5

The Genetics of ADHD

The science of genetics is fast-moving and has arguably provided the strongest evidence for a biological component in the etiology of ADHD. How the genes associated with ADHD translate into behavior is still subject to conjecture.

There are a number of ways in which the genetics of ADHD can be assessed, ranging from patterns of inheritance through to molecular studies looking for specific genes.

Looking at the genetics of ADHD also provokes the question: Why does ADHD have a heritable component? What possible benefit does it confer? Some have argued that ADHD may have an adaptive function to past environments [187]. However, we are not just an expression of our genes; the development of behavior is seen as a product of interactions between genetics, the environment, and perception. Behavior will be determined by the genetic makeup of an individual and also by their experiences, interpretations, and perceptions of the environment [532]. This gives rise to the important notion that we are not, and must not be, passive victims of our genetic inheritance. Just because we have a vulnerability to a certain disorder does not justify a failure to attempt to subvert it. For example, if you have a gene that increases your vulnerability to heart disease, you can do a lot to minimize its impact, such as modify your diet, take exercise, and avoid stress. The same goes for ADHD: if and when a gene, or genes, is found for ADHD, this does not mean our fate is determined. We can do a lot to offset the inheritance, and with the knowledge we now have we can put some of the symptoms to good use. There is no point in having ADHD and having the career aspiration of an air traffic controller, where sustained attention is required; you may be better placed in the security business, where hyper-vigilance is an advantage.

The Evidence for (and against) ADHD as a Genetically Inherited Disorder

The idea that there is a genetic basis to ADHD comes from familial studies of behavioral genetics. These studies are not concerned with the actual genetic basis of the disorder, e.g. what gene is responsible, but they are more concerned with patterns of inheritance. The essence of such studies is to determine if ADHD is more common in biological relatives of those affected rather than those not affected. The evidence to date argues for a familial transmission of ADHD (see [533] for review). Clearly such studies fail to address a genetic basis; they just tell us ADHD runs in families. There could be a genetic component, but then again there is as much chance of there being an environmental component. After all, if you are brought up by parents with ADHD or other psychopathologies and psychosocial adversity, you are more likely to be exposed to such behaviors and be diagnosed with the disorder [287].

In an attempt to tease apart the genetic and environmental factors of ADHD, behavioral geneticists have looked at twins reared together or apart. Twin studies have been an influential method for attempting to clarify genetic factors. Such studies look at two types of twins: monozygotic (MZ) twins and dizygotic (DZ) twins. MZ twins are genetically identical because they are formed by a single sperm fertilizing a single egg that subsequently splits to form two embryos; they share 100 percent of their genes. DZ or fraternal twins share 50 percent of their genes as they are a result of two eggs being fertilized. DZ twins are like other siblings born separately.

As MZ twins are genetically identical, then they should both be more closely associated with a characteristic (such as ADHD) compared to DZ twins. If the factor is environmentally mediated, there should be no difference between MZ and DZ. Such studies present a heritability estimate, where 1 is entirely genetic and 0 entirely non-genetic (not necessarily completely environmental, as neural damage may be a factor). Heritability estimates are statistics about the variance of a characteristic in a population that can be accounted for by genetics. They cannot provide a precise breakdown in individual cases: suggesting, for example, that in any one individual the ADHD is 75 percent genetic and 25 percent environmental. To place the data in context, height is highly heritable (0.88), as demonstrated in one study [534]. Yet it is critical to acknowledge that despite a high heritability estimate, there are environmental factors also involved in height, e.g. availability of a good diet. To take one example from the ADHD literature, Kuntsi et al. [535] found a correlation of 0.86 for MZ twins and 0.47 for DZ twins using the Conners rating scale from a population of nearly 4,000.

