Two weeks ago I talked about how we are starting to move into the age of personalized medicine. Our goal at The Great Plains Laboratory is to determine what factors lead to chronic illnesses and what treatments may help. Previously I discussed how the Organic Acids Test (OAT) and the GPL-SNP1000 DNA Sequencing Profile work well together to determine both the risk for and causes of many chronic illnesses and how useful these two tests are in helping practitioners develop individualized treatments. Last week I specifically discussed the DNA methylation pathway, of the GPL-SNP1000. This week I am going to go over the mental health pathway of the this same test. I will talk about what genes are most important, some specific polymorphisms to be aware of, how the OAT can help diagnosis these disorders, and what treatments seem to work best.
The two most important genes in this pathway are MAO-A (monoamine oxidase A) and COMT (catechol-o-methyltransferase) (Please see Figure 1). Both enzymes are required for metabolizing neurotransmitters critical to mental health. Mutations to either one can have serious consequences relating to how we think, feel, and interpret the world around us.
Monoamine oxidase A is important for the metabolism (breakdown) of biogenic amines such as the neurotransmitters dopamine, norepinephrine, and serotonin (figure 2). Mutations to this gene have also been linked to depression, borderline personality disorder, and bipolar disorder.
There are two different types of polymorphisms involved with MAO-A. The first type, which is characterized by rs6323 , causes an increase in activity of the enzyme. Rapid metabolism resulting from this mutation causes depletion in the neurotransmitter. This depletion is directly related to the extent of the enzyme activity which can be determined on the Organic Acid test (OAT) by measuring the production of Homovanillic acid (HVA) and Vanillylmandelic acid (VMA) which are the end products of dopamine and epinephrine metabolism (see figure 1). Patients who are rapid metabolizers will show an increase of HVA of VMA (Figure 3). Such patients will have a depletion of these neurotransmitters which leads to multiple neurological diseases including depression. Treatment for these polymorphisms includes supporting the methylation pathway which helps to promote the cofactor required for neurotransmitter synthesis and providing neurotransmitter precursors such as tyrosine, B6 and 5-HTP.
A second type of polymorphism to MAO-A is one that decreases activity (rs72554632, Gln296X), whichcauses a premature stop codon in the gene.. This polymorphismwill lead to a buildup of neurotransmitters, which can lead to the development of Brunner syndrome. Brunner syndrome is characterized by a decrease of mental capabilities, increased impulsivity, mood swings, and sleep disorders. These individuals will have a decrease of HVA and VMA metabolites on the OAT. Without the benefit of genetic testing, these results could lead a practitioner to treat with neurotransmitter precursors. Increasing neurotransmitters for individuals with this type of mutation would actually exacerbate the condition. Treatments include decreasing the amine containing foods such as fish, cheese, and fruit, taking progesterone to increase MAO; taking inositol(which reduces 5HT2A serotonin receptor), taking riboflavin (increases MAO activity), or taking ginkgo, which has been shown to decrease aggressiveness in MAO-A deficient patients.
Catechol-O-methltransferase (COMT) is present in the body in two different forms. The short form is called soluble catechol-O-methyltransferase (S-COMT). The longer form is called membrane-bound catechol-O-methyltransferase (MB-COMT). MB-COMT is mainly present in the nerves of the brain, while S-COMT is located in the liver, kidney, and blood. In the brain, MB-COMT is responsible for degrading neurotransmitters called catecholamines, which include dopamine, epinephrine, and norepinephrine. Therefore the membrane bound form is believed to have a greater affect on mental health, though both forms may be implicated in disease since both are capable of metabolizing catecholamines.
GPL-SNP1000 analyzes six different SNPs for COMT. Of these, the most extensively studied is a mutation to rs4680 (Val158Met). Despite the many studies available about this mutation, the scientific community is still at odds about the degree to which this mutation causes disease. What is known is that individuals with this mutation have lower activity of the enzyme. Mutations to COMT will lead to dopamine and epinephrine not being broken down properly, which can be detected by a decrease in the HVA metabolite in the Organic Acids Test.
Interestingly, some individuals may benefit from increased dopamine while others may benefit from less. Dopamine functions differently depending on the area of the brain it is produced in and there are likely other mutation to this gene may also influence its function and expression. These interactions are still being investigated and are why GPL is looking beyond the most common mutation to help inform results. Conditions associated with these mutations include OCD, depression, and schizophrenia. Symptomatic patients may benefit from treatment aimed at promoting the enzyme function so that dopamine and epinephrine can be metabolized. This is a SAM dependant enzyme and methylation support can be helpful in patients with this mutation.
Apolipoprotein E (APOE) combines with lipids in the body to form lipoproteins. Lipoproteins are responsible for packaging cholesterol and other lipids and carrying them through the bloodstream. Like so many genes in the human body, this is not its only function. The ApoE protein is involved with more than was originally thought. In this case, it has a role in immune expression, cognitive function, and telomere regulation. There are four different gene versions of APOE called e1 (the double mutant), e2 (rs7412), e3, and e4 (rs429358). The most common version is e3, the most detrimental is e4
Mutations to APOE can lead to an increased risk of developing Alzheimer’s disease. People who inherit even one copy of the APOE e4 allele have an increased risk of developing the disease. Certain mutations to this protein impair the ability of the body to phosphorylate NMDA (glutamate) receptors causing a reduction in activity (Glutamate receptors have been implicated in a number of neuropsychiatric disorders including depression, biopolar disorder, schizophrenia, and Autism (PMID: 12404584, 21315104). While this gene is being extensively studied for its role in Alzheimer’s disease, vulnerable patients may also be predisposed to other psychiatric disorders. (PMID: 25751510, 15557508). Patients with certain ApoE mutations may develop cognitive symptoms well before onset of Alzheimer’s disease (http://psycnet.apa.org/journals/neu/16/2/254/). Patients with these polymorphisms should look for early signs of the development of Alzheimer’s disease. Treatment with estrogen has demonstrated some encouraging results.
The D-amino acid oxidase activator (DAOA) protein (also known as G72) is a 153 amino acid protein that localizes in the brain, spinal cord, and testis. This protein is located in the endoplasmic reticulum and the mitochondria cellular compartments. DAOA is a modulator of D-amino acid oxidase (DAO) activity. If DAO is hyper activated it can result in a decrease in the D-serine level and hypo function of the NMDA receptor. Overexpression of DAOA has been found in schizophrenics and those suffering from bipolar disorder. Mutations to DAOA have been linked to a higher incidence of schizophrenia and bipolar disorder.
It is important to remember that our genes influence our mental health and well being but do not necessarily determine the eventual outcome. There are countless factors that play an equal role in how we perceive the world including diet and lifestyle. I believe that understanding the most common mutations and their function is very helpful in diagnosing, treating, and preventing different neurological disorders. Using the GPL-SNP1000 test in combination with the OAT can further help determine the extent to which our genes are being expressed metabolically. The combination of these two tests can help bring about the best chance to achieve emotional health and physical well being.
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