Did you know that about 1 in 5 people will deal with an anxiety disorder at some point in life? From generalized anxiety to separation anxiety to panic disorder – there are underlying physiological and genetic factors involved.
This article covers genetic variants related to anxiety disorders. This is a big topic, and new research is coming out all the time. The information presented here is for educational/informational purposes. Which means… learn all that you can about the physiological and genetic reasons for anxiety disorders, but do talk with your doctor before making any medical decisions.
Anxiety Disorders and Genetics
The lifetime risk of anxiety disorder is over 20%. If you’re dealing with anxiety, you are not alone!
‘Anxiety disorder’ is a general term that can include generalized anxiety, panic disorders, social anxiety, PTSD, phobias, and more. This is a complex group of disorders with various ways of presenting, but there are some underlying biological similarities in their causes.[ref]
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 behavioral alterations in order to avoid some social situations. This can lead to stress or an 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 disorder 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]
How can genetic studies shed light on anxiety disorders?
Genetics plays a role in anxiety disorders, with heritability estimated to be up to 50%. The other half of the picture here is environmental and lifestyle factors.[ref]
The big takeaway here is that anxiety disorders have a genetic component, for most people. And that the genetic component causes a physical alteration in the way the brain works or in the physiological response to stress.
Knowing your genetic ‘kryptonite’ may help you to find the right solution to your anxiety problems.
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 variants 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 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.
Let’s take a look at the specific genes linked to anxiety disorders:
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, an important biological compound, is made up of an adenine molecule and a d-ribose sugar molecule and found in every cell in the body. 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).
Adenosine also may sound familiar because it is part of the ATP molecule (adenosine triphosphate).
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 binding to the adenosine receptor and blocking it 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 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 on alert, startling more easily, and jittery (especially with high caffeine).
Oxytocin: anxiety when separated from loved ones
Oxytocin is a hormone and a neuropeptide researchers link to both emotional functioning and social empathy. In women, large quantities of oxytocin are released during childbirth and breastfeeding and are part of the mother-child bonding. (For anyone who has been induced in childbirth, this is done using oxytocin or Pitocin.)
Anyone who has had kids understands that there is a connection where a mother can recognize their own baby’s cry. In fact, oxytocin is a big part of a mother’s neuroendocrine response to their baby’s crying. Researchers study this by brain imaging using an fMRI on mothers listening to crying babies.[ref] It is a built-in, physiological response based on oxytocin.
Going beyond mother-infant bonding, oxytocin, in general, plays a role in social attachment and trust. In fact, if you give normal adults oxytocin intranasally (up the nose), there is a substantial increase in trust amongst people, which increases the benefits of social interaction.[ref] If you want to get into the geeky details on 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, 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]
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, which is classified as an anxiety disorder.
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]
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]
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]
This section gets specific on genetic variants of the pathways discussed above. Note that there are other genetic variants that could also impact these pathways. The variants included below are found in 23andMe or AncestryDNA data and also have multiple studies to back up the assertions. (In other words – I left out some variants with conflicting data or research that wasn’t replicated.)
Member’s quick visual overview:
|Gene||RS ID||Risk Allele||YOU||Notes about the Risk Allele:|
|ADORA2A||rs5751876||T||—||TT only: Increased risk of panic disorders|
|OXTR||rs53576||G||—||GG only: more empathetic, increased separation anxiety|
|GNB3||rs5443||T||—||Combined with OXTR, increased separation anxiety|
|SLC6A4||rs140701||T||—||Increased risk panic disorder, social anxiety disorder|
|BDNF||rs6265||T||—||Decreased BDNF levels, increased risk anxiety disorders|
|FKBP5||rs1360780||T||—||TT only: incomplete cortisol recovery, increased anxiety after psychosocial stress|
|CHCR1||rs110402||G||—||Increased cortisol in childhood trauma|
|ACCN2||rs10875995||C||—||Heightened reactivity to high CO2 levels, incr. risk panic disorders|
|ACCN2||rs685012||C||—||Heightened reactivity to high CO2 levels, incr. risk panic disorders|
ADORA2A gene: adenosine receptor 2A
Check your genetic data for rs5751876 (23andMe v4, v5; AncestryDNA):
- T/T: increased risk of panic disorder[ref] increased anxiety with caffeine consumption (150mg) and with amphetamines[ref]
- C/T: most common genotype
- C/C: typical
Members: Your genotype for rs5751876 is —
OXTR gene: codes for the oxytocin (love hormone) receptor
Check your genetic data for rs53576 (23andMe v4, v5; AncestryDNA):
- G/G: more empathetic; increased separation anxiety (both adult and child) risk when coupled with GNB3 rs5443 – T allele [ref], less stress (cortisol response) if receiving social support[ref] higher adult separation anxiety in depressed patients.[ref]; altered cortisol levels and altered blood pressure with social rejection[ref]
- A/G: less empathetic, less sensitive to social rejection (more resilient)
- A/A: less empathetic, less sensitive to social rejection (more resilient)
Members: Your genotype for rs53576 is —.
GNB3 gene: G-protein is involved in signaling, variants are linked to high blood pressure, night blindness, and mood disorders
Check your genetic data for rs5443 (23andMe v4, v5; AncestryDNA):
- T/T: increased separation anxiety (both adult and child) risk when coupled with OXTR G/G genotype (above)[ref]
- C/T: increased separation anxiety (both adult and child) risk when coupled with OXTR G/G genotype (above)
- C/C typical
Members: Your genotype for rs5443 is —.