A number of studies have found that MZ twins are more likely to express the symptoms of ADHD [536–537], which has a stable association with genes over a five-year period [538]. In a review of 21 studies, Bennett et al. [533] conclude that there is a high genetic component to ADHD; however, they note that defining ADHD, comorbidity, and the age and gender of the population studies are confounding variables in such estimates. Studies since have also added support [539]. The average heritability estimates range from 0.75 to 0.91 [540–542]. Some studies have looked at individual symptoms and subtypes, but a conclusive view is not established (e.g. [543–544]). Others have argued that neuropsychological factors such as the Stop-Signal Reaction Time task are more closely related than global ADHD measures [545], which gives some support for looking at BI in ADHD as discussed in chapter 4. However, endophenotypes were only moderately predictive of an ADHD diagnosis [546]. Remember the endophenotype was thought to be a way of identifying genes for behavior rather than a global set of symptoms that are characteristic of the disorder.

Others have not found evidence for a genetic contribution to the symptoms of ADHD, although these were investigated within a general population of twins [547].

Psychological sciences have placed great faith in the twin study method as a means to unraveling the complex interplay between gene and environment. Jay Joseph provides an important and thought-provoking critique of the use of behavioral genetics [548]. All the twin studies, according to Joseph, have not looked at twins reared apart. The assumption of twin studies is that the environment remains equal (the Equal Environment Assumption [EEA], according to Joseph) for both twins. That is, each twin (or sibling for that matter) shares the same environment. Thus the greater association seen in MZ compared to DZ twins must be attributed to genes. Such an assumption has been questioned [549]. The evidence for MZ and DZ differing in genes only is not supported. Joseph [550] has reviewed the literature and states that MZ twins are more likely to spend time together, have close emotional bonds, have the same friends, and be treated the same by others, and to have more identity confusion. Thus the environment of MZ twins is different for the very reason they are MZ twins and precludes that a definitive genetic basis of ADHD be upheld. Furthermore, longitudinal studies of twins are further challenged by the changing nature of diagnostic criteria [551] and who is reporting on the symptoms, with teachers reporting more shared environment effects [552].

Essentially, twin studies are useful, but limited by their theoretical assumptions.

What about if we look at people who have been reared apart? This way the genes are the same but the environment is different. Again if there is a higher rate across MZ, the case for genes is greater. This is the premise of the adoption studies; ideally we could look at MZ twins in this way, but such studies have not been conducted. Adoption studies therefore work on the basis that adopted children share the genes, but not the environment with their biological parents – thus similarities between child and biological parent are attributed to genes. Conversely, adopted children share the environment and not their genetics with the adoptive parents. If you show similarities with your biological parents, then this is down to genes. If you show similarities with your adoptive parents, this is purely down to environmental factors, e.g. child-rearing practices.

Early studies looking at hyperactivity have found that there is an increased likelihood that children with ADHD who were adopted came from biological parents with ADHD-like symptoms and/or comorbidities [553–554]. In one study, 6 percent of the adoptive parents of ADHD children had ADHD whereas 18 percent of the biological parents of non-adopted ADHD children had ADHD [555]. The link does not appear to hold for all symptoms of ADHD, and therefore possibly not all subtypes, e.g. those with inattention [556]. Furthermore, adversity factors have been associated with attention and hyperactivity in a group of institutionalized children [557], which indicates a further variable that needs to be disentangled for the gene/environment debate.

The adoption method has looked at general psychiatric problems or delinquency in the biological parents and found that they were linked to ADHD symptoms [558–560]. Others have argued that the environment produced by having a depressed mother or general adversity in the pre-adoptive family might be a risk for ADHD rather than the genes themselves [561–562].

Joseph is also critical of adoption studies. The studies mentioned above have failed to look at the biological parents of the adoptive child, thus limiting the conclusion that can be made [548, 550]. Indeed the studies have indicated that environmental adversity is also a big factor. Furthermore, Joseph points out that the adoptive families are different by the very virtue of the act upon which they are engaged – adoption. Adoptive families are screened for mental health as part of the process of adoption and therefore less likely to have adverse environments. The adoptive family are carefully chosen for their health, whereas the biological family are not, thus we have two very different groups to compare, again limiting the conclusions of a genetic basis [548, 550].

