Thursday, September 25, 2008

ADHD Gene #7 SNAP 25 Gene

ADHD Genes

ADHD Gene #7: SNAP 25 Gene, T1065G allele, Human location: Chromosome #20 (20p11.2)

This will be our final installment in a series of 7 ADHD genes. Much of the information here is summarized in a publication by Faraone and Khan in a 2006 article in the Journal of Clinical Psychiatry. There will be further discussions on the topic of genes related to ADHD, so please stay tuned for future posts.

Nevertheless, the final ADHD gene, referred to in this post as SNAP 25, is of importance for discussion. SNAP 25 is short for the term "Synaptosomal-Associated Protein 25 Gene", which is located in the "p11.2" region on human chromosome #20. For more details on genes and gene locations and how they are relevant to our discussion on ADHD, please click here.

Of particular interest is the fact this SNAP25 gene is found to have a 100% match (meaning the DNA sequences are identical) in both chickens and mice. Because of this close match-up among the different species, genetic studies of this "ADHD gene" in mice (of which there are many) may provide information which is much more relevant to humans than other "ADHD genes" that have been covered. In other words, although the relative number of human studies involving this gene and ADHD is limited, a number of studies of the "mouse form" of this gene should be taken seriously.

In mice, a deletion (removal of part of a gene) for this gene results in spontaneous hyperactive behavior. Furthermore, motor abilities are noticeably compromised and physical changes to a part of the brain called the hippocampus (a part of the brain responsible for learning, memory development, emotional responses and various personality traits) were also seen. Therefore, some of the deficient "side effects" that are often seen in ADHD, such as poor memory, inappropriate emotional responses to certain situations and social maladjustments, may be affected, in part, by having the "ADHD form" of this gene. While the information surrounding this in humans should be viewed as only speculative at the present time, the direct behavioral correlations with the gene in mice are tough to ignore.

Unlike other ADHD genes, such as one in a previous post, where most of the "ADHD" behavior is tied to one single block of DNA, the correlation between the SNAP 25 gene and ADHD is more likely affected by multiple blocks of DNA on the gene. Nevertheless, the most statistically dominant form of the gene (also called allele, for more information on this, please click here) is thought to be what is called the T1065G allele. This "T1065G" notation means that the presence of a Thymine DNA base (Thymine is referred to as "T") instead of a Guanine ("G") at the DNA base 1065 (this a number is reference to where on the gene this replacement is located) results in a statistically-increased likelihood of developing ADHD.

If you are unfamiliar with the concept of DNA bases, please click here for a more detailed explanation.

While not of the statistical significance as the T1065G form, there is another nearby section of the gene that also may affect ADHD. In fact these two regions may "work together" to increase the likelihood of developing ADHD. This second form, which is backed by less statistical evidence than T1065G, is called the T1069C allele. This refers to a substitution of a Thymine (T) for a Cytosine (C) located on the 1069th base position in the gene. Keep in mind that these two regions are very close, separated by only 4 individual DNA bases. For more on what DNA bases are, please click here.

Among the key findings that we should draw from this research (as well as from other related studies) is this:
Individuals who have the "T" form at position 1065 in the gene instead of the "G" form are more likely to develop ADHD. Additionally, but to a lesser statistical degree, individuals who have the "T" form instead of the "C" at position 1069 are more likely to have ADHD as well. When combined (i.e. "T's" at both spots), the statistical likelihood of having ADHD goes up even further. Therefore, the SNAP 25 gene, located on the 20th chromosome in humans, is a good candidate gene to study and investigate for insight into an individuals genetic susceptibility to ADHD.

Again, if this explanation is difficult to visualize, please click here for another post with a relevant explanation.

Of course, SNAP25 is just one of many potential ADHD genes. However, if one is to have several of the "right forms" or alleles of multiple ADHD genes, the statistical likelihood of developing ADHD will continue to climb. Look for another post in the near future where I will summarize the results of the 7 "ADHD genes" that have been discussed in this section.

