ADHD gene SLC6A4 favors males over females

In our last post, which asked the question "Are ADHD genes Gender Dependent?" we introduced four genes believed to be associated with the disorder of ADHD:

• SLC6A4 gene
• COMT gene
• SLC6A2 gene
• MAOA gene
  

In the next four posts, we will investigate each of the 4 ADHD genes listed above.

SLC6A4 gene, gender effects, and ADHD:

Out of the four genes listed above, the SLC6A4 gene has the least gender-based effects. The authors of the original paper on gender effects of four genes actually concluded that the gender specific influence of SLCA4 gene was not statistically significant. Nevertheless, the authors briefly noted that there was a greater influence on males than females for this particular gene (in the summarizing abstract portion of the paper).

The particular region of investigation on the SLC6A4 gene, which is located on the 17th human chromosome, was at a specific marker rs2066713 (If you are not familiar with this terminology, this is not important, it is just a way of citing a specific region of DNA and can be used to pinpoint a more exact location on a gene for studies on genetic variations, mutations, etc.). According to the study, at this specific marker on the SLC6A4 gene there was a higher likelihood that ADHD boys would receive the DNA base thymine ("T" for short) at this particular location than did ADHD females. This suggests that this "T" form (or "allele", which is a particular form or variation of a gene) at this particular spot on the 17th human chromosome which contains the SLC6A4 gene is more likely to be passed on to males with ADHD than females with ADHD. In other words, this "T" form of the SLC6A4 gene may be more associated with ADHD in males than in females. Of course, we must reiterate, that although a gender difference was observed, it was not sharp enough to be considered statistically significant, according to the original study.

Some other thoughts about the SLC6A4 gene and potential relevance to ADHD symptoms and behaviors:

• The SLC6A4 gene is often referred to by other more common names: the serotonin transporter gene (also abbreviated as 5-HTT, Serotonin Transporter, and SERT) is believed to be associated with a number of depression-related mechanisms. Interestingly, the link between the serotonin transporter gene and depression may also be susceptible to stress and other environmental factors. This gene is responsible for coding for and ultimately producing a serotonin transporter protein, which is frequently implicated in depression-related illnesses and is the target of antidepressant medications, such as Paroxetine (Paxil), Imipramine (Tofranil) and Fluoxetine (Prozac). In addition, the products of the SLC6A4 gene are also affected by amphetamines, which among some of the most common types of ADHD stimulant medications. In other words, the different forms of this SLC6A4 gene may actually play a role as to how an individual acts to a particular antidepressant or amphetamine medication. Again, keep in mind that there is often a fair amount of overlap of depression with ADHD (some experts argue that a "Depressive" form of ADHD should actually warrant its own ADHD subtype), so it is possible that gender based differences in this gene may be related to this hypothetical subtype in particular.

• However, other evidence suggests that the SLC6A4 gene may not be exclusively labeled as a "depressive gene". A study done on multiple genes believed to affect aggression and impulsivity (the latter being a common trademark of ADHD, while the former is occasionally seen extreme cases, although much more rarely, and typically only in the presence of additional comorbid disorders to ADHD), and found a nominal association between this SLC6A4 gene and cognitive impulsivity. Cognitive impulsivity, in essence, is associated with an individual making hasty decisions without carefully considering the consequences of one's actions, which frequently leads to negative or even dangerous outcomes. Not surprisingly, this is seen at much higher rates in ADHD individuals. Similar features are seen in ADHD individuals who have underactive functioning in the right frontal lobe region of the brain (a diagram of this region is given in an earlier blog post on differences in ADHD kids' brain regions), as well as those who have low tryptophan levels (which often correlates with depression and depression-like symptoms).

• There is also a possible connection of this particular SLC6A4 gene and autism, although numerous other studies have shown conflicting results. Nevertheless, given the fact that there appears to be a notable (but incomplete) overlap of ADHD and autistic symptoms, and the fact that autistic disorders are much more prevalent in boys, it is possible that there may be a tie-in between this "male-dominated" SLC6A4 gene form and a possible ADHD-autism connection.

• Finally, studies have linked variations in this serotonin transporter gene to bipolar disorders. This is also of interest because ADHD and bipolar disorders can occur together frequently and can sometimes be difficult to differentiate, especially at the pediatric level.

In the next few posts, we will be investigating three other ADHD genes believed to have gender-specific effects, which each have a potentially greater sex-related differences than this SLC6A4 gene.