According to Deutsch et al. [563], adoptees are more likely to be diagnosed with ADHD, which limits the conclusions yet again [550]. Why are they more likely to get such a diagnosis? The mere fact they have been adopted can be psychologically distressing (the feeling of abandonment) with long-term consequences [550]. One also has to remember that adversity factors are also implicated in ADHD [286–287, 564–566], and one can assume that these factors may preexist in adoptees’ biological families. It is not just the adversity found in some families that can have an impact; as mentioned above, some studies have found that institutional deprivation is linked with ADHD [557, 567–569].

What, then, do these studies say about the genetic basis of ADHD? They find that ADHD clusters in families, that it is transmitted via biological families, and that there is a higher concordance in MZ twins [569]. Their limited methodologies do not allow for definitive conclusions; they are proven neither right nor wrong. What we end up with is a situation in which we have a complex interplay between genetics and environmental factors (e.g. [570]). Despite the limitations of behavioral genetics, however, there is a concerted effort to locate the actual genes for ADHD. Molecular genetics has the potential to make such arguments historical, but as yet we are not in that position.

Evolution and the Continuation of ADHD

We have the idea now that ADHD runs in families and that this transmission is most likely to be genetic, although the evidence cannot be regarded as conclusive. The question as to why it runs in families and how this has evolved is the subject of evolutionary psychology. The idea that species change and evolve over time is now a well-established biological fact, unless you are a creationist who regards God (a god?) as the designer. Charles Darwin proposed that all animals (including humans) are related and share a common ancestor. His theory of descent with modification encapsulated how modern organisms are adaptations of previously successful generations. How do these modifications occur? The answer lies in the process of natural selection. Certain characteristics are more beneficial to the organism in a particular environment. Therefore those organisms that possess such beneficial characteristics are more likely to survive and reproduce. Via reproduction, these characteristics are passed to the next generation, who survive in the environment and reproduce – and so the process continues with successive generations. This ability to survive and reproduce is the whole purpose of life. Organisms that are not ideally suited to their environment have a reduced chance of being able to do so; those organisms that fit into their environment have greater success – otherwise known as the survival of the fittest.

The Darwinian account is a very good example of how the environment changes biology and behavior, albeit over an extended period of time. This should be the case under Darwin’s perspective, but is ADHD always maladaptive? After all, people with ADHD are very good at reproduction. When it comes to breeding, people with ADHD are more likely to have children at a younger age and with different partners [16], thus perpetuating the transmission of ADHD genes; in evolutionary terms that’s job done! Yet evolutionary accounts have attempted to explain that a gene may confer a beneficial set of behaviors in our ancestry [187], so how can the symptoms of ADHD be beneficial to the individual, the species, and the social group.

The notion of an evolutionary advantage to psychiatric disorders is not new and dates back to the late 1960s [571], with more recent accounts placing evolution and psychiatry in a socio-political context [572]. Such accounts are not restricted to ADHD (see [187] for a review).

Initially it was suggested that ADHD may have served an adaptive function and may have been selected by the environment for survival [573], in particular as the hunter rather than farmer [574–575]. Jensen et al. [576] argue that hyperactivity is useful for exploration, especially when food is scarce; rapidly shifting attention (or, as we would describe it, inattention) is a form of hyper-vigilance that is beneficial for monitoring threat or danger in the environment; and impulsivity is a negative term that is used to describe rapid reflex actions to stimuli, without apparent thought. So let us go back in time to a period when we had to hunt for food in a hostile and dangerous environment. The symptoms of ADHD would increase the likelihood of survival. The hunter needs to have stamina, energy, and physical prowess in order to catch his prey. Our hunter may also be hunted and therefore needs to attend to changes in the environment and orient to them rapidly – a failure to do so may make him dinner for another animal. Sustained focused attention, as required in school, is not needed. Finally, our hunter does not have time to think of the alternatives when confronted by hostile predators – the hunter needs to react instinctively to ensure survival. This may involve mobilization of flight or fight responses. Planning and evaluating the outcomes of several options of behavior is too slow, by the time a plan is put into action it may be simply too late!

