Anxiety: Genetics, heredity, and personalized solutions

Key takeaways:
~ There’s a strong genetic component to anxiety that interacts with environmental factors.
~ Different physiological changes in the brain can cause anxiety.
~ Understanding your genetic susceptibility may help you find the right solutions, tailored for your underlying cause.

Anxiety Disorders and Genetics: What role does heredity play?

If you’re dealing with anxiety, you are not alone! The lifetime risk of anxiety disorder is over 20%, and researchers estimate the heritability at 50%. Anxiety disorder is a term that includes generalized anxiety, panic disorders, social anxiety, PTSD,  phobias, and more.

These disorders are a complex group with various ways of presenting, however, there are some very interesting underlying biological similarities in their causes.[ref]

First, here are some of the terms for anxiety disorders:

• Social anxiety disorder is really common and affects up to 10% of the population. People with social anxiety disorder have severe enough anxiety in social situations to cause them to alter their behavior in order to avoid social situations. This can lead to stress or an overall inability to function well in society.[ref]
• Generalized anxiety disorder (GAD) is a condition in which people worry more than normal about everyday things. People with GAD may feel on edge, irritable, tense, and they may have problems sleeping well.
• People with panic disorders have a sudden onset of anxiety. They have physical symptoms of acute fear, such as feeling like they can’t breathe, trembling, dizziness, and an increased heart rate.[source]

Genetic research explains the underlying causes of anxiety disorders:

Genetics plays a role in anxiety disorders, with heritability estimated to be up to 50%. The other half of the picture is environmental and lifestyle factors. Genes + Environment shape our physiological reactions. [ref]

The big takeaway here is that research shows:

• Anxiety disorders have a genetic component for most people.
• Genetics explains the physical alteration in the way the brain works or in the physiological response to stress.

Knowing and understanding your genetic kryptonite may help you find the right solution to your anxiety problems.

How can genetics show the underlying cause?

When it comes to understanding the physiological causes of anxiety, researchers investigate how genes influence the risk of a disease/condition through several methods:

• One way is to first assume that genes in a certain pathway are important and then investigate those genetic variants (SNPs) in detail.
• Another way is to do a Genome-wide Association Study (GWAS), which looks at all the genes in people with a disease to see which variants differ from a control group.
• A final approach is to look at how specific genetic variants interact with lifestyle factors to influence disease risk.

All of these methods have their pros and cons, and often all of the different methods end up being used by different research groups investigating a topic.

Here’s an overview of specific genes linked to anxiety disorders:

Let’s go into each of these in more detail…

1) ADORA2A and Adenosine: Jittery and startled

One gene linked with anxiety in multiple studies is the ADORA2A gene. ADORA2A codes for the adenosine 2A receptor, which is important in the way that the brain works.

Adenosine is made up of an adenine molecule and a d-ribose sugar molecule. It’s found in every cell in the body.

DNA: Adenine is a nucleotide (the “A” in your DNA raw data). D-ribose is the sugar that makes up part of the DNA molecule (deoxyribonucleic acid).

ATP: Adenosine also may sound familiar because it is part of the ATP molecule (adenosine triphosphate). ATP is made in the mitochondria and used for energy in every cell of the body.

Brain balance: In the brain, adenosine is important in the way that the neurons work. It helps to fine-tune the way that neurons communicate, and it also helps to balance the inhibitory and excitatory neurons.[ref]

Adenosine levels in the brain increase over the course of the day. This higher level of adenosine is what causes you to feel sleepy at night – called the homeostatic sleep drive.

Caffeine works to make you feel awake by blocking the adenosine receptor so that the adenosine can’t attach to it. Genetic variants in the adenosine receptor alter people’s response to caffeine.

