Genes, Omega-3's, Alcohol and ADHD

In our last discussion, we were exploring the theory behind omega-3 fatty acid supplementation for ADHD, and alluded to the fact that there may be some genes at work involving this process. Additionally, there is some evidence that alcohol use can inhibit the effectiveness of some of the enzymes that are coded for by these genes, and possibly be a factor in the onset of ADHD. We will be exploring these associations in this blog post.

Omega-3 fatty acids are crucial for our overall well being for a number of reasons, with many of them being tied to maintaining the structure of all different types of cells in our bodies. Among these omega-3's are alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). ALA converts to EPA (and eventually DHA) through a series of steps, several of which use the enzymes governed by the genes listed above. A summary of this process is highlighted below (original file source here):

The diagram above may look quite complicated, but we're just focusing on a few of the objects listed above.

As a quick side note: a lot of the other objects on this diagram above are showing the role these omega-3's and omega-6's play in the inflammatory process of immune reactions. This discussion is beyond the range of this post, but I have included it to illustrate that omega-3 and omega-6 fatty acids play a critical role in regulating a number of different functions and systems. Omega-3 imbalances can lead to immune dysfunction, which is thought to be one of the reasons why individuals with ADHD, who often have lower blood levels of omega-3's than their peers, are also more likely to have immune system disorders such as allergies. This ADHD/allergy connection will be explored in the future. Also, notice that omega-3's and omega-6's use the same enzymes. This is important, and was discussed at length in the previous post.

The section on the left of the above diagram describes how one omega-3 fatty acid is converted to another, for example, the a-linolenic acid (top left) eventually makes its way to forming EPA (fourth one down on the left), which eventually is converted to DHA (last one in the left column). Bringing our attention to the center, we see a series of enzymes with names like ∆6 desaturase, elongase, etc. These enzymes play a major role in the actual chemical conversion process of one type of omega-3 fatty acid to another.

Keep your attention on the enzymes that have the key term desaturase in their title. These are the ones we need to be concerned about when dealing with the aforementioned genes and alcohol. Without these enzymes functioning at their highest level, the incorporation of dietary omega-3's into the actual structure of the cell membrane is significantly. Genetic differences and the presence of external factors (such as alcohol or other types of fats) can significantly impair the function of these enzymes and slow the conversion process (and ultimately uptake and incorporation into cell membranes) of these critical omega-3's.

A number of these desaturase enzymes are all coded from a specific genetic region located on the 11th chromosome in humans, located at the 11q25 region (chromosomes have 2 "arms", a "p" and a "q", the numbering refers to relative location on that arm, so "11q25" refers to the 25th region on the "q" arm on the 11th chromosome). Interestingly, this region is located near the 11q22 region, which has been linked to ADHD. The closer two genetic regions are, the higher the chances they will be co-transmitted (passed on together from parent to child). In other words, gene forms which are located near each other on a chromosome are more likely to be passed on together, suggesting the possibility that the 11q22 ADHD region may in fact be influenced by some of the genes from nearby 11q25 region.

Brookes and coworkers did a study on the association between these desaturase genes and ADHD (on a personal note, I would like to acknowledge the authors of this particular study. Much of the information in these past two posts is gleaned from their work, and this paper provided a great starting point for much of my research for this post). They found that the 11q25 region contained three genes which code for desaturase enzymes located next to each other: Fatty Acid Desaturase 1, Fatty Acid Desaturase 2, and Fatty Acid Desaturase 3 (abbreviated as FADS1, FADS2 and FADS3, respectively). These genes each exist in different forms, called alleles, which have slightly different DNA configurations (which can differ by as little as one letter in the DNA "code").

Key findings from the Brookes study: This group saw a significant difference in the prevalence of ADHD stemming from two different alleles in the FADS2 gene. It appears that a single point difference was all it took to boost the likelihood of association with ADHD. Individuals with ADHD were significantly more likely to have the "C" form of the FADS2 gene than the "T" form of the gene at marker 498793 (this number just gives the detailed location on which spot of the DNA this form can be found).

Additionally, it appears that the onset of ADHD stemming from prenatal alcohol exposure may be somewhat genetic as well. For individuals who were exposed to alcohol via maternal consumption during pregnancy, there is some nominal evidence linking "G" allele instead of the "C" allele at two different locations on the FADS1 gene was correlated with a higher likelihood of being diagnosed with ADHD. However, the authors concluded that this connection was only "speculative".

This possible ADHD/genetics/fatty acid consumption/alcohol exposure connection is somewhat intriguing. The study established a strong ADHD connection to a specific allele of the FADS2 gene on the 11th chromosome, and also cited a number of other studies on the effects of omega-3 consumption on ADHD symptoms, but the connections with alcohol are more strained. Nevertheless, the findings from other studies offer support for this possible alcohol association with these other factors:

1. We have seen before that omega-3 fatty acid deficiencies are more prevalent in individuals with ADHD. The previous post describes the process of how omega-3's affect cell membrane integrity, which, in turn, can effect the passage of key chemical signaling agents such as dopamine (which has repeatedly been found to deficient in specific brain regions of ADHD individuals). The desaturase enzymes, which are products of the genes listed above are partly responsible for the process of omega-3 metabolism and incorporation into the cell membranes.



2. Different alleles (alternate forms of a gene) can result in slightly different forms of these enzymes, some of which are more efficient than others. In other words, enzymes coded for by one form of a gene are somewhat better at metabolizing omega-3's and incorporating them into cells than the "alternate" enzymes coded for from the "alternate" forms of the gene. As a result, small changes in the gene code in these aforementioned regions can indirectly affect the efficiency of omega-3-to-membrane incorporation.



3. Several studies have pointed to the the connection between alcohol and fatty acid metabolism in animal models of ADHD.



4. It also appears that an individual may be able to "recover" from some of the negative effects on cognition due to alcohol exposure by an increase in dietary omega-3's. This includes increasing maternal dietary levels of omega-3's during pregnancy (based on animal model studies).
   

To summarize the whole post (as well as the previous one), it appears that omega-3 fatty acid metabolism plays a major role in ADHD. This is thought to be at least in part to the effects of omega-3's on maintaining cell membrane structure and integrity and their effects on regulating levels of the brain signaling agent dopamine (which is a crucial neurotransmitter and is often deficient in ADHD cases). However, properly functioning enzymes are required for these steps. Desaturase enzymes are coded for by a genetically "hot" region for ADHD on the 11th chromosome in humans. Different versions of these genes can result in a reduction in enzyme function and potentially affect the way these omega-3's are metabolized. In mammals, alcohol exposure can also lead to reduced desaturase enzyme activity. Additionally, there is at least some evidence that alcohol can increase the likelihood of specific forms of FADS1 gene giving rise to ADHD. This may be due to the two factors combining to reduce desaturase enzyme activity to a point where omega-3 metabolism falls past a hypothetical "break-point" resulting in a sharp increase in the onset of ADHD and other related disorders.

We have been focusing heavily on the ADHD and alcoholism connection for the past couple of weeks. We will be investigating a few more studies on this connection in the upcoming posts.