In modern societies these behaviors are no longer advantageous. It has been suggested that evolutionary changes in the dopamine genes selected to increase cognitive and behavioral flexibility (of benefit to hunters) may now be associated with attention problems (ADHD) [577]. The goodness of fit that may be conveyed by ADHD symptoms works well for some environments, but now those same characteristics are seen as maladaptive [578]. Whilst this is really just theoretical conjecture that places a positive spin on ADHD, there has been a relative lack of evidence to support it until recently. Using genetic studies, most notably those looking at dopamine genes, Arcos-Burgos and Acosta have found support for the evolutionary hypothesis. They argue that the ADHD child’s hunter gene has been

rewarded by natural selection over millions of years of human evolution. However, the fast revolution of human society during the past two centuries brought new challenges rewarding planning, design and attention while limiting behaviors associated with ADHD.

[579] (p. 237)

Such a role is supported by the evolutionary function of the dopamine systems and a mismatch with current environments [580].

Of course, not everyone agrees with the evolutionary adaptiveness of ADHD. Barkley takes a strong view on the evolution of EF. He claims that the development of executive functions through our ancestors has

the ultimate utility function of conveying an enhanced survival and reproductive advantage to individual and the species at large. In contrast, ADHD should be found to reduce the survival and reproductive advantage conveyed by the executive functions and self-regulation when observed to operate over substantial time periods of an evolutionary scale.

[48] (p. 304)

Brody [581] takes exception to this characterization of the hunter’s traditional qualities and claims that waiting, planning, cooperation, and rehearsal are important traits for the hunter. These traits are not highly demonstrated in ADHD. Thus the disorder may be maladaptive and not of functional benefit at any time during our ancestry [581–584].

So how do these behaviors continue to flourish? The behaviors associated with ADHD have been referred to as spandrels [582]. Spandrels are not adaptations and are not reproductively beneficial in early human evolution. Spandrels occur and evolve because they are genetically linked to other advantageous adaptations such as language [584]. Essentially the behaviors associated with ADHD were not themselves advantageous, but they happened to keep in the good company of another advantageous trait, e.g. language.

One of the features of the evolutionary literature is how language is used to describe the symptoms of ADHD. The accounts that see ADHD as having some adaptive function view the symptoms positively, and some argue that they still have some benefit today, with particular occupations been favored by those with ADHD [585]. Those who see it as maladaptive often cite evidence of how ADHD children behave in today’s western world (e.g. [583]). I am not convinced that using behaviors in a twenty-first-century context provides strong evidence for a maladaptive case; it could be a maladaptive society, as some have suggested. Clearly, evolutionary accounts of behavior describe how environments shape the selection of traits, and we come back to the perennial problem of deciding if ADHD is real or merely a social label that is more informative about our intolerance of certain behaviors. As Klimkeit and Bradshaw put it, “while the prevalence of ADHD genetically may not have changed, what we might be witnessing is the decline in the capacity of western culture to cope with and raise these children” [585] (p. 472). However, from a different view on the evolutionary significance of ADHD, Matejcek states that the disorder would have been an even greater burden on the family and society than it is today, though he falls short of saying that those affected should have died out [583].

Some websites have associated the negative qualities associated with ADHD as really being the signs of gifted children.¹ These are noble attempts to put a positive spin on ADHD, and indeed there are many positives, but Goldstein and Barkley are scathing of those who use evolutionary accounts, and warn that

the community of advocates for ADHD that would encourage such practices must take care because they cannot have it both ways. They cannot on the one hand argue that ADHD needs to be taken seriously as a legitimate developmental disability. Then on the other hand simultaneously sing its praises as a once successful adaptation that leads to higher intelligence, greater creativity, and heightened sensory awareness, but that now results in suffering due to an over-controlled, linear-focused, and intolerant culture. All such claims fly in the face of available scientific evidence.

[586] (p. 4)

I am not convinced that they do fly in the face of all the evidence, but the pro-adaptationists are extremely selective about the behaviors that are used to prove the point. As Goldstein and Barkley continue:

it is also time for us to acknowledge and accept ADHD as a condition that can be significantly impairing to those so affected in our society. This is neither to pathologise, patronize, nor demonize those with ADHD. It is to say that having ADHD is no picnic.

