with a graded dose-response, and 1.2 mg/kg/day seems to be as effective as 1.8 mg/kg/day and is likely to be the appropriate initial target dose for most patients. Treatment with atomoxetine was generally safe and well tolerated.

Although ATX may be less effective than stimulant medication, it is safe and useful for both acute and long-term treatment of ADHD in children, adolescents, and adults. ADHD treatment guidelines recommend ATX as a first-line treatment option and it may be especially helpful for patients who have ADHD and comorbid anxiety. ATX should also be considered when patients with previous stimulant exposure have had efficacy or tolerability concerns. A history of substance abuse with patient or family members may also make ATX a viable treatment option in that population.