Is There A Genetic Cause For ADHD?

What we know is that ADHD is associated with problems in dopamine receptors, or the neurons in the brain that respond to the neurotransmitter dopamine. There are five kinds of dopamine receptors (that have been identified) in the brain, and five genes (that have been identified) that code for the construction of these neurons. These kinds of neurons are simply numbered D1 through D5, and the associated genes that code for building these neurons are simply numbered DRD1 through DRD5.

The DRD4 Gene

The DRD4 gene is very interesting. Li et al (2006) explain this gene includes 3400 pairs of nucleobases, and there are several additions, deletions, and repetitions that are commonly seen in this gene. There is a particular subset of 48 of these base pairs that seems related to ADHD. Sometimes this subset of 48 base pairs appears only once on the gene, which is the “normal” version of the gene. However, sometimes this subset of 48 base pairs is repeated, which makes for an allele, or a different version of the gene. This repetition can happen anywhere from one to nine times. This would mean there is one gene, but that scientists have identified 10 different versions of it. These different versions are simply numbered to represent how many times the subset of 48 base pairs occurs. Thus, DRD4 represents the “normal” gene with this subset of 48 base pairs included only once, and DRD4 2R, DRD4 4R, and DRD4 7R refer to the alleles where this subset of 48 base pairs occurs two times, four times, and seven times respectively.

Why would this section of the gene be repeated? It’s not clear, but Seaman et al., 1999 identified a section of 120 base pairs that also seems to be repeated, and that occurs at the beginning of the gene. They believe that a repeat in this early section of the gene causes repeats in the later 48 base pair section. Further, they note that chimpanzees, gorillas, and orangutans do not have this 120 base pair section of the gene, and further do not show repeats in the 48 base pair section like humans do.

Chang et al (1996) studied genetic samples from 36 populations around the world and found:

the DRD4 2R allele was less common, as they found it in 8% of the genetic samples; however, it was not evenly distributed, as they found it much more common (18%) in genetic samples from East and South Asia
the DRD4 4R allele was very common, as they found it in 64% of genetic samples; it was evenly distributed around the world and so it appeared at about the same rate across the world
the DRD4 7R allele was less common, as they found it in 21% of the genetic samples; however, it was not evenly distributed, as they found it in 48% of genetic samples from North and South America, but only in 2% of genetic samples from East and South Asia
the DRD4 9R allele was rare, as they did not find it in any of the genetic samples around the world
the DRD4 10R allele was uncommon, as they found it in only 0.2% of the genetic samples around the world

Li et al (2006) r eviewed 50 studies of the DRD4 gene, and found:

the DRD4 4R allele was very common, existing in 60% to 77% of study samples, and was less likely (based on 27 studies) to be associated with ADHD (though, as noted below, it may be less related to hyperactive behavior associated with ADHD)
the DRD4 5R allele was uncommon, as they found it in 0% to 8% of study samples (all European), and it was also strongly associated (based on 20 studies) with ADHD
the DRD4 7R allele was also less common, existing in 9% to 25% of European study samples and none of the Asian samples, and was strongly associated (based on 33 studies) with ADHD

Farone et al (2001) review the literature and report, based on 22 studies with over 2800 people with ADHD and over 4600 people without ADHD, that these studies support that people with the DRD4 7R allele are more likely to have ADHD. Further, Farone et al categorized these studies according to the different methodologies, or different ways to recruit participants and identify their genes. The results do not appear to be based on methodology. Thus, the link between ADHD and the DRD4 7R allele is solid, and is not a link that is shown only when scientists conduct the study one way and not when they conduct it a different way.

Interestingly, Krämer et al. (2009) note the D4 dopamine receptor is important in inhibiting activity in the pre-frontal cortex, and inhibition is a problem in ADHD. They asked a small group of people with the DRD4 4R (10 people) and DRD4 7R (10 people) alleles to perform a “Go/No-go” task. For this kind of task, participants respond under certain conditions (for example, press a button on a keyboard when they see a “V” on the computer screen – the “Go” condition), and do not respond under other conditions (for example, do nothing when they see an “5” on the computer screen – the “No-go” condition). The task can be made more easy or more difficult:

An easier task would be to use “V” (Go condition) and “5” symbols (“No-go” condition), as these symbols do not appear very similar (so it is easier to tell a “go” from a “No-go” condition), and to present them on the screen for longer periods of time (so participants have more time to decide whether it is a “Go” or “No-go” condition).
A more difficult task would be to rotate the “V” and “5” symbols or move them around the screen so they are harder to recognize, or use “1” (number one for “Go” condition) and “l” (letter L for “No-go” condition) symbols, as these symbols look alike (so it is more difficult to tell a “Go” from a “No-go” condition). Alternately, responses for the “Go” condition can vary so that participants press a button with the left hand if the symbol is on the left side of the screen or right hand if the symbol is on the right side of the screen. Further, symbols can be flashed on the screen for shorter periods of time (so participants have less time to decide whether it is a “Go” or “No-go” condition).

Participants with the 4R allele were just as accurate as those with the 7R allele when the task was simpler. However, as the task became more difficult, the 4R group became less accurate in their performance. While they responded just as quickly and made just as many errors (they did press the button when they should not have done so), they responded correctly less often (they did not press the button when they should have), indicating they had more difficulty paying attention to the task.