ADHD Genes

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Wednesday, September 24, 2008

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

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Monday, September 22, 2008

Genetic terms and background information

ADHD Genes

Genes, Chromosomes, DNA and alleles: What are they and how do they relate to ADHD?

Author's Note: I realize that a lot of readers may not have any sort of background in genetics, which is why I constructed this page. If you are unfamiliar with how genes, DNA, Chromosomes, and alleles all tie together, this should serve as a great resource page. I tried to make it as straightforward as possible and use an analogy that makes the concept of genetics easy to follow. A number of other posts deal with the fact that a lot of causes of ADHD are inherited from parents to children. I am posting a number of sections on specific genes and alleles that are tied to the disorder of ADHD. Please check out the resources below:

Genes are comprised of long strings of DNA (typically numbering in the thousands or ten-thousands) and serve as a blueprint instructing the body as to:

1.) Which products (enzymes, hormones, etc.) to manufacture

2.) Where to manufacture the desired products

3.) How much of the products to manufacture

4.) When to stop, inhibit, or shut down manufactured products

Scientists generally agree that there are somewhere between 30,000 and 50,000 different genes in the human system.

DNA is short for the term Deoxyribo Nucleic Acid. It comes in four flavors or bases.

1.) Adenine (abbreviated as "A")
2.) Guanine (G)
3.) Thymine (T)
4.) Cytosine (C)

With all of the genetic diversity and variation among humans out there, it might seem strange that it all comes from four primary bases or options. However, we can see that, with four different options at every spot, we can build up a huge number of different possible sequences. Given the fact that the total length of DNA in humans is around 3 billion bases long, this means that there are an ENORMOUS number of possible combinations at our disposal.

For example, a segment of DNA may be in the following sequence: "CCGATA". This means that a Cytosine is strung to another Cytosine, which is connected to a Guanine, which is connected to an Adenine, which is connected to a Thymine, which is connected to another Adenine.

DNA's structure is typically in the helical form (think of a winding staircase). It can exist either in the single-stranded form or double-stranded form. The double-stranded form contains two strands bound together, winding up in staircase form called a double helix. The double-stranded form is relatively stable, because of a phemonomena called base pairing.

Base pairing:

The four DNA bases (A, T, C and G) tend to pair up with each other in what it called complementary base pairing. "A" tends to pair with "T" and "G" tends to pair with "C". In other words "A" and "T" are complementary, and "G" and "C" are complementary.

For example, consider our earlier sequence of "CCGATA": If this sequence is part of one DNA strand, the other one will typically match up with a complementary strand of "GGCTAT".

Do you see how that works?
CCGATA <---- strand 1 GGCTAT <---- strand 2
The C's on strand 1 match up with the G's on strand 2, the A's on strand 1, match up with the T's on strand 2 and vice versa. This pairing up and bonding between the two strands of DNA makes the DNA double helix quite stable. Since we know how the strands match up with each other, if we can find out the sequence of one strand, we can figure out what the other one would look like. For example, if we have one strand that has the following sequence:


we can predict that the other one will "match up" with


Again, the A's from one strand match up with the T's from the other and the G's from one strand match up with C's from the other and vice versa.

Genes and DNA: The "highway and towns" analogy

Genes actually make up a relatively small percentage of the body's total DNA (thought to be less than 10 or 15%). One of the best ways to think of this is to envision a large highway that connects a number of towns together, but also passes along through long stretches of open country. The "highway" is the DNA, while the towns, (where the functional stuff "happens") are analogous to the specific genes. The stretches of highway in between the towns serve a limited function; their main purpose is to serve as a buffer space between the important towns. Similarly, the vast majority (over 85%) of DNA is not in the genetic region and is of limited function.

