How Genetic Variants Can Affect the Brain & Cause Symptoms

Brain Related Genes, the Proteins They Code For & How These Can Cause Symptoms Such As Depression, Anxiety, Brain Fog, Fatigue, Anger, Hyperactivity & Psychosis

Bridges - Cut paper & Ink

In this newsletter, I hope to demystify the various ways that genes contribute to brain-related symptoms.

I’ll discuss:

• The relationship between genes and the proteins they code for

• Role of methylation and oxidative stress in gene expression

• The types of proteins that are especially important in brain health

• Examples of variants that can impact neurotransmitter functioning and thus symptoms

We Inherit a Vulnerability Not a Condition

Psychiatric symptoms are not necessarily caused by a specific gene. Instead, certain genes, or rather certain genetic variants, raise our vulnerability to developing brain-related symptoms.

Oxidative Stress

We each have well over a thousand genetic variants (snps).  Most of these we’ll never hear from unless they are expressed.  Oxidative stress, which can impact this expression, is when our antioxidant system is overwhelmed by things like toxins, high inflammatory states, trauma and/or other insults. Most people with brain-related symptoms are dealing with oxidative stress.

The brain is a good barometer of oxidative stress.

Methylation

The expression of our genetic variants is also impacted by methylation - a chemical reaction in which a small molecule (a methyl group) is added to DNA, proteins, or other molecules. Our ability to methylate, which is very important for our health, is impacted by a number of genes. These genes can also have variants. MTHFR is the most important, but not the only one of these genes.

Genes Make Proteins

Each of our genes makes a protein.  Having a variant on a gene means that protein may not work as well.  We inherit our genes from both parents. Having a variant from both parents on a particular gene can have a greater impact than having a variant from one parent.

Proteins Related to Brain Health

There are different types of proteins with different jobs.  Below are the types of proteins that are especially relevant in brain health:

• Enzymes - speed up chemical reactions in the body.  Enzymes can be involved in:

  • making neurotransmitters

  • metabolizing or removing neurotransmitters

  • turning one neurotransmitter into a different neurotransmitter

  • methylation

  • detoxification 

• Receptors - Neurotransmitters (which I’ll describe below) allow one nerve cell to communicate with the next.  A nerve cell releases neurotransmitters that bind to receptors on the next nerve cell. This results in a change in the receptor, which causes an electrical signal to travel down that nerve cell. 

• Re-uptake Receptors - There are also receptors at the synapse (the space between cells) that take up the neurotransmitter, such as serotonin re-uptake receptors. SSRI’s block these receptors so more serotonin is available.

• Ion Channels - These are involved in the movement of ions (e.g. sodium and potassium) across nerve cell membranes. This causes an electrical impulse to travel away from the synapse and down the nerve cell to the next synapse.

• Storage proteins - Metallothionein plays an important role in the detoxification of toxic metals and copper-zinc balance.

• Transport proteins - These carry things like certain trace metals or hormones around in the blood. One example is ceruloplasmin, a protein that binds copper.  If it is relatively low, free (unbound) copper can be high and cause symptoms.

Neurotransmitter Activity

We have many neurotransmitters. These are the ones considered most commonly in psychiatric research and treatment.

• Serotonin - joy, well-being, enjoyment, pleasure, interest, restful sleep 

  • Low activity -  depressed or anxious mood, lack of enjoyment, difficulty falling and staying asleep

• Dopamine - pleasure and reward  

  • Low activity  - lack of motivation, difficulty starting and finishing tasks, low-stress tolerance, social isolation, helplessness and hopelessness 

  • High activity - worry, insomnia, brain fog, paranoia, mania, psychosis

• Norepinephrine - arousal

  • Low activity - can contribute to depression

  • High activity - can contribute to nervousness and insomnia

• GABA - the major inhibitory neurotransmitter, involved in calming and rest

  • Low activity -  anxiety, high inner tension and feelings of overwhelm

• Glutamate - the major excitatory neurotransmitter in the brain, involved in learning, memory, mood regulation. Excessive glutamate can cause over-excitation and cell death.

• Histamine - involved in sleep and wakefulness 

  • Too much can cause brain fog, headaches, nervousness, sleep disturbance and fatigue

• Acetylcholine -plays a role in learning, memory and attention

  • Low activity - problems with memory, word finding, learning new information and brain fog 

We can have a lot of a particular neurotransmitter, but if we have very few receptors for it to bind to on the next cell, we could have symptoms.   Too many re-uptake receptors (mentioned above), could mean more neurotransmitter is picked back up at the synapse and thus less of that neurotransmitter is available to bind to the receptor. This too could cause symptoms. 

This is one of the reasons many of us do not find measuring neurotransmitters (or their metabolites) very useful.

Examples of Genes Coding For Proteins That Impact Brain Health

Some of these variants can be identified with genetic testing. Some of these genes appear to be impacted, however, a specific location on the gene has not been identified or there are so many possible locations that genetic testing isn’t useful.

1. Enzymes Involved in Methylation

From a Walsh perspective, we look at methylation as happening on a spectrum from undermethylation to overmethylation (with optimal methylation in between).  Methylation is determined by the balance of a number of genes (not just the MTHFR) and their variants. 