Animal studies are great for showing exactly how a gene works. Mice have greatly increased anxiety when researchers knock down the ADORA2A (adenosine receptor) gene expression. They also had an increased heart rate, increased platelet aggregation, and an altered pain response, because adenosine is important in a lot of different functions in the body.[ref]

But what about in humans? There is a common genetic variant in the ADORA2A gene that alters its function.  An fMRI study found that ADORA2A variant carriers had increased connectivity between two regions of the brain: the prefrontal cortex and the insula (part of the cerebral cortex).[ref]

One more way  ADORA2A variants impact the risk of anxiety disorder is through the impact on the startle response and the maladaptive emotional reactivity.[ref]

All in all, this paints a picture of the adenosine receptor being important in how neurons communicate. Alterations in this pathway may cause people to be more on alert, startling easily, and jittery (especially with high caffeine).

2) Oxytocin and separation anxiety

Oxytocin is a hormone and a neuropeptide that researchers link to both emotional functioning and social empathy. In women, large quantities of oxytocin are released during childbirth and breastfeeding. It’s a big part of mother-child bonding. In fact, oxytocin is involved in a mother’s neuroendocrine response to their baby’s crying. Researchers study this using fMRI brain imaging on mothers listening to crying babies.[ref] It is a built-in, physiological response based on oxytocin.

Going beyond parent-infant bonding, oxytocin, in general, plays a role in social attachment and trust. For example, if you give normal adults oxytocin intranasally (up the nose), there is a substantial increase in trust among people, which increases the benefits of social interaction.[ref]

If you want to get into the geeky details of what brain imaging shows with intranasal oxytocin, here is a new study illustrating the fMRI changes in activity levels in certain areas of the brain. It’s pretty cool…

Stressful situations cause the body to increase oxytocin levels, which acts quickly to decrease anxiety. But oxytocin creates an anti-anxiety effect only under stressful conditions.[ref] In other words, boosting oxytocin when you’re not stressed doesn’t change anything. It is only a ‘chill pill’ in situations that have your body on alert.

Adult separation anxiety is a disorder linked to oxytocin levels and oxytocin receptor genetic variants in several studies. It is characterized by feeling anxious when separated from a loved one or even a pet.[ref][article]

Related article: Oxytocin genes

3) Serotonin: anxiety and depression

Serotonin is a neurotransmitter involved in mood. This pathway is a common target of antidepressant and antianxiety medications known as SSRIs. Serotonin is also important in gut motility and in sleep (as the precursor for melatonin).

Researchers still have a lot of questions about how serotonin works in anxiety. The key may be that serotonin acts differently in situations of fear or panic, compared to situations that cause general anxiety.[ref][ref]

Several genetic variants in serotonin-related pathways have been linked to PTSD, a type of anxiety disorder.

Related article: Serotonin genes

4) BDNF: additive factor

Brain-derived neurotrophic factor (BDNF) has multiple functions in the brain including neuroplasticity and potentiating neurotransmitter function. Basically, it helps grow new neurons and helps neurotransmitters work better.

BDNF genetic variants are linked with an increased risk of depression and anxiety, but the common variants in this gene also interact with other genes and with stress in changing the risk for depression. The Val66Met variant (listed below) has been investigated in over a thousand studies. The Met allele carriers have reduced BDNF activity.[ref][ref]

A recent animal study tested the theory that BDNF genetic variants interact with stress as a ‘two-hit’ combo for impacting mood and brain function. The researchers gave normal mice and BDNF-reduced mice (Val/Met heterozygous mice) a stress hormone (cortisol) in their water. Then they tested the effects of different environments. Mice that were housed in an enriched environment (toys, tunnels, more open housing, exercise, mazes, etc) did not have brain changes in the BDNF + stress hormone mice.  But the female mice in a non-enriched environment exposed to the ‘two-hits’ had changes in spatial memory, maze performance, and the hippocampus.[ref]

Related article: Increasing BDNF

5) HPA Axis: Cortisol and stress response

The HPA axis (hypothalamus-pituitary-adrenals) controls the body’s cortisol release in times of stress.  The adrenals release cortisol after exposure to physical or mental stressors. This system works great when you are being chased by a tiger once in a while, but chronically elevated cortisol is linked to a number of health problems including depression.

