ADHD gene #5: Serotonin transporter gene (5-HTT)

ADHD Genes

ADHD Gene #5: Serotonin Transporter Gene (5-HTT, also referred to as "SLC6A4"): 5-HTTLPR long allele, location 17q11.1-12

This is the fifth gene that is being discussed on our list of ADHD genes. If you are not familiar with some of the terms in this post, here is a section on background information as it pertains to our study on ADHD genes. For a list of the other ADHD genes, please click here. The Serotonin Transporter Gene is found on human chromosome #17 (the q11.1-12 refers to a more specific region on the chromosome, and is not important for the time being). As mentioned in previous posts, genes come in different forms or alleles. One of the forms, or alleles of the Serotonin Transporter (5-HTT) gene has been associated with an increased risk of developing ADHD.

It is important to note that the terms Serotonin Transporter Gene, 5-HTT, and SLC6A4 all refer to the gene as a whole. The term "5-HTTLPR" refers to a specific section or part of the gene that can vary from individual to individual. For more background information on how genes are structured, please click here.

When the results of several family studies was pooled statistically, individuals with the "long" allele of the gene ("long" refers a form of the gene that has slightly longer DNA sequence than the shorter form of the gene), had an increased likelihood of developing ADHD than those with the "short" allele of the gene. Nevertheless, there is still some evidence that the "short" form may be tied to a higher incidence of ADHD as well (however, the trend in evidence typically favors the "long" allele).

Based on three different studies, there is some preliminary evidence suggesting that this "ADHD gene" (5-HTTLPR long allele), may be linked to autism as well, but a number of more recent studies have failed to support this claim. Nevertheless, it is known that individuals with certain forms of ADHD may possess higher levels of the neurochemical serotonin, which is also typically seen at higher levels in autistic individuals. Keep in mind that the gene of discussion in this post, 5-HTTLPR, is responsible for transporting serotonin into cells, with the "long form" (the "ADHD form"), transporting more serotonin than the "short" or "non-ADHD" form.

Based on how the most recent classifications, definitions, and diagnoses of mental disorders are done, individuals that fall anywhere on the autistic spectrum cannot be labeled as "ADHD" or vice versa (i.e., an individual may be diagnosed as being one or the other, but not both). However, a number of individuals with ADHD exhibit a number of symptoms that overlap with autism as well as vice versa. Of potential interest, our gene of topic, 5-HTTLPR, is responsible for shuttling serotonin into immune cells called lymphoblasts. Lymphoblasts are essentially an early, immature form of lymphocytes, which play a major role in an immune reaction such as an invading pathogen or an allergic response. The "long form" or "ADHD form" of this 5-HTTLPR gene shuttles more serotonin into the lymphoblast immune cells than does the short, "non-ADHD" form.

Higher levels of serotonin in these types of immune cells have been tied to an increase in migraine headaches, something that is also seen at higher levels in ADHD individuals. However, at the time, the cause is thought to be due more to an improper serotonin breakdown and disposal in these immune cells than transport mediated by the 5-HTTLPR gene. Nevertheless, it is an observation of potential interest.

Serotonin transporters, such as 5-HTTLPR, are also thought to play a role in seasonal affective disorders and depression. Higher activity levels of serotonin transporter proteins are seen during the fall and winter months (when depression is typically higher) than in the spring and summer. Although this 5-HTTLPR is likely not the primary culprit, the "ADHD form" of this gene does result in an environment similar to the "winter blues". This is due to the fact that the longer "ADHD form" of the gene transports more serotonin into cells and away from the space in between the cells. The net result is lower levels of free serotonin, which is typically seen in patients suffering from depression. Not surprisingly, depression is seen in much higher levels in several types of ADHD when compared to the general population.

One caveat here: some of the comparisons here are meant to simply report on a potential genetic overlap among ADHD and other disorders or diseases (migraines, autism, depression, etc.). At this point, there is not enough information to adequately confirm that the "ADHD version" of the Serotonin Transporter gene being discussed in this post is the primary cause of some of these other disorders. However, keep in mind that some of the underlying mechanisms of action are very similar and should suggest further investigation.