SLC6A4 gene: serotonin transporter
Check your genetic data for rs140701 (23andMe v4; AncestryDNA):
- C/C: typical
- C/T: increased susceptibility to panic disorder and social anxiety disorder
- T/T: increased susceptibility to panic disorder and social anxiety disorder[ref][ref]
Members: Your genotype for rs140701 is —.
BDNF gene: brain-derived neurotrophic factor
Check your genetic data for rs6265 (23andMe v4, v5; AncestryDNA):
- T/T: decreased BDNF[ref] referred to in studies as Met/Met; increased trait of ‘Harm Avoidance'[ref] some studies show increased risk of panic disorder, anxiety disorders [ref][ref][ref][ref]
- C/T: somewhat decreased BDNF, referred to as Val/Met; increased Harm Avoidance;
- C/C: typical BDNF, referred to as Val/Val
Members: Your genotype for rs6265 is —.
FKBP5 gene codes for a chaperone protein that regulates the sensitivity of the glucocorticoid receptor (GR). (HPA axis, cortisol response – stress)
Check your genetic data for rs1360780 (23andMe v4, v5, AncestryDNA):
- C/C: typical
- C/T: typical anxiety risk
- T/T: incomplete cortisol recovery and increased anxiety after psychosocial stress [ref ]
Members: Your genotype for rs1360780 is —.
CHCR1 gene: codes for the corticotropin-releasing hormone receptor involved in the signaling for cortisol released due to stress.
Check your genetic data for rs110402 (23andMe v5, AncestryDNA)
- G/G: elevated cortisol in people exposed to childhood trauma [ref ]
- A/G: slightly increased risk of depression in childhood trauma
- A/A: typical, decreased risk of MDD in non-smokers [ref]
Members: Your genotype for rs110402 is —.
Carbon dioxide, panic disorder variants:
ACCN2 gene: codes for a protein important in sensing CO2 levels in the brain
Check your genetic data for rs10875995 (23andMe v4; AncestryDNA):
- C/C: heightened reactivity to low oxygen (or high CO2), greater amygdala volume, increased risk of panic disorder[ref]
- C/T: heightened reactivity, greater amygdala volume, increased risk of panic disorder
- T/T: typical
Members: Your genotype for rs10875995 is —.
Check your genetic data for rs685012 (AncestryDNA):
- C/C: increased risk of panic disorder, heightened reactivity to low oxygen (or high CO2) [ref][ref]
- C/T: increased risk of panic disorder
- T/T: typical
Members: Your genotype for rs685012 is —.
The following are solutions that may work for the 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.
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.
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]
Experiment with different levels of caffeine – your sweet spot may be less than 150mgs. 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.
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]
If you carry the BDNF variants, you may want to experiment with boosting your BDNF levels on a long-term basis.
Sunlight: Exposure to sunlight or bright light during the day increases BDNF levels.[ref] Go outside!
Animal studies show that increased branch 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 that 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.
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.
Ashwagandha, an ancient medicinal herb, reduces cortisol in multiple clinical trials and research studies. (Read more about ashwagandha research) One study, for example, tested 300 mg/twice a day vs. placebo. After 8 weeks, cortisol was reduced by an average of 22%. Weight also went down for the Ashwagandha group.[ref][ref]
Holy Basil shown in animal studies to inhibit cortisol release. You can get Holy Basil as a supplement or drink it as Tulsi tea.[ref]
Sleep is 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 ] So you need good quality sleep and a good quantity of sleep, every single night.
If you carry the genetic variants related to cortisol levels and anxiety, it may be time to take a hard look at how much stress you deal with every day…
Read more about the lifehacks for modifying cortisol levels.
Panic disorder and CO2:
Realize that with the ACCN2 gene variants, the panic or anxiety trigger is based on the physiological response to the very basic human need for oxygen (or rather, the balance with CO2 and oxygen). So 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).
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 investigate may include left nostril breathing (yoga) or Wim Hof breathing.[ref] Undertake these with help from an expert, though, in case the altered breath training triggers a panic attack.
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 breathing, or exercise, and sunlight along with avoiding caffeine.
Related Genes and Topics:
Is inflammation causing your depression and anxiety?
Research over the past two decades clearly shows a causal link between increased inflammatory markers and depression. Genetic variants in the inflammatory-related genes can increase the risk of depression and anxiety.
Seasonal Affective Disorder (SAD) is characterized by recurrent depression with a change in the season usually in fall/winter for most. Scientists think this is possibly due to an aberrant response to light – either not enough brightness to the sunlight or not enough hours of light. Your genes play a big role in this responsiveness to light.
Lithium Orotate + B12
For some people, low-dose, supplemental lithium orotate is a game-changer when combined with vitamin B12. But other people may have little to no response. The difference may be in your genes.
HPA Axis Dysfunction and Cortisol:
Cortisol is a hormone produced by the adrenal glands in times of stress, and it also plays many roles in your normal bodily functions. It is a multi-purpose hormone that needs to be in the right amount (not too high, not too low) and at the right time. Your genes play a big role in how likely you are to have problems with cortisol.