Since there are so many genes (towns), in humans, it would make more sense to create multiple highways to incorporate all of them instead of having just one long one. Essentially this is what nature does. It subdivides the DNA into different “bundles” or "groups" called chromosomes. The number of different “highways” varies from species to species; in fruit flies, the number of highways is 4, in humans, the number is 23. Additionally, human beings actually have two “pairs” of highways, one coming from each parent. Going back to our road analogy, think of our highway as a divided one, with one way going eastward and the other going westward. The two highways are “paired up”, that is, they go through the same towns and cover the same stretches of land in between, but there are now two highways instead of one. Therefore, with humans, we (typically) have 23 pairs of chromosomes (highways), for 46 total.

For humans, one of those pairs of highways is sex-determinant. If both highways are marked “X”, then you are female, if one of your highways is “X”, but the other is “Y”, then you are a male (you cannot have both highways or chromosomes as “Y” because your mother can only pass on an “X” chromosome, while your father can pass on either an “X” or a “Y”). While sex determination is a critical function of the sex chromosomes, it is important to realize that these “X” and “Y” highways also contain a number of genes themselves. These genes are referred to as “sex-linked”. If certain traits or inherited disorders show up exclusively or highly disproportionately in males or in females, chances are, at least one “sex-linked” gene is responsible.

Doing a bit of math we can see that with around 30,000-50,000 different genes (towns) and 23 pairs of chromosomes (highways), we would expect a typical highway to contain somewhere from 1000 to 2000 genes (towns). While the number of genes are not evenly distributed (some chromosomes or highways are larger than others), 1000-2000 genes per chromosome is a good estimate. Keep in mind, too, that the genes or towns vary in size as well; some may be cover a much longer stretch of highway than others. The distribution of genes among chromosomes normally does not vary from individual to individual, so you, your sister, your best friend and your next door neighbor will all typically have the exact same number of genes in the exact same order on a particular chromosome.

Taking this analogy a bit further, where we can identify a certain town as a "gene", we can further subdivide that town into smaller sections (think of individual blocks within a town). For example, one of the “ADHD genes” called the Dopamine Beta Hydroxylase Gene (DBH), has a location of “9q34”. What that means is that this gene is located on Chromosome #9 (“Highway 9” to follow the analogy), section “q34”. “q34” actually does not refer to one particular town, it still covers a slightly larger space than that (think along the lines of a county), but it does help narrow the location down quite a bit. Further numbers or letters beyond the “34” (which typically follow a “.”, such as “34.1”), can help narrow the location down even further to the city, and eventually block or even specific building level.

As mentioned, almost all humans carry the same number of genes in the same order, on the same chromosome. In other words, town #487 on chromosome 12 will be the same “gene” for you, as it is for Bob. Additionally, most of the blocks in your 487th town will look exactly the same as they would in Bob’s 487th town. However, there are some specific blocks that will show some variation between your town and Bob’s town. These slightly different forms of the same town are what are referred to as alleles (slightly different forms of the same gene).

Some genes have different alleles that differ in only one spot. For example, the first 8 blocks of your town and Bob’s town may contain the exact same buildings in the same order, but the 9th block in Bob’s town may contain a McDonald’s while yours contains a Burger King. Also, some alleles may differ by having a slightly longer or shorter segment for a particular block. For example, Bob’s town (allele) may have an extra gas station between blocks 15 and 16, while yours may have additional park space between blocks 19 and 20. A genetic analogy to this would be having a few extra pieces of DNA than Bob in a particular section of a gene.

Either way, it is important to remember that your genes and Bob’s genes are over 99% identical, there are just some minor differences such as those mentioned above. However, even these minor differences can have a number of prolific effects. For example, if your town and Bob’s town have the same number of residents, but Bob’s has 3 more gas stations than does yours, who do you think will be better adapted to supply enough gasoline for the town in the event of a fuel delivery truck failing to show up on a particular day? If your town has one additional power station than Bob’s, and a recent heat wave pushes up the power demand for a week, whose town will be better suited?

