Saturday, March 14, 2009

ADHD, Gender and the MAOA gene

The MAOA gene will be the last of the four-part series on genes believed to be connected to ADHD that exhibit a gender effect. The four genes, which were discussed in an article by Biederman and coworkers are listed below:

  • SLC6A4 gene (also referred to as SERT or Serotonin Transporter Gene)
  • COMT gene (also referred to as Catechol Methyltransferase Gene)
  • SLC6A2 gene (also referred to as NET or Norepinephrine Transporter Gene)
  • MAOA gene (short for Monamine Oxidase)

The first two genes on the list above are believed to exhibit a greater influence on males with ADHD than on females with the disorder. In other words, specific "ADHD" forms of these two genes often show up at significantly higher relative frequencies in males with the disorder than in females with ADHD.

In contrast, however, the SLC6A2 gene, which codes for the critically-important norepinephrine transporter protein, seems to have some type of genetic predisposition to ADHD females. We discussed this in the previous post on SLC6A2.

Location of the MAOA gene in the human genome:

Unlike the other three genes we've discussed, which appear on the first 22 chromosomes, the MAOA is unique in that it is located on the X chromosome (which is a sex-linked chromosome). Because of this, it is, perhaps without surprise, a possible gender-linked difference in ADHD connected to different forms of this gene.

The relevance of the MAOA gene to dosage levels of ADHD medications:

In a previous post, we covered extensively the different forms of the COMT gene and the implications on medication dosage levels. For MAOA, there is apparently an analogous gene-medication dosage connection as well.

Monoamine Oxidase inhibitors (MAOIs) are a class of drugs often used for treatment of depression and related disorders. This class of antidepressants have a mechanism of action that targets the enzyme Monoamine Oxidase, which is coded for by this ADHD gene MAOA. Given the fact that depressive disorders often occur more often and with greater severity makes the gender-based difference of the MAOA gene even more intriguing.

Blogger's personal note (feel free to skip this section, which reflects my personal opinions as to the direction that the ADHD medication battle may soon be heading in the near future):

I have mentioned in previous postings that I believe that analyzing specific genes believed to be associated with ADHD and screening individuals for which forms of the gene they have can be an immensely useful tool in the very near future. Given the fact that even slight variations in a specific gene can result in huge differences in the level of expression enzymes and other proteins encoded by these genes, having one of the "underactive" forms of a certain ADHD gene may play a huge role as to what level of medication dosage one must take.

Since many ADHD medications (as well as medications for many other types of disorders) are initially tailored by the individual's size and weight (in addition to the severity of the symptoms, of course), one's genetic makeup may be an equally important determining factor. For example, let's assume that an individual is exhibiting a number of depression-like symptoms, and is placed on a monoamine oxidase inhibitor drug (Which is actually unlikely, at least initially, since MAOI drugs are typically more dangerous than most other antidepressants, and are often used only as a last line of defense. Nevertheless, for the sake of example, let's consider it.).

Monoamine Oxidase Inhibitor (MAOI) drugs, as their name suggests, reduce the activity levels or expression of the monoamine oxidase enzyme (which is coded for by the MAOA enzyme). Now let's assume that an individual has a relatively rare genetic form of the MAOA gene, which produces an enzyme with only one percent of the activity of the more common MAOA gene forms. Because much less enzyme is produced or expressed compared to a normal case, this particular individual would likely need less of the MAOI drug to do the trick than would someone who expressed a much higher level of the enzyme. As a result, instead of giving a 30 mg dose of the drug (determined by the patient's size and symptom severity), the prescribing physician might want to initially start with a lower dosage. For a similar argument with regards genes and medication dosages dealing with the COMT gene ("COMT" is short for Catechol Methyltransferase) please see an earlier blog entry titled ADHD Genes Influence Medication Dosage.

Other diseases and disorders affiliated with the MAOA gene:

Anxiety: As previously mentioned, girls with ADHD are typically more prone to comorbid anxiety disorders than are boys with ADHD. There is some evidence, based on the mouse model (which is often a surprisingly good approximation of human behaviors with regards to psychological disorders, a topic which will be reserved for later posts) that mutations in the MAOA gene that reduce its function may be related to higher anxiety levels.

Aggressive, antisocial and criminal behaviors and MAOA:

Deficiencies of the enzyme Monoamine Oxidase, which is coded for by the MAOA gene, have been linked to impulsive aggression and related behaviors in mildly retarded individuals. Keep in mind, however, that this was obtained from a small study and that the disorder, known as Brunner Syndrome, is relatively uncommon.

A more focused study found that the MAOA gene may actually play a role in the "nature/nurture" debate as to why some individuals exhibit violent and aggressive behavior and why others do not. This study focused on children who had been mistreated and analyzed which of the mistreated children were prone to aggressive, violent or criminal behavior. According to the study, children who had "high levels of MAOA expression" (that is, children who had genetic variations of the MAOA gene which produced higher levels of the enzyme monoamine oxidase) were less prone to violent behavior, while those who had lower activity forms of the MAOA gene were more prone to criminal behavior.