ADHD genes

ADHD Gene#4: Dopamine Beta Hydroxylase Gene (DBH)

ADHD Genes


ADHD Gene #4: Dopamine Beta Hydroxylase Gene (DBH), Location: Chromosome 9 (q34)

Dopamine Beta Hydroxylase (DBH) is the fourth gene on our list of ADHD Genes. For humans, it is listed on the 9th Chromosome ("q34" refers to a the specific location on the chromosome for the gene). For a list of the other ADHD genes that are being discussed, please click here.

What makes this DBH such an interesting gene associated with ADHD is the fact that several diseases or disorders that are often comorbid (existing alongside of or with) ADHD also have ties to this gene. Among them are smoking (both in tendency to smoke and the number of cigarettes smoked per day) and suceptibility to migraine headaches. Additionally, there is a suggested genetic linkage between a particular form (allele) of this DBH gene and a built-in resistance to Parkinson's disease. Of somewhat interest is the fact individuals with ADHD are statistically more susceptible to contracting Parkinson's later in life than the rest of the general population.

In studies with mice, an analogous DBH gene has shown to play a strong role in regulating body temperature as well as being a key component in response and sensitivity to common antidepressants including Prozac, Paxil and Zoloft.

A major function of the Dopamine Beta Hydroxylase (DBH) gene is to produce an enzyme of the same name, dopamine beta hydroxylase. This enzyme is responsible for converting the important nervous system chemical dopamine into another important chemical called norepinephrine. Individuals with ADHD often show abnormal levels of one or both of these chemicals (typically on the low side). For this enzyme to function properly, it requires adequate levels of the mineral copper as well as ascorbate (a form of Vitamin C). Deficiencies in either of these two dietary components inhibit this enzyme's effectiveness and produce similar symptoms to a DBH deficiency. It is therefore advisable that ADHD individuals take in adequate levels of both of these key nutrients (roughly 2 mg/day for copper for the average person and at least 60 mg/day for vitamin C).

However, even with adequate intake of these two nutrients, ADHD symptoms can definitely persist. One of many possible causes could be an inherited form of the DBH gene that is statistically linked to ADHD. This can be determined by a personal genetic screening. One allele (form) of this ADHD gene is called the DBH A1 allele. Several studies have shown that there is a significant association between this A1 form and ADHD.

In addition, there is some evidence that another allele (form) of this DBH gene on the 9th human chromosome may also play a role in developing ADHD. This form is called the DBH A2 allele. Although there is a somewhat weaker association between this form of the gene and ADHD than the A1 form, several family studies have shown a notable correlation between the presence this form of the gene and the development of ADHD. Additionally, some research has suggested that the presence of this A2 form of the gene is tied to a parental history of ADHD (often with a higher correlation to the father), and the subtype of ADHD. Some evidence (which has not been repicated extensively) points to a correlation between this A2 form of the gene and an ADHD subtype called the combined subtype.

The combined subtype refers to a subtype that encompasses both the inattentive component and the hyperactive/impulsive component. The inattentive component has been tied to two other "ADHD genes" previously discussed, the DRD4 gene, and the DRD5 gene, while the impulsive/hyperactive component of ADHD which has been associated with another previous post of a gene and its "ADHD form" called the DAT gene.

The next post will soon be up on another "ADHD gene" of topic, the Serotonin Transporter Gene (5-HTT).

For a list of other posts on ADHD Genes, please click here.

ADHD genes

ADHD Gene#3: DAT

ADHD Genes

ADHD Gene #3: Dopamine Transporter Gene (DAT, SLC6A3), Human Chromosome #5

There have been a number of recent postings on genes thought to be connected with ADHD. Previous ones discussed include the ADHD form of the Dopamine D4 receptor Gene (DRD4), the ADHD form of the Dopamine D5 Receptor Gene (DRD5), and, to a lesser degree, the DRD2 ADHD gene. However, one of the most intriguing ADHD genes is a gene called the Dopamine Transporter Gene, abbreviated as DAT. An ADHD form (also called allele), of this gene, which is located on the 5th chromosome in humans, has been tabbed. The ADHD gene DAT has been discussed in another recent post, where it has been tied to a mutated form of a protein called the dopamine transporter protein that "shuttles" an important brain chemical, called dopamine, in and out of neuron cells. While the regular form of this protein functions, normally, the mutated form causes it to run in the opposite direction at high speed, significantly changing the distribution of the dopamine chemical throughout the brain. This balance can result in extreme ADHD symptoms, and has also been seen in bipolar individuals.