[586]

Whilst the knowledge that the behaviors associated with ADHD were once of some benefit is neither here nor there, the important point is how best to accommodate the needs of those with ADHD and reduce any suffering that they have. However, I think it is necessary to highlight the positive aspects of ADHD, as this may help individuals maximize their potentials – even in the twenty-first century.

The use of modern genetics may help support or refute some of the evolutionary arguments. The dopamine receptor gene, DRD4, has been associated with ADHD, most notably a type of variation in the gene called the 7R variant. This genetic variant was not always associated with cognitive deficits, and some argue it may confer an advantage in conflict resolution (see [587]).

The DRD4/7R gene has been found to be increased in nomadic tribes rather than settled tribes [588–589]. Recent research in Kenya has concluded that individuals with the DRD4/7R gene who still live a nomadic life are better fitted for their environment, but those who have adopted a more urban life show reduced fit. Those with the DRD4/7R gene who were still nomads were better nourished than those without the gene. This led to widespread media coverage suggesting that the ADHD-related gene may encourage behavior that is beneficial for a nomadic lifestyle. The chances are, however, that more than the DRD4 gene is involved in ADHD [590], and that many changes that occur in the brain and influence behavior are likely to have a role [591].

One of the key features of ADHD is the great deal of variability on tasks (see [592]). Whilst ADHD subgroups may have similar composite scores on ratings scales, those with the DRD4/7R variant had normal speed and variability on a reaction time task, whereas those without the variant did not [593]. Swanson et al. argue that many accounts of ADHD are guilty of over-inclusion and assume that all those with ADHD exhibit the same characteristics of the group [587]. Such variability has led Williams and Taylor [8] to claim that it leads to unpredictability, which is of value to the group when it only exists in a minority. More specifically, during group exploration tasks, unpredictable behavior by some of the group optimizes the overall group result, whilst risk taking is confined to a minority and information sharing is enhanced. Thus those with ADHD can explore the possibilities of an environment without the group placing itself in danger; the group can then learn from the valuable experiences of the person with ADHD [8]. From this perspective, the person with ADHD is a hunter, explorer, risk taker, teacher, and altruist! This evolutionary advantage is restricted to the ADHD-HI subtype [8]. Quite how ADHD-I fits into an evolutionary framework is not clear and lends itself more to the arguments of maladaptation.

The evolutionary accounts obviously implicate genetic inheritance. In order to understand these evolutionary accounts of ADHD requires some understanding of genetics. Darwin’s accounts of evolution started the ball rolling for such understanding, but he did not specify the mechanisms that underlie the modification of the species through descent. The mechanisms of genetic transmission were first highlighted by Mendel in the 1860s and then the molecular basis of genes was reported by Crick and Watson with the discovery of the double-helix structure of DNA in 1953 [594]. Mendel’s work accounts for the inheritance of behavioral as well as physiological and anatomical characteristics. If the notion of animals being used to study ADHD is too far-fetched, remember that Mendel’s evidence was derived from his experiments with pea plants (or is this a step too far!?). Essentially he stated that there are two variants of a gene: a dominant trait and a recessive trait. Which of the two gets expressed depends upon the combination of variants. From such a perspective, ADHD would involve simple hereditary patterns of transmission through families, and ultimately lead to a single gene for ADHD. But can Mendelian genetics be extrapolated to ADHD? The simple answer is no. It is much more complicated than that. Because ADHD does not follow Mendelian transmission, it is considered a complex disorder [595] in comparison to PKU, for example, which does have a simple genetic basis following Mendelian principles. There would appear to be a number of genes that are now associated with ADHD [596].

In trying to understand the genetics of complex disorders such as ADHD, Waldman and Gizer [597] have summarized the challenges that lie ahead: (1) multiple genetic and environmental factors will be involved; (2) the multiple genes involved will only have a small role in the overall picture; (3) there is likely to be genetic heterogeneity inasmuch as the same gene can have a different effect, and the same effect can be derived from different genes; (4) there are likely to be phenocopies, i.e. disorders that look genetic but are in fact purely environmental; (5) the genes involved are likely to have low penetrance, which means that there is a low chance of having the ADHD if you have the gene [598]; and (6) environmental factors are more likely to play a prominent role in ADHD. Despite technological advances that can identify individual genes, all of these factors make the genetic analysis of ADHD extremely difficult.