Altered cortisol levels with low cortisol and a stronger negative feedback loop are found in people with PTSD.  While the research is still ongoing, there seems to be a subset of people for whom altered cortisol response is at the root of either their anxiety or depression.[ref]

The body’s baseline level of cortisol rises and falls in a circadian rhythm over the course of 24 hours. Having this rhythm in sync with the rest of the body is important for both physical and mental health.

Research shows that people with panic disorder have higher overnight cortisol levels and they have an exaggerated response to novel stressors.[ref]

Related article: HPA Axis genes

6) Carbon Dioxide: a physical trigger for panic attacks – for some

In severe anxiety or panic disorders, people often feel like they are short of breath or suffocating.  Interestingly, people with panic disorder also have a heightened sensitivity to carbon dioxide. Most people, when inhaling higher percentages of carbon dioxide don’t have a response, but in people with panic disorder, inhaling a higher-than-normal amount of CO2 can actually trigger a panic attack.[ref]

Increasing the CO2 levels in the blood increases the acidity (lower pH). Researchers theorize a chemical sensor in the amygdala is involved in the detection of pH levels. In mouse studies, inhaled CO2 drops the pH in the amygdala and causes fear behaviors. This is mediated by the acid-sensing ion channel-1a subunit (coded for by the ACCN2 gene in humans).[ref][ref]

7) Inflammation as a physiological cause of anxiety:

For some, a root cause of depression and/or anxiety can be chronic inflammation. Some people are just wired to produce a higher inflammatory response, and this can cause the physical alterations linked to anxiety.

This is such a huge topic, I’ve created a whole article on: Is Inflammation Causing Your Depression or Anxiety

Lifehacks for Anxiety (personalized for your genes):

The following are solutions that may work for specific genetic variants. Everyone is different, of course. Use your best judgment and talk with your doctor if you are under a doctor’s care for anxiety.

Here’s an overview of where we are going here:

ADORA2A:
If you carry the ADORA2A receptor variant and drink beverages containing caffeine, try cutting down on caffeine to see if it helps with your anxiety.

• Low doses, half-calf: Caffeine at low doses seems to help some people with anxiety, so cutting out coffee altogether may not be the right move. If you’re a coffee drinker, try switching to half decaf/half regular, and decrease caffeine levels to less than 150mg per day.[ref]

OXTR variants:
Understanding the way that social interaction and empathy are important to you personally, may help you to modify your interactions.  If you carry the G/G allele and you have anxiety when separated from loved ones, you may want to see about boosting oxytocin levels at times when you feel anxious. Here are a couple of ways to raise oxytocin levels:

• Gazing into a dog’s eyes and petting a dog both increase oxytocin levels.[ref][ref] Don’t have a dog nearby? Try puppy videos.
• Vitamin C is a co-factor for creating oxytocin. Perhaps some extra vitamin C before going to a group function might help to increase oxytocin.[ref][ref]

Increasing BDNF:
If you carry the BDNF variants, you may want to experiment with boosting your BDNF levels on a long-term basis.

• Exercise: Even a single bout of exercise increases BDNF levels in the hippocampus.[ref][ref] Find some kind of activity that you can enjoy daily: walking, jogging, weight lifting, tennis, pilates, biking…
• Sunlight: Exposure to sunlight or bright light during the day increases BDNF levels.[ref] Go outside!

Animal studies show that increased branched chain amino acid (BCAA) intake promoted BDNF growth and made the animals less anxious and more resilient to stress. This was shown to affect the same pathway that exercise affects, but adding BCAA to exercise didn’t have a synergistic effect.[ref] Thus, it may be worthwhile to experiment with increasing BCAAs on days that you don’t exercise to see if there is an effect on anxiety. Supplemental branch chain amino acids are often sold in the weight-lifting section of a health foods store.

Cortisol response:

If your genetic variants indicate that cortisol may be part of your anxiety susceptibility, you may want to consider adaptogenic herbal supplements.