The ADHD and Bulimia Connection

ADHD is a disorder that has numerous comorbids ("comorbids" refer to disorders that often accompany or are seen alongside of ADHD). These include, but are not limited to: Depression, Tourette's, Conduct Disorders, Sleep Disturbances, Restless Legs Syndrome, Body mass and obesity issues, dysgraphia (poor writing skills and abilities), processing disorders, sensory integration disorders as well as several others.

In the midst of all of these co-occurring disorders, there are a few that often evade the attention of both researchers and the general public. One of these is the disorder bulimia nervosa. Bulimia nervosa (which is often simply referred to as bulimia), which is often characterized by eating (and often binging) followed by purging, is a major issue in many industrialized nations, especially among teens and young women. Based on a study by Surman and co-workers, it appears that there is a relatively high correlation and prevalence of bulima and ADHD. A link to a quick synopsis of the study can be found here, but for sake of time, I will summarize a few key findings from the article:

• Impulsive behavior is a hallmark characteristic of ADHD, and impulsivity is also thought to be a major factor in bulimia as well. It is even hypothesized that some type of underlying factor may be responsible for governing both disorders.

• Given the fact that the disorder of bulimia is expressed at much higher frequencies in young females in late adolescence and early adulthood, it is interesting to note that correlations between the two disorders were relatively weak for men and non-adult women. Additionally, this is worth mentioning because the percentage of individuals with ADHD is heavily skewed towards the male side. That being said, the fact that there was not more of a correlation between ADHD and bulimia in males could be a reflection of either a poor sample size or representation of t he general population, or a relatively weak connection between the two disorders (i.e., one this is unable to override the so-called gender bias of bulimia favoring women and ADHD favoring men).

• These results were tallied from 4 relatively large sample pools previously constructed to evaluate the effects of ADHD over an extended, longitudinal, multi-year period of time. This suggests that some of these relatively strong bulimia/ADHD correlations did not appear simply due to random statistical chance.

• Like ADHD, bulimia has been tied to functional imbalances involving several systems of neurotransmitters, which include serotonin and norepinephrine. It is also possible that hormonal surges during puberty may increase imbalances of neurotransmitters like serotonin, especially in females. Since serotonin levels are tied to feelings of satiation or fullness, imbalanced in this key neurotransmitter can interfere with the feedback of normal eating patterns. In addition to social and environmental pressures, this neurotransmitter imbalance may be another contributing factor to the prevalence of bulimia, anorexia and other eating disorders in females of this age.

• Stimulant medications, such as methylphenidate, which are often the first line of treatment for individuals with ADHD, especially those showing pronounced signs of impulsivity and hyperactivity, have shown potential in the treatment of bulimia, albeit through studies with very small sample sizes.

Taking this one step further, it appears that genetics may be an additional overlapping factor involved in stimulant medication treatment for ADHD. For example, some research suggests that different forms of DAT1 may be responsible for the effects of methylphenidate on appetite and eating behaviors including purging (DAT is short for "Dopamine Transporter Gene"). We have seen previously that there is a connection between the DAT gene and ADHD. Located on human chromosome #5, DAT1 has been linked to Parkinson's, Tourette's and substance abuse.

Additionally, proteins coded for by the DAT gene are expressed in high concentrations in the basal ganglia region of the brain. The basal ganglia is essentially responsible, among other things, for determining how fast a person's brain "idles" For example, "type A" individuals, who are often workaholics, easily stressed, and always on the go at 100 miles per hour often have overactive basal ganglia, while the more relaxed, easy-going, "type B" personalities typically have less activity in this critical brain region. While there also appears to be a significant overlap between bulimia and depression, individuals with bulimia typically display higher basal ganglia activities than those with isolated depressive symptoms.

Given the prevalent distribution of this gene's expressed proteins in key brain regions like the basal ganglia, and the role of involvement of these brain regions in eating disorders, the DAT gene may be an important determining and regulating factor for bulimia and other eating disorders, especially in the context of comorbid ADHD.

Please note: These final remarks are simply this blogger's opinion on the subject:
I personally find this connection between ADHD and bulimia to be interesting. However, I do believe that we should be cautious when investigating ADHD comorbid disorders. It is tempting sometimes to fall into the trap of falsely assuming that correlation always implies causation, and trying to find underlying causes for disorders and attempting to link ADHD to every other disorder under the sun.