Molecular Genetics

Darwin and Mendel did not have the advantages of modern science and technology to evaluate their theories. The search for genes started once DNA was discovered [594]. Genes are located on chromosomes that are contained in the nucleus of a cell. Chromosomes come in matched pairs; humans have 23 pairs, the most famous being X and Y, which are the sex chromosomes. If you unravel a chromosome, you have strands of DNA. The strands of DNA that make up the chromosome are composed of chemicals called nucleotides. The two strands of DNA are held together by a mutual attraction of the nucleotides. This double-stranded structure is the famous double helix. There are essentially four nucleotides that when placed in a specific order make up a code. That code is the gene. What does DNA do? DNA has two functions: (1) it replicates itself to make new cells, and (2) it provides the code that makes proteins and determines the function of the cell. Proteins are extremely important and constitute 50 percent of the dry weight of a cell [599]. There are many thousands of proteins that are used in a variety of ways. It is early days in molecular genetic research. We can add another layer of complexity to the expression of the gene with the phrase epigenetics. Epigenetics refers to the mechanisms which can control gene expression. In all cells the same DNA sequence exists; however, the expression is different in a liver cell compared to that of dopamine neuron. Epigenetic effects are also invoked in a cell’s acute response to environmental factors [600]. How such factors work in ADHD remains unknown, but is worthy of investigation [601].

We might believe from the media that we have isolated the gene for every ailment. This is far from the case, and it might never be true. The pathways that mediate the genotype and phenotype are too indirect to allow such conclusions [602]. The Human Genome Project has provided us with much information, and there are only an estimated 20,000–25,000² protein coding genes, which is surprisingly low for such a complex species [603]. Whilst this number is small, it is still a lot of genes to look at when considering a gene for ADHD. And if we consider ADHD to be a polygenetic disorder with individual genes contributing only a modest effect, the search is all the harder – the needle in the haystack. The search for the genes involved in ADHD is in essence the search for the biological cause of ADHD.

The main method for examining the actual genes involved in ADHD (or any other disorder) is the investigation of an association and/or linkage between ADHD and candidate genes – genes that are likely to be involved [597]. In association studies, two groups are looked at: those with ADHD and those without ADHD. Fortunately, DNA samples are comparatively easy to obtain and do not involve obtaining blood. The sample of DNA in each group is analyzed for the presence or absence of a high- or low-risk form of a candidate gene. The assumption is that the high-risk version will appear more often in the ADHD group. One point needs to be clear: genes exist in two forms called alleles – these forms can be the same or different. The two alleles come from each of the parents. One of these alleles may increase the risk for ADHD. We have already seen the DRD4/7R allele in action in the previous section. Variations of the association method have looked at the alleles that have been transmitted to the affected child compared to the unaffected child.

In linkage studies a connection between the ADHD and an unspecified DNA marker in family members is established. If there is an excess of this DNA marker within family members with the disorder, then one assumes that this is a part of the genome worth looking at. However, the DNA marker may not be the gene at fault in ADHD; it is just a guide to suggest that the gene is very close by and has not been disrupted by recombination during cell division. That is, the DNA marker is linked with the gene of potential interest. Once identified, the search can be narrowed down, or sections of the gene that do not show linkage can be ignored.

Scanning of the whole genome has found some evidence of association [604–609]. Not all studies have had such success, but these may have been limited by small numbers and other methodological features [610–611]. Despite their lack of success, however, they have found candidate genes involved in ADHD [611–613]. What is the candidate gene? This is a gene that is decided upon in advance of the study to look at. The candidate gene is derived from the scientific evidence about the neurobiology of ADHD. Not surprisingly, the vast majority of candidate genes are dopaminergic. Given the large amount of genes one could possibly look for, this method narrows down the search. However, a limitation is that you are only looking for known genes; there may be others involved that are missed.

Given that methylphenidate acts on the dopamine transporter (DAT), this is a good place to start looking. Furthermore, in mice if you remove the DAT1 gene and thus the DAT, you get hyperactivity [613] and impaired BI [614].