Statistically speaking, there is a weaker correlation between the above form of the gene and ADHD behavior than the previous two genes. Nevertheless, this gene serves as an important target for stimulant medications (such as Ritalin) for both rats and humans. A number of studies have been done on an analogous gene in mice has shown that altering this gene function resulted in a noticeable increase in hyperactivity and decrease in behavioral inhibition and control.

Remember, two ADHD genes mentioned in previous posts, the DRD4 ADHD gene, and the DRD5 ADHD gene are both thought to be more affiliated with the inattentive component of ADHD. In contrast, individuals with the DAT gene mentioned in this posting, above are more prone to hyperactivity and behavioral inhibition problems associated with ADHD. We will soon discuss the various components and subtypes of ADD and ADHD in later posts, but for now, please keep in mind that a number of different genes may be at work within and ADHD individual.

There is still a fair amount of research to be done on this gene, but for now, we can cautiously assume that there is a correlation between forms of this DAT gene, located on the 5th human chromosome, and ADHD.

ADHD genes

ADHD Genes: DRD2

ADHD Genes

Dopamine D2 Receptor Gene (DRD2): TaqI A1 allele, chromosome 11 q22-q23

Based on the same overview study (Faraone and Khan, J Clin Psychiatry 2006; 67 (sup 8), 13-20) as the other seven ADHD genes, there has been some association between a gene on the 11th human chromosome and likelihood of developing ADHD. The form (also called "allele") of this gene associated with ADHD is called the Dopamine D2 Receptor Gene (DRD2) TaqI A1 allele. The findings from the main study on this gene were not replicated, but one study found that individuals possessing the above form of the gene showed an increased likelihood of having ADHD.

Interestingly, this form of the gene is also associated with at least two other disorders that are known to frequently occur alongside of ADD and ADHD. Individuals carrying the TaqI A1 form of the gene also showed a significant increased likelihood of having Tourette’s disorder. Tourette’s is a relatively common comorbid (meaning “occurring along with” or “occurring along side of”) disorder of ADD or ADHD. For those not familiar with the disorder, Tourette’s is a disorder that can result in involuntary behaviors such as “tics”, involuntary twitching, and, in some cases, outbursts of inappropriate speech and profanity. Along with ADD and ADHD, Tourette’s is also seen alongside of other disorders such as Obsessive Compulsive Disorder (OCD) at relatively high frequencies.

In addition to Tourette’s, there is evidence has linked the TaqI A1 form of DRD2 to Parkinson’s Disease (Grevle, et. al, Allelic association between the DRD2 TaqI A Polymorphism and Parkinson’s disease, Movement Disorders 2001, Volume 15, Issue 6, 1070-74). Several findings have pegged ADD and ADHD individuals to having a higher likelihood of developing Parkinson’s later in life. There is a distinct possibility that this form of the gene may be a significant underlying factor between the two disorders.

ADHD genes

ADHD Gene #2 DRD5

In another post, I described that there were at least 7 well-known genes that are associated with ADHD. In fact, since the publication of this paper, additional ones have been identified. Within the past couple of months, another key study on ADHD genes has been discussed.

ADHD Gene #2: Dopamine D5 receptor gene (DRD5): CA repeat, 148 bp

In a previous posting, we discussed an ADHD gene found on the 11th chromosome in humans, called the DRD4. One of the forms (also called alleles) of this gene was associated with the disorder of ADHD, in particular the inattentive component of ADHD.

A second ADHD gene called the "Dopamine D5 receptor gene", or DRD5, is also thought to have strong familial ties to the disorder. Like the DRD4 gene listed above, DRD5 has multiple forms (or alleles). This is located on chromosome number 4 for humans. The "ADHD allele" which is referred to as "CA repeat, 148 bp" (this notation is commonly used by geneticists and refers to the length and DNA makeup of the "ADHD form" of the gene, the exact details aren't entirely important) is slightly greater in length than the non-ADHD form(s). While different studies on this allele have produced different results, it appears that this form of the gene, like the form of the DRD4 ADHD gene listed above, is tied more towards the inattentive than hyperactive component of ADHD. Statistically, however, there appears to be a weaker association between the DRD5 gene and ADHD than the DRD4 gene.