Methylation impacts the expression of many other genes, however, it also plays a very big role in neurotransmitter functioning. Most people with brain conditions have a methylation imbalance with undermethylation being much more common. 

Those who are undermethylated (and have depression or anxiety) more often will have a folate excess. This impacts how tightly wound DNA is. How tightly wound our DNA is can result, in this case, in an increase the the expression of those serotonin re-uptake receptors. This lowers serotonin activity in the synapse and worsens depression. In overmethylation there is a folate deficiency and the opposite occurs.

Image from the Walsh Research Institute

2. Enzymes That Metabolize (Get Rid of) Catecholamines

1. COMT codes for Catechol-O-methyltransferase -  an enzyme that metabolizes catecholamines (dopamine, epinephrine, norepinephrine) and estrogen

   1. A “Slow” COMT means a build-up of catecholamines, especially when under stress. This can cause high anxiety.

   2. A “Fast” COMT can result in catecholamines being cleared too quickly. This can result in cravings, addictive tendencies and excessive sleepiness

2. MAOA also metabolizes catecholamines and can be slow or fast, however, it also metabolizes serotonin and histamine, and not estrogen.

3. Enzymes That Break Down Histamine

A variant in one or more of these genes could cause high histamine states.

1. DAO codes for Diamine oxidase, an enzyme that breaks down histamine in food.

2. HNMT codes for Histamine N-methyltransferase, an enzyme that breaks down histamine in cells

3. MAO codes for Monoamine oxidase, an enzyme that breaks down histamine, tyramine (in anything aged, fermented or cured), and as mentioned, catecholamines.

4. Methylation genes, of which MTHFR is the main player, collectively impact our body’s ability to break down histamine.

Enzymes usually end with “-ase.”

4. Proteins Involved in Metal Detoxification

MT genes code for metallothioneins, which are proteins involved in metal detoxification, and the regulation of copper and zinc among other things.  The epigenetic expression of the gene for metallothioneins is dependent on the presence of zinc.  Though we don’t have an identifiable snp, a weakness in this gene can be evidenced in families with high copper conditions and suspected in those with especially high copper.  High copper is common in ADHD, anxiety, angry outbursts, postpartum depression, anxiety and psychosis  and other hormonally related brain symptoms.

5. Enzyme Involved in Cortisol Production

21-hydroxylase is an enzyme that helps produce cortisol, which is needed to maintain blood sugar levels, protect the body from stress, and suppress inflammation.  A weakness in this gene (of which there could be many and not easily identified) can result in inflammation, including brain inflammation when under stress.  While there are many other enzymes involved in hormone pathways, I would rank this one as the most important (fitting with RCCX theory). A weakness in this gene is thought to be very common in psychiatric disorders and other chronic complex health conditions (CIRS, EHS, MCAS, and CFS). 

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I share these next five, not because they are on the forefront of my mind (as the top five are) when I’m providing treatment or a consultation, but because they speak to the further complexities of how our variants can impact our brains.

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6. Enzymes That Turn One Neurotransmitter Into Another

GAD1 codes for Glutamate Decarboxylase, an enzyme that breaks down glutamate (which is anxiety-inducing) into GABA, which is calming.  A variant on GAD1 could result in too much excitatory Glutamate and too little GABA.

7. Receptors for Neurotransmitters

There are many genes that code for the many types of receptors, including, for example, the genes for dopamine receptors, DRD1, DRD2, DRD3, DRD4 and DRD5.

8. Complement - C4

This is a protein, which is part of the complement system, is found on certain cells and is involved in immunity and autoimmunity. C4 variants have been associated with a higher likelihood of schizophrenia, seemingly because they control synaptic pruning that normally happens during development. The C4 gene is more active in the brain tissue of people with schizophrenia compared with unaffected people. This translates to more pruning - more removal of neuronal connections resulting in symptoms. 

9. Enzymes Involved in Detoxification

As mentioned, oxidative stress plays a big role in mental health and in the expression of our variants. There are many enzymes involved in phase I (Cytochrome P450 genes) and phase II detoxification.  Methylation is involved in detoxification as well. And, last and I would say actually least….

10. Not Useful (in my experience) -  HLA-DR Gene 

I’ll mention this group of genes that many people believe is important when it comes to mold toxicity - a common cause of brain symptoms.  Like my mentor Neil Nathan, MD, I have not found this, often referred to as the “dreaded gene,” to be useful in predicting who will have mold toxicity, the severity of their symptoms or their prognosis.  This “dreaded” gene, however, does create a lot of stress and is not something that I test for.

Support Our Variants

How can we support these genes so they can do their best work? We can lower oxidative stress (which many of these newsletters are about), support methylation and more specifically support the enzymes or proteins that don’t appear to be working up to speed. In an upcoming newsletter, I’ll discuss how specific targeted nutrients can promote the synthesis and functioning of some of these enzymes and proteins.

Until next time,

Courtney

P.S. In this week’s newsletter, I’ll be applying this information to examples using family histories.