What these studies do is to look for differences in the gene between those with and without ADHD. These differences or mutations are called polymorphisms. Numerous studies have identified DAT1 polymorphisms in ADHD (see [597] for review). However, the association was noted for the hyperactive and impulsive subtype of symptoms, and not attention [615]. There was an association between poor performance on neuropsychological tests and the DAT1 gene in ADHD [616], but the neuropsychological tests used are not sensitive to ADHD per se. The importance of diagnostic accuracy is illustrated in another study that associated the DAT1 with some of the common comorbidities of ADHD, such as anxiety and Tourette’s syndrome [617]. Of course one gene can have many effects and thus be involved in multiple phenotypes. A recent meta-analysis revealed that the methodology of the study was an important variable in identifying the DAT1 involvement with ADHD [618], as not all studies have found an association (see [597], [619]). As the DAT is the site of action for methylphenidate, it has also been argued that polymorphisms of the DAT1 gene are predictive of the type of response to treatment [620–621].

Along with the criticisms of positive publication bias comes language that can mislead the novice. For example, in one abstract that did not find an association, the authors report: “There was a non-significant trend for an increased frequency of the DAT1 allele” [622] (p. 273). Another meta-analysis of 36 studies did not find a strong association of DAT 1 and ADHD, but rather pointed to other dopamine genes [623].

The next gene that has had considerable attention is the DRD4 gene. This is a dopamine receptor gene and has also been associated with a number of behaviors (e.g. [517]). We have seen earlier that polymorphisms of the DRD4 gene were associated with beneficial characteristics in nomadic Kenyans. However, like the DAT1 gene, there are conflicting accounts of the strength of the association between the DRD4 gene and ADHD [597]. Some have found an association (e.g. [624–625]) and others have not (e.g. [626]), with a recent meta-analysis generally being supportive [596]. In a mouse model of ADHD, the DRD4 receptor was associated with hyperactivity and poor behavioral inhibition [627]. Some have seen the DRD4/7R allele as being associated with a more benign ADHD [593, 628], and with a good response to methylphenidate [629–630], but apparently not in Brazilian children [631], thus indicating an important role of ethnicity in genetic studies and drug response.

There are a number of other dopamine receptor genes that have been looked at with varying degrees of success. There are fewer studies on these compared to the DRD4, and therefore conclusions are harder to derive. Starting with the DRD1 gene, there appears to be a tentative association with ADHD [632] and in particular with inattention [633]. However, more work needs to be done to replicate such findings. The DRD2 gene has surprisingly had little attention given the extensive knowledge gained by studying the D2 receptor. Of those studies that have been conducted, there is again no firm conclusion to be derived [597], although more recent studies are starting to find an association with hyperactivity [634–635]. An interesting study by Waldman exemplified the gene/environment interaction [636]. Waldman found that there was an interaction between the DRD2 genotypes and mother’s marital status and number of marriages or cohabiting relationships. Not many genetic studies look for such interactions.

The DRD3 receptor again has few studies attending to its association with ADHD. Such studies do not place the DRD3 receptor in an important position regarding ADHD [597]. The DRD5 receptor has appreciably more evidence to support a role in ADHD, as indicated in a recent meta-analysis [596]. But like all the other studies on dopamine receptor genes, the effect size of this gene is described as only modest [637].

Dopamine is synthesized and metabolized by several enzymes that have identified genes (see chapter 7). The role of tyrosine hydroxylase appears to be non-existent, whereas dopamine decarboxylase (which converts the precursor DOPA into dopamine) has some evidence to support its involvement, as well as the enzyme dopamine beta hydroxylase, which converts dopamine to noradrenaline [598]. The metabolic degradation of dopamine by catechol-O-methyl-transferase has shown some promising association with ADHD, but others have not found an association [638]. The effects of this gene are also different in males and females, with males been more affected by it [639].