However, the role of the DAT genes, which have been tied to ADHD, do offer at least some credence to at least some degree of genetic predisposition to both ADHD and bulimia. This claim is further strengthened by the degree of overlap involving medication treatments of the two disorders, namely stimulants. However, there have been several documented cases of the disappearance of bulimia symptoms following treatment with methylphenidate (Ritalin, Concerta, Daytrana, etc.) for comorbid ADHD.

As a result, we may be faced with a "chicken and egg" question: "Does bulimia increase the risk of ADHD or does ADHD increase the risk of bulimia?" (or even "Are they both side effects of an even larger underlying cause?"). Another plausible explanation is that ADHD is a culmination of secondary effects involving bulimia and other eating disorders. Constant purging will typically wreak havoc on the digestive system and lead to improper food and nutrient absorption. I have hinted in previous posts that digestive disorders such as celiac disease can often manifest symptoms which closely approximate those of ADHD. Given the mounting evidence connecting ADHD (or other disorders which exhibit closely related symptoms which could potentially lead to a "false" diagnosis of ADHD if one is not careful) to nutrient deficiencies, it is quite possible that ADHD and its symptoms are secondary effects of nutritional deficits caused by eating disorders such as bulimia.

ADHD gene #6. Serotonin receptor 1B gene (HTR1B)

ADHD Genes

ADHD Gene #6: Serotonin Receptor 1B (HTR1B), human chromosome #6 (section q13)

This is our sixth gene of topic in our discussion of ADHD genes. The Serotonin Receptor 1B gene (HTR1B). Like the 5 ADHD genes previously discussed, the gene HTR1B is thought to have at least some influence on the development of ADHD. (If you would like some more background information on what genes, chromosomes, DNA and alleles are, and how they relate to ADHD, please check out this link to another section of the blog here. I have outlined some of the specifics in this area). As its name suggests, this gene is responsible for creating a specific binding site (or think of a "docking site"), for the important neurochemical serotonin. Essentially, there are multiple forms of this gene, which is located on the 6th chromosome in humans (the "q13" refers to a more specific location of the gene on the chromosome, if you would like further explanation on how this looks, please click here).

As mentioned in another post, sometimes the smallest changes in DNA can produce noticeable results in the resulting biology, and ultimately, behaviors, of an individual. This gene appears to be no exception. At one specific point of this serotonin receptor gene (HTR1B), some individuals have a DNA base of "G" (short for "Guanine"), while others have the DNA base of "C" (short for "Cytosine", for more info on what this means, please click here). It appears that the simple change of one small piece of DNA from a "C" to a "G" on this particular "ADHD gene" can have a significant effect with regards to ADHD. Individuals with the "G" form of this particular gene are statistically more likely to have ADHD than those with the "C" form.

Furthermore, the connection with ADHD seems to be strongest to a particular subtype of ADHD. Individuals with the "G" form, or allele, tend to exhibit behavior that is more concentrated on what is referred to as the inattentive subtype of ADHD. The inattentive subtype, as its name suggests, is a form of ADHD in which the inability to maintain attention for a necessary period of time is the dominant negative attribute of the disorder (in contrast to other subtypes of ADHD, which have a more concentrated impulsive component, and/or hyperactive components, which are highlighted by highly impulsive or hyperactive behavior, respectively). While other genes may be tied to these other types of ADHD, the "G" form of the HTR1B serotonin receptor gene appears to be significantly correlated primarily with the inattentive ADHD subtype.

Please remember that the "G" form of this gene is not some weird mutation or genetic malfunction. It is a perfectly common form of the gene that is found in a number of regular individuals. Furthermore, there have been several studies done on this form or allele of the HTR1B gene, including one done on fraternal twins that did not show a significant correlation between the "G" form of the gene and the frequency of ADHD. Nevertheless, the data from several other studies, when pooled together, have strongly suggested a significant statistical correlation between the "G" form and the likelihood of exhibiting inattentive ADHD behavior. In other words, we should be cautiously optimistic about this association. Keep in mind, however, that the presence of this form of the gene, or any of the previously discussed "ADHD genes" does not, single-handedly, "doom" an individual to ADHD, it simply means that individuals with this form of the gene are statistically more likely to develop ADHD. We will be wrapping up this section of posts on ADHD genes with the seventh and final ADHD gene, the SNAP 25 gene, in tomorrow's blog.

ADHD genes