• Ashwagandha, an ancient medicinal herb, reduces cortisol in multiple clinical trials and research studies. (Read more about ashwagandha research)[ref]
• Holy Basil is shown in animal studies to inhibit cortisol release. You can get Holy Basil as a supplement or drink it as Tulsi tea.[ref]

Related article: HPA Axis Dysfunction: Cortisol and Stress.

Panic disorder and CO2:

Realize that with the ACCN2 gene variants, the panic or anxiety trigger is based on the physiological response to the basic human need for oxygen (or rather, the balance with CO2 and oxygen).

Think about this one with an eye towards regulating breathing – and also making sure that you don’t have anything that would prevent breathing (face coverings, scarves, tight clothing, turtlenecks).

Physiological sigh:
You can change your CO2 and O2 levels by sighing. There is a change in brain state from sighing. [ref – open source, lots more info] The practice of doing a ‘physiological sigh’ can reduce anxiety for some people.

Physiological sigh:

• Breathe in through your nose, then take one more quick sniff in through your nose.
• Sigh out through your mouth – big exhale (you know how to sigh :-)

Practice breathing exercises, such as box breathing, so that you know how to do them when in anxiety-inducing situations.

Supplement stacks and lifestyle changes:

☑ Ashwagandha has many studies on it showing that it impacts cortisol and may help with anxiety. This would be my number one “go to” for anxiety connected to cortisol or stress. One study tested 300 mg, 2x a day vs. placebo. After 8 weeks, cortisol was reduced by an average of 22%, which is significant. Weight also went down for the Ashwagandha group.[ref] Stacking ashwagandha with resistance exercise may help with increasing muscle mass also.

Related article: Ashwagandha research studies

☑ ADORA2A: Cutting out caffeine suddenly can be hard – and slightly stressful, which you don’t want. Experiment with different levels of caffeine, reducing it to less than 150 mg and cutting it off by noon. It takes time for the adenosine receptors to adjust, so give this experiment a week or more to see if it decreases your anxiety. In my opinion, the best way to know if something is working is to track the results. So be deliberate in noting the amount of caffeine you drink in a day and also what you feel that your anxiety level was by the end of the day.

☑ Sleep is vitally important in cortisol response. A recent study showed that getting more sleep the night before leads to a decreased stress response during the morning and afternoon, but that effect wore off by evening.[ref ] Thus, you need good quality sleep and a good quantity of sleep, every night. Most important for circadian rhythm is that sleep timing needs to be consistent, so go to bed at the same time every night. Eliminating bright light at night can help a lot in promoting sleep and increasing melatonin.

☑ For BDNF: Lion’s Mane mushroom extract has been shown to increase BDNF levels.[ref] Lion’s mane is available as a supplement, or you may be able to find fresh lion’s mane mushrooms at your farmer’s market (they taste like lobster!).  Bacopa increases BDNF expression when given chronically.[ref] Bacopa is an herbal supplement that has been used for thousands of years in India. It is known for its positive effect on memory and cognition.

☑ Breathwork: Carriers of the ACCN2 gene variants may want to look into the different types of breathing therapy. Look into hypoventilation therapy or talk with your doctor about your options here.[ref] Other options investigated may include left nostril breathing (yoga) and other types of breathing exercises.[ref] If you are prone to panic attacks, undertake these with help from an expert in case the altered breath training triggers a panic attack.

Recap of your genes:

Graphical Abstract:

Putting it all together:

It is entirely likely that there is more than one genetic pathway involved in anxiety for most people. Figure out which tools you need in your toolbox – e.g. cortisol regulation plus breath work, or focusing on sleep, along with avoiding caffeine.

Not finding your answer here? Check out these articles as well:

GABA could be playing a role in anxiety

Lithium Orotate + Vitamin B12 can be helpful for some people

L-theanine: research studies and how it works

Histamine intolerance  and/or Mast Cell Activation Syndrome can cause anxiety symptoms

Related Articles and Topics:

Is Inflammation Causing Your Depression and Anxiety? The Science Behind the Link

Genetics and Seasonal Affective Disorder