As a result, screening individuals who have unfortunately endured a history of abuse for specific genetic variations, may actually help predict (and get a leg up on early treatment options for) the likelihood of that particular individual of developing violent, criminal or abusive behaviors themself. While we must guard against the tendency to put too much emphasis into one particular gene (or even group of genes) for predicted a complex and multi-faceted behavior pattern, I personally believe that we should try to take advantage of every little point of potentially valuable information at our disposal.

MAOA and Bipolar disorders:

One note of potential interest, however, is the fact that Brunner Syndrome (mentioned earlier) carries with it relatively high degree of overlap with bipolar disorders. Bipolar disorders may both occur alongside ADHD or exhibit such a similarity of symptoms (especially in younger children) that misdiagnoses between the two can occur. A study by Lim and coworkers found an association between the MAOA gene and bipolar disorders. However, while some other studies have supported this connection between bipolar disorders and the MAOA gene, other studies have brought in to question or refuted the findings. Also, please note that the study was done in males, which, according to the Biederman study are less susceptible to genetic difference-based ADHD than are females with the disorder.

Restless Legs Syndrome:

We have previously discussed some of the connections between ADHD and Restless Legs Syndrome. We have hinted at an underlying iron deficiency, which may affect levels of the important signaling chemical dopamine. A study was done on the MAOA gene and restless legs sydrome and concluded that for individuals with a "high activity" form of the MAOA gene were significantly more prone to developing restless legs syndrome. A note of further interest is that the same study saw an assocation in the MAOA gene variant and restless legs syndrome in females but not in males, lending credence to the possibility that girls may be more susceptible to MAOA gene differences in disorders besides ADHD.

The MAOA gene and disorders associated with specific brain regions:

Attention span: The MAOA gene (like most genes) does not express itself uniformly throughout the body. Instead, certain regions appear to be more targeted more than others. The cingulate is a region of the brain which we've discussed on more than one occasion in previous posts, and essentially acts as the brain's gear shifter. If this brain region is overactive, the individual can become overly focused on one particular topic or action (obsessive compulsive disorders or OCD-like behaviors can ensue), while underactivity in the cingulate region of the brain can result in someone's attention being scattered all over the place, like in most ADHD cases.

A study by Fan and coworkers found that different alleles (different versions of the same gene, which vary from individual to individual) of the MAOA gene corresponded to different levels of activity in the cingulate portion of the brain. These genetic variations and different levels of cingulate activity corresponded to differences in reaction timing to certain attention-based tests. The actual test used in the study was an "arrow test", which is described in more detail in an earlier blog post titled Gene Variations Which Affect Attention Control.

MAOA Gene, Brain Size and Tendency Towards Impulsive Behavior and Violence:

The different forms of the ADHD gene MAOA may affect more than just activity level in the cingulate region of the brain. A 2006 publication by Meyer-Lindenberg and coworkers titled Neural mechanisms of genetic risk for impulsivity and violence in humans found that individuals who had "lower activity" forms of the MAOA gene (and protein which it encodes) actually had smaller volumes in specific brain regions, including the cingulate (as well as larger volumes in other brain regions, some of which are believed to be affiliated with specific forms of ADHD).

There was at least somewhat of a gender-based difference with regards to this MAOA gene/brain size association, which was higher in males, according to this particular study. Thus it appears that while the MAOA gene may play a greater role in ADHD, anxiety and a handful of other disorders in females, it may have more of male-based effect in other disorders (some of which frequently occur alongside of ADHD themselves).

MAOA and Autism:

The gender based differences of the effects felt by different forms of the gene MAOA can also be seen in autism (which is a predominantly "male" disorder), at least based on the findings of some studies. Cohen and colleagues found that male children who had a lower-activity version of the MAOA gene displayed more severe autistic behaviors than those with higher-activity forms of the gene MAOA.

I realize that this has been a long and extensive post on the MAOA gene. To quickly summarize:

  • The MAOA gene is located on the X chromosome, which makes it more susceptible to sex-linked differences (since females have two copies of this chromosome and males only have one).
  • For ADHD and some other disorders which can often occur alongside of ADHD, such as anxiety, the MAOA gene has shown a tendency to have more pronounced effects in females.
  • For other disorders, such Bipolar Disorders, Autism, and Violent/Aggressive behaviors, the MAOA connection appears to be stronger in males. Environmental factors (such as a previous history of abuse) may have a greater interaction with genes such as MAOA than we previously thought.
  • The specific allele or form of the MAOA gene that a particular indivual has may play a role in governing the type of and optimal dosage levels of that individual's medication needs.

This concludes our four-part series on ADHD genes thought to exhibit gender-specific effects. However, we will continue to re-visit some of these topics in future posts on this blog.

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Kelly in Big D said...

This is fascinating! I have an almost 8 year old son with a diagnosis of PDD-NOS (on the autism spectrum) and he tends strongly toward ADHD-inattentive type. He tends to be low arousal, somewhat moody, and sometimes over-focused on preferred activities. He's REALLY running into attention problems at school, so we're looking at trying an ADD med for him.

I was diagnosed ADD-inattentive years ago and have successfully been treated with Adderall, so I'm wondering if, based on his MAO-A (R296R) +/+ (type T) status, would you think something like Vyvanse would be good for him?

I know this isn't medical advice - just looking for other opinions. :) Thanks!

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