Similarly, a few small differences in individual variations of the same genes can play notable roles when dealing with disorders such as ADHD. A few key changes can significantly enhance or inhibit levels key proteins or neural chemicals. For example, the compound dopamine is an important signaling agent in the nervous system in which adequate levels are needed for proper brain function in areas such as maintaining an attention span. Not surprisingly, a number of ADHD individuals have lower than normal levels of dopamine in the frontal regions of the brain. Certain genes are responsible for producing key enzymes that aid in the manufacture and delivery of this important brain-friendly compound. Unfortunately, some forms or alleles of these genes are less effective in manufacturing these key enzymes. As a result, individuals with these alleles are more prone to dopamine imbalances in key regions of the brain. As a result, they are more prone to having ADHD. In the context of attention deficit disorders (ADD) and attention deficit hyperactivity disorders (ADHD), we will examine which forms or alleles of specific genes are tied to ADHD.

ADHD Genes

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Friday, September 19, 2008

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

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Saturday, September 6, 2008

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

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Friday, September 5, 2008

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

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Thursday, September 4, 2008

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

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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.

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Monday, September 1, 2008

ADHD Protein on "Speed"?

ADHD treatment options and resources

New mutation found on an "ADHD gene"

I was going to post some more information on the second ADHD gene on the list, but I recently came across a very interesting article on genetic mutations and ADHD, which can be found here.
The original study was recently published in the July 9, 2008 issue of the Journal of Neuroscience by the groups of Aurelio Galli and Randy Blakely. Several subtypes of ADHD are thought to be caused by an imbalance in the levels of of dopamine, an extremely important chemical found in the brain and nervous system that regulates proper neural functioning. There is an ideal balance between the amount of dopamine that is stored in neurons and the amount that is present in the "gaps" between different neuron cells.

It is here, that a critical protein comes into play. A special protein called the Dopamine Transporter (DAT) protein acts as a type of "shuttle" or "ferry" that helps balance dopamine levels inside and outside of the neuronal cells by aiding in the transport of dopamine in and out of the cells. This protein is actually "coded" for by the third ADHD gene on the list of a recent post.

It is strongly suggested that individuals diagnosed with ADHD have lower than normal levels of this dopamine in the gaps between neuron cells. As a result, a number of ADHD drugs focus on this DAT "shuttle" in an attempt to manipulate its ability to clear dopamine to the cells (think of the analogy of building a dam to trap and collect a stream of water in a region where it is scarce). In essence, this helps "fix" the problem of the low dopamine levels in this space, which is associated with ADHD.

Here is where it gets interesting. A rare mutation causes this shuttling DAT protein to essentially run in reverse at high speeds. Instead of "mopping up" dopamine and carrying it into the surrounding neurons, this mutated form of the protein essentially "squeezes" dopamine out of the cells and into the open space. This mutant protein actually functions in a very similar way to amphetamines such as the popular ADHD drug Adderall (which, incidentally, is chemically similar and has a similar, but much more benign, mode of function as the drug "Speed"). Here lies the paradox-- we would think that this mutated transporter protein, which behaves like a drug used to treat ADHD would be beneficial for ADHD individuals. However, the opposite is true. Individuals which possessed this mutation exhibited noticeable ADHD behavior.

Further complicating the issue is the fact that Adderall, while behaving much like this mutation by making the DAT shuttle run backwards, actually blocks some of the key negative effects of the mutation. Think of it as an almost homeopathic-like solution, treating "like" with "like". Ritalin, another ADHD medication which, in turn, can counteract the ability of Adderall to make this shuttle protein move backwards. For sake of brevity, I will save this discussion for a later post in the near future!

Finally, it is also interesting to note that this DAT mutation is very rare. Outside of this study, only one other case had been seen by the researchers, that of a bipolar girl. I found this interesting because it is sometimes difficult to distinguish differences between ADHD and pediatric bipolar disorders. The overlap of this mutation between the two disorders may lend some credence to underlying genetic mechanisms that both disorders seem to share.

ADHD treatment options and resources

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