Monday April 18 2011
A mix of genes and environment are likely to cause ADHD
The Daily Mail has today reported that scientists have identified “a mutant gene that almost trebles the chances of a child being hyperactive”. The newspaper says that the discovery paves the way for new drugs to treat attention deficit hyperactivity disorder (ADHD).
The research in question examined a gene called GIT1 in 192 children with ADHD and 196 children without the condition, and found that a specific variation in the gene was more than twice as common among the affected children. However, this link will need to be confirmed in further, larger samples. The study also found that young mice genetically engineered to lack Git1 (the mouse equivalent of the gene) were more active than normal mice, but that this could be reversed by treating them with drugs used to treat human ADHD.
ADHD is a complex condition, and both genetic and environmental factors are thought to play a role. The gene identified in this study may play a role, but many other genes have also been investigated in this condition, and may also play a role. Much more research will be needed before we fully understand the causes of this condition. The results do suggest that mice lacking Git1 may be useful for testing new drugs for ADHD. However, this animal model cannot fully replicate this complex condition and, therefore, mouse models will only prove useful for initial drug testing.
Where did the story come from?
The study was carried out by researchers from Korea Advanced Institute of Science and Technology and other research centres in South Korea. It was funded by the Ministry of Education, Science and Technology in Korea, the National Research Foundation of Korea; the Seoul National University Hospital Research Fund and a TJ Park doctoral fellowship.
The study was published in the peer-reviewed journal Nature Medicine.
The Daily Mail report provides an accurate account of what the researchers did. However, its suggestion that the first genetic variants in the DNA of children with ADHD were identified “last year” is puzzling. ADHD has long been thought to have a genetic component and studies conducted earlier than last year have already found a number of genetic variations to be associated with ADHD. It is also not yet clear whether this finding will lead to new drugs for ADHD, as the news reports have suggested.
What kind of research was this?
This research included a case control study looking at whether variations in a particular gene, the GIT1 gene, were associated with ADHD. It also included animal research looking at the effects of a lack of Git1 in mice.
This research combines two of the steps that are used in looking at whether specific genetic mutations are capable of causing disease. These are the identification of associated genetic variations and testing to determine what effects these might have in animals. Conditions such as ADHD are complex and, although tests in animals may further our understanding of them to some extent, it is very difficult to replicate this type of condition in animals.
What did the research involve?
Previous genome-wide analyses have identified various regions of DNA that contain variations associated with ADHD. The researchers assumed that genes that could influence whether a child develops ADHD must be involved in nervous system function. Therefore, they looked at these regions of DNA to identify genes known to play a role in the nervous system. One such gene that they identified was GIT1.
First, they compared the sequence of the GIT1 gene in 192 Korean children with ADHD and 196 age-matched controls. They looked in and around the GIT1 gene for the presence of 27 single nucleotide polymorphisms (single letter variations within the genetic code). They were looking for variations that were more common in children with ADHD than in controls.
The researchers then genetically engineered mice to lack their equivalent of the human GIT1 gene (called Git1 in mice), and looked at the effect this had on their behaviour. They also looked at the effect the drugs amphetamine and methylphenidate had on these mice. These drugs are used to treat ADHD in humans, and researchers wanted to see whether they would affect the animals’ behaviour.
What were the basic results?
The researchers identified one particular single letter variation in the GIT1 gene, called rs550818, which was more common in children with ADHD than controls. Of the children with ADHD (cases),
19.3% carried at least one copy of the variant, compared with 9.2% of controls. After taking into account differences between groups that could affect the results (including gender and IQ scores), the odds that children with ADHD carrying one copy of the variant were 2.7 times higher than the odds of controls carrying this variant.
The researchers found that about half of the mice genetically engineered to lack the Git1 gene died shortly after birth. The remainder of the mice lacking Git1 weighed a lot less than normal mice of the same age (60-70% less), but otherwise looked normal.
In behavioural tests, eight-week-old mice lacking Git1 were more active than normal mice when exposed to a new environment, and in their home cages at night (the time when mice are normally most active). By the time the mice lacking Git1 reached the age of seven months, their activity levels were similar to those of normal mice. Mice lacking Git1 also had impairments in memory and learning compared with normal mice.
Mice lacking one copy of the Git1 gene (they usually have two copies) did not appear to differ in their behaviour from normal mice.
When eight-week-old mice lacking Git1 were treated with amphetamine or methylphenidate it reduced their activity to the same level as normal mice treated with a placebo injection of salt water. Normal mice treated with these drugs became more active.
How did the researchers interpret the results?
The researchers concluded that their study has identified a previously unknown involvement of the GIT1 gene in human ADHD. They also say that the lack of this gene in mice leads to ADHD-like characteristics that respond to the types of drugs used to treat human ADHD.
This study has suggested a role for the GIT1 gene in human ADHD. ADHD is a complex disorder, and several genes as well as environmental factors are likely to play a role. Many genes have already been investigated for potential links to the condition, and this study adds one more.
The number of children in the case-control part of this study was relatively small (388 individuals in total) and, ideally, the association between the variation identified and ADHD would be confirmed through further studies. It is also important to note that not all children who carried the GIT1 variant had ADHD, and most children with ADHD did not have the GIT1 variant.
Although removing the Git1 gene in mice led to them having hyperactive behaviour at a young age, this does not necessarily confirm that the variant identified in humans is having the same effect. It would be of interest to see whether mice carrying the genetic variation associated with human ADHD (rather than lacking the gene entirely) showed any behavioural effects.
The results suggest that mice lacking the Git1 gene may also provide an animal model for studying ADHD and for investigating potential new drug treatments. However, as with all complex human conditions, the model will not be able to replicate the condition fully.
Studying the genetic contribution to complex diseases such as ADHD is difficult. Much more research will be needed before we fully understand the causes of this condition.