While this was a small study, Krämer et al. note that the results show that a specific form of the gene can be linked to different patterns of behavior and performance. This strengthens the argument for a genetic cause for ADHD, as well as for a complex genetic cause in which different genes and combinations of genes could produce different behavioral (more impulsive behavior with the 7R allele) and cognitive symptoms (more inattention with the 4R allele).

While Krämer et al. focus on the 4R allele, other studies have focused on the 7R allele. Settle et al., (2010) note that the DRD4 gene has been associated with the brain’s reward system (for everyone, not just for people with ADHD). This means the dopamine receptors tied to the DRD4 gene are associated with seeking sensation and novelty to feel excited, and avoiding monotony to to avoid feeling bored. The 7R allele especially has been linked to these traits in many studies, but not in all student of the gene. However, they note that behaviors like sensation-seeking are shaped by genes as well as by the environment and social setting. Thus, people with the 7R allele might seek stimulation by associating with people who hold a wide range of different beliefs, and so might tend to be more politically liberal. Thus, the 7R allele might support holding more liberal political beliefs and having more friends, but would not determine beliefs or friendships.

To test this, they studied genetic profiles of people who participated in the National Longitudinal Study of Adolescent to Adult Health (Add Health). The Add Health study collected a nationally representative sample of over 90,000 people, and followed them from adolescence (age 13 to 15 years) into young adulthood (age 24 to 32 years). As part of the Add Health study, researchers surveyed/interviewed participants four times over a 13 year period about their adjustment and the development of their relationships, personality, and political and spiritual beliefs. As part of the study, they also collected some genetic samples, allowing Settle et al. to identify about 1000 people with the 7R allele and about 1500 without it for their study.

As expected, Settle et al. found that having the 7R allele was not significantly associated with the number of friends a person has, or with the political beliefs a person holds. However, having 10 or more friends during adolescence was associated with being more likely (by 40%) to hold more liberal views in young adulthood, but this held true only for people with the 7R allele. There was no relationship between friends and political beliefs for those without the 7R allele.

The authors are clear that, as they expected, results do not show that the 7R allele determines political beliefs or number of friends. Rather, for people with the 7R allele, having more friends supports holding more liberal political beliefs. While not a study about ADHD, the Settle et al. study strengthen the connection between genes and behavior (in a social context), and show a link between genes related to ADHD and behaviors associated with ADHD.

The DRD4 Gene in Other Cultures

Leung et al., (2005) note that the research supporting the link between ADHD and the 7R allele is promising, as is the fact that the 7R allele is twice as common in ADHD children (43% to 49% have this allele) as compared to non-ADHD children (21% to 23%). However, these findings are based on children of European ancestry; as noted above, the 7R allele is not common in Asian samples. They studied a small sample of Chinese children diagnosed with ADHD, and found that none had the 7R allele, but 33% had the 2R allele. They also examined five samples of Chinese people from around the world, and found 18% to 22% of people in those samples showed the 2R allele. Thus, the 2R allele was almost twice as common (1.65 times as common) in ADHD Chinese children as compared to non-ADHD Chinese children.

Other Genetic Evidence

The DRD5 gene likely is also related to ADHD. Li et al (2006) explain this gene contains 2031 pairs of nucleobases, and there is a particular set of 148 base pairs that can be repeated. They found that it was strongly linked to ADHD (based on nine studies). There is also a particular set of 136 base pairs on this gene that can be repeated, and repeated sections seems to confer a protective effect (based on three studies), in that children with that allele were less likely to have ADHD even if other family members did. Thus, while there is a good deal of research on the DRD4 gene and alleles, there likely are other, perhaps many, many other, genes that work with the DRD4 gene and lead to ADHD.

Fliers et al., (2012) note that 5% of children show motor coordination problems, ranging from delayed crawling and walking to problems in general coordination. Heritability estimates show that as much as 69% of the causes for these kinds of problems is likely to be genetic. Researchers explaining how these problems happen suggest general delays in brain development, and as well as problems in specific areas of the brain (including the basil ganglia). Fliers et al., (2012) further add that 30% to 50% of children with ADHD also show coordination problems, and heritability estimates show that as much as 50% of the causes for ADHD is also genetic. They wondered whether they could find a link between the genes linked to ADHD and the genes linked to motor problems.

They studied a sample of genes from almost 900 children between the ages of 5 and 17 years, 85% of them male, from 8 different countries, all diagnosed with ADHD. Further, 22% had diagnosed motor problems (most showed developmental coordination skills in the lowest 15th percentile in areas like handwriting and coordination), and another 25% showed motor problems without a diagnosis. While they found no single gene was associated with both motor problems and with ADHD, they found a number of genes related to motor problems and ADHD were present in both groups of children:

A large number of these genes are involved in the networking of neurons, or the interconnections between neurons and groups of neurons that form the basic wiring of the brain.
A large number of these genes are also involved in motor and muscle control, and are linked to the development of Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig’s Disease) and Restless Leg Syndrome (RLS). They note that while about 2% of children and adolescents without ADHD have RLS, 44% of those with ADHD show symptoms of RLS, and 26% of those with RLS shows symptoms of ADHD.
Genes in common were also related to depressed neurotransmission, or a reduced use and effectiveness of neurotransmitters (like Dopamine).

Thus, this kind of research does not show exactly which genes cause ADHD, but it does show that the genes we know are involved in the problems associated with ADHD are more common in people with ADHD.