Friday, March 13, 2009

ADHD, Gender and the COMT gene

We have previously introduced a list of four ADHD genes which are being investigated for gender-specific effects. A list of the four can be found below:

In the previous post, we investigated the SLC6A4 gene, which is located on the 17th human chromosome, and has a possible (but, at the current time a statistically questionable) preference towards being expressed in ADHD males than in ADHD females.

The second gene on the list, the COMT gene, is also believed to have a male-favoring genetic effect with regards to ADHD individuals. The COMT gene is located on the 22nd human chromosome. "COMT" is actually an abbreviation for catechol methyltransferase, which is an important enzyme involved in a number of neurological functions which have numerous ADHD-like implications. This important enzyme is coded for by the COMT gene (many genes share a name with the proteins which they encode). Unlike the SLC6A4 gene, this COMT gene has more grounds for statistical significance, both in gender-dependent and overall studies of genes believed to be associated with ADHD.

We have discussed the COMT gene and its role in ADHD in previous posts. We have also explored the possibility that COMT gene variations may affect attention control. Additionally, the presence of a specific form of the COMT gene, combined with a low birth weight, may be correlated to a higher prevalence of conduct disorders (aggressive, violent, oppositional and even criminal behaviors), which are sometimes seen at higher-than-normal levels within a subset of the ADHD population. Finally, different variations of the COMT gene may influence medication dosage levels for stimulants and other ADHD drugs.

Gender specific effects of the COMT gene and ADHD:

It is important to note that there is a fair amount of diversity in individual genes among the human (as well as other species) populations. Many of these genetic variations do not exhibit direct effects or physiological differences. However, in some cases, variations caused by a single bit of DNA in a key region of a gene can have significant effects. Such is the apparent case with the COMT gene.

Individual pieces of DNA (or nucleotides), are numbered for reference purposes. For the COMT gene, the Val158Met variation (also known as a polymorphism, which is another word for a variable form of the same gene), has been studied relatively extensively. "Val158Met" essentially refers to a DNA sequence change at the 158th position in the COMT gene which results in either a Valine (Val) or Methionine (Met) amino acid at a specific location in the COMT enzyme. This single DNA change in the COMT gene (and subsequent single amino acid change in the COMT enzyme) can result in drastic changes in the COMT enzyme effectiveness. This slight change can have effects on executive brain functions, response to morphine and other pain medications (as well as other drugs, as mentioned in a previous blog post titled ADHD genes influence medication dosage), differences in the overall pain response (among many other factors) and may even play a role into one's predisposition towards cannabis use.

Out of the "Val" and "Met" forms of the COMT gene (and resulting enzyme), there are believed to be gender-related differences. According to a publication on gender-based gene effects in ADHD, Biederman and coworkers found that males with ADHD had a greater likelihood of carrying the "Met version" (or allele) of the COMT gene than did females with the disorder. Another study by Qian and coworkers saw similar results. In addition, the Qian study found that the "Val "form of the COMT gene showed up at higher frequencies in females with ADHD than in males with the disorder.

Taking this one step further, the Met allele of the COMT gene has been tied to impulsive behaviors and aggression, two behaviors more commonly associated with males. Interestingly, a recent study just came out, which found the Met form of COMT gene to be associated more with the inattentive subtype of ADHD, while the Val form of the COMT gene was more connected to oppositional defiant disorders (which are often connected to the hyperactive/impulsive or combined subtypes of ADHD). As a result, the specific allele one has of the COMT gene may be a potentially useful tool as far as predicting which subtype of ADHD a person would be predisposed to, should they actually be diagnosed with the disorder.

Given the numerous associations of COMT in areas related to (as well as unrelated to) ADHD, we should remain on the lookout for future studies regarding the gene. The Val158Met polymorphism of this gene continues to be a hot topic of discussion and study. Additionally, the fact that a number of these associations have gender-based implications, makes COMT potentially the strongest of the four ADHD genes previously mentioned which are believed to have gender-dependent effects and expressions.

In our next post, we will investigate the SLC6A2 gene and its role on the gender dependence of ADHD. Unlike the COMT and SLC6A4 genes we've just discussed, which both have a predilection towards males with the disorder, this SLC6A2 gene is believed to have more of an influence on females with ADHD.