I have focused on dopamine, like so many geneticists have, but that is not to say that there aren’t any other potential genes to study. Noradrenaline and serotonin genes have all been identified in ADHD [596]. How these translate to ADHD is uncertain. What is interesting is the role of noradrenaline, as this is where atomoxetine works to bring about change. Other systems involved in neural functioning have also been assessed with varying degrees of association (see [597]). A recent study looked at adult ADHD and a number of genes plus personality and stress factors. The authors found no association across several genes (SLC6A3, DBH, DRD4, DRD5, HTR2A, CHRNA7, BDNF, PRKG1, and TAAR9), but did find an association of personality types and the scores on a rating scale [640].

We clearly have lots of genes enjoying a modest association with ADHD. But how does this translate to ADHD? This is yet another holy grail of science. Up to this point we have seen that genes are associated with ADHD and this implies a single direction of action. We are aware that the expression of the gene is dependent upon environmental factors, but can the genes be influenced themselves? A report emerged in 2007 suggesting that methylphenidate altered the DNA of rats in relation to cancer. This report noted the effect was greatest in dopamine-rich areas of the brain [641]. Since then, however, studies in humans have not found any evidence to support such claims [642–643].

Summary

Whilst there is some evidence that ADHD is a disorder that may be genetically transmitted, there is no actual gene for ADHD. ADHD runs in families, but so does religion! Understanding why ADHD runs in families is important in terms of a biological basis, but also for the environments that can trigger the expression of the gene. With ADHD a single gene is not an option. In fact there is no gene for any psychiatric disorder [644–645]. Kendler states

that the phrase “X is a gene for Y,” … [is] inappropriate for psychiatric disorders. The strong, clear, and direct causal relationship implied by the concept of “a gene for …” does not exist for psychiatric disorders. Although we may wish it to be true, we do not have and are not likely to ever discover “genes for” psychiatric illness.

[644] (p. 1250)

According to Professor Sir Michael Rutter,

genes do not code for behaviours. Genes are casually implicated … in the biochemical pathways that play a role in individual differences in susceptibility to behaviours of all kinds, normal and abnormal.

[602] (p. 35)

Where does this leave us? Faraone [646] conducted an analysis on over 1,100 families of those with ADHD and concluded that there are no large gene effects. By contrast, Kuntsi et al.

envisage a rapid increase in the number of identified genetic variants and the promise of identifying novel gene systems that we are not currently investigating, opening further doors in the study of gene functionality.

[647] (p. 27)

Clearly ADHD is genetically complex with many environmental factors having a large effect. Difficulties in identifying genetic and environmental interplay will continue, but that is not to argue that the search is futile. The idea that all ADHD is caused by the exact same mechanism is a faulty assumption – we need to be open-minded about the cause of the disorder. It may be that understanding the biological bases of behaviors such as impulsivity and the genes that code for such biologically mediated behavior will be a more successful approach than looking at a poorly defined heterogeneous group such as all those with ADHD. Before we can identify the genes for ADHD, we have to know more about the disorder and how to define it. We must also remember that the diagnostic criteria avoid assumptions about cause, and that this is actually a strength when we consider multiple etiological routes to ADHD.

One might have hoped that genetics would have helped with diagnosis – it would certainly have silenced some of the critics of ADHD. Sadly, such conclusive diagnosis is extremely unlikely. We would benefit from a robust marker for ADHD, diagnosis would improve, but the search for a marker is also hindered by a lack of specificity of diagnosis which leads to a circular argument (chicken vs egg) and frequent comorbidity.

Evolutionary accounts of ADHD are an interesting aside in the debate. I consider them to be more entertaining and thought provoking, rather than actual evidence.

Finally, if there was a gene found that was clearly related to ADHD without ambiguity, what would we do about it? Just by having a gene that is associated with a particular outcome does not mean that it will definitely happen and that we are passive victims of the gene. We can modify environments to minimize the chance that the gene will it express itself. We can use genetic susceptibilities and markers to guide treatment [648]. But we should express caution when looking at genes for behaviors; genetic theories were instrumental in guiding some of the atrocious views and policies of Nazi Germany.

Notes

1 http://www.ritalindeath.com/Gifted-Children.htm.

2 http://www.ornl.gov/sci/techresources/Human_Genome/faq/genenumber.shtml.