ADHD, Gender, and the SLC6A2 gene

We are currently plowing through the four candidate ADHD genes listed below which have been investigated for gender dependence based on an article by Biederman and coworkers. The four genes are:

• SLC6A4 Gene
  
• COMT Gene
• SLC6A2 Gene
• MAOA Gene

We have seen in previous posts that both the COMT gene, and to a lesser extent, the SLC6A4 gene have exhibited a gender dependent behavior with regards to the disorder of ADHD. In other words, certain forms of these genes tend to turn up at a higher frequency in males with ADHD than in females with ADHD. While both SLC6A4 (which is often referred to as a Serotonin Transporter Gene or SERT), and the COMT (short Catechol Methyltransferase, an important enzyme of relevance to ADHD and related disorders) gene effects on ADHD are suggestively greater in boys, the SLC6A2 and MAOA genes are believed to have a greater impact on ADHD in girls. We will be investigating the SLC6A2 gene here:

Location of the SLC6A2 gene:
SLC6A2 is a gene located on the 16th human chromosome. It is responsible for coding the important protein Norepinephrine Transporter Protein 1, and hence, the gene (as well as the protein that it codes for) frequently go by the abbreviation NET.

Clinical relevance of this SLC6A2 gene:
Norepinephrine is an important signaling agent in the nervous system, and deficiencies of this important chemical are often seen in various brain regions of individuals with ADHD. The protein is analogous to other proteins we've previously discussed, such as the Serotonin Transporter Protein, which is often abbreviated as SERT (which is coded by the SLC6A4 gene which was previously mentioned), and the the Dopamine Transporter Protein (DAT), which we've discussed in other previous posts. The NET, SERT, and DAT proteins are responsible for clearing Norepinephrine, Serotonin and Dopamine from the areas in between nerve cells and into the surrounding cells themselves, which aims at establishing an optimal balance of these three signaling chemicals in and out of the cells.

This is especially important and clinically relevant to ADHD, where the signaling chemicals (especially Norepinephrine and Dopamine) are often out of balance, often exhibiting a sub-optimal concentration of these signaling agents on the outside of the cells. Many stimulants and other ADHD medications work by correcting this imbalance by targeting these protein transporters which shuttle the signaling chemicals in and out of the cells and surrounding areas.

However, different gene forms can actually affect the activity of these shuttling transporters as well, which can disrupt the balance of these important neuro-signaling chemicals Norepinephrine, Dopamine, and Serotonin. As a result, different forms of the genes that code for these transporter proteins may actually play a role of how great the imbalance of these signaling chemicals is, which can affect how much of a particular medication is actually needed to correct these imbalances. In other words, the amount of stimulant medication one may need for ADHD may ride, at least in part, on which form of COMT, NET and DAT genes that particular person has. For a more visual and detailed look at this gene-medication relationship, please see this earlier blog post on titled ADHD genes influence medication dosage.

Other disorders associated with the SLC6A2 gene:
Anorexia:
There is widespread discussion as to the overall prevalence of eating disorders in individuals with ADHD compared to the general population. However, several studies have linked ADHD to significantly higher rates of eating disorders. If this holds true for the population, another study of potential interest may involve the SLC6A2 gene. A particular form of this gene (referred to by the alternate term norepinephrine transporter gene in the paper) was associated with doubling the risk of developing anorexia nervosa.

Orthostatic Intolerance:
Orthostatic intolerance is a disorder in which noticeable physiological differences (heart rate, lightheadedness, fainting, etc.) occur as a result of postural changes (i.e. going from laying down or sitting to standing). Of course, some of these signs occasionally affect everyone, but for some individuals, the differences are much more pronounced and much more severe.

According to a study done by Shannon and coworkers, it is believed that the SLC6A2 gene (again, called norepinephrine transporter in this paper) may play a role in the effects of orthostatic intolerance. A mutant form of this norepinephrine transporter gene resulted in around a 50-fold reduction in functional ability of the norepinephrine transporter protein coded for by this mutant form of the SLC6A2 gene and was susceptible to major changes in norephinephrine levels and pronounced physiological changes upon changing postural positions (to the standing position). As a result, a fully functional SLC6A2 gene is apparently critical in regulating stable physiological functions in individuals.


Male vs. Female Differences of SLC6A2 and ADHD:
Like the SLC6A4 gene (and unlike the COMT gene) mentioned previously, the SLC6A2 gene showed statistically significant gender-based differences in preliminary tests, but failed to reach statistical significance upon a more detailed analysis. However, the authors of the study were quick to point out that there were gender-based differences in a specific sub region of this gene. Nevertheless, we must keep in mind that this gene, should it actually influence gender-based differences in ADHD patients, would play a much more minor role in the process than would other genes such as the previously-discussed COMT gene and the soon-to-be discussed MAOA gene.

As a note of potential interest, animal studies have actually shown differences based on analogous forms of this gene. For example, a study on rats (which, in general, shows a surprisingly high degree of overlap with human psychological disorders), showed that there was a gender-different responses to stress, even after gender-based hormonal differences had been taken into account. In addition, another analogous rat-based anxiety study (note that we previously discussed how females with ADHD exhibit more comorbid anxiety disorders than do ADHD males) showed that female rats without the SLC6A2 gene were much more prone to exhibiting behaviors of fear and anxiety than were male rats without the gene.

This possibly suggests a greater gender dependence of this gene, that is a greater "need" for a fully functioning SLC6A2 gene in females than in males. This may have potential implications in ADHD individuals, (many of whom exhibit some sort of anxiety-related disorder alongside their ADHD) by demonstrating a gender-based genetic influence into the mix. In this blogger's opinion, it is possible that genetic and clinical screenings for the SLC6A2 gene may be potentially useful factors in predicting one's likelihood of developing ADHD with a co-occurring anxiety disorder in the near future.

In the next post, we will finish our discussion of the four gender-based ADHD genes by going over the last gene of the series, the MAOA gene.