ANK3: Bipolar Disorder and Brain Development

The brain is simply amazing – controlling thoughts, movement, essential bodily functions, emotions, mood, and life. At a basic level, all of this brain activity is dependent on electrons flowing through neurons, which is where the ANK3 gene comes in.

I will attempt to explain how ANK3 impacts neuronal formation and transmission – and how this ties into an increased risk of psychiatric disorders. Included also are ANK3 genetic variants to check in your raw data.

As always, the information here is for educational purposes. If you think you have bipolar disorder or schizophrenia, please seek help from a medical professional.

What is ANK3?

Ankyrin 3 (ANK3) is a protein that acts in neurons as a partner, or scaffold, necessary to the voltage-gated sodium channels important in neuronal firing.

Neurons are the brain and nervous system cells that transmit electrical signals — they tell your muscles to move, heart to beat, and brain to think. The impulses sent via neurons are little electrical charges that build up and then ‘fire’.

Along the neuron is a myelin sheath that insulates it, but spaces interrupting the myelin sheath allow ions to flow in. It is where ANK3 comes in — helping the axon structure to initially form and function well. Specifically, it helps to put the sodium channels in the right place.[ref]

Here’s a very quick overview video of how neurons work:

 

The genetic variants in the ANK3 gene impact the risk of psychiatric disorders that include bipolar disorder and autism spectrum disorders, and heart arrhythmia.

Wiring the brain: AKN3

ANK3 helps wire the brain in two ways:

  1. ANK3 interacts with the way that neurons transmit signals
  2. ANK3 is important in neuron formation during fetal development[ref]

There are several different versions, or isoforms, of ANK3, which act in multiple ways in the brain and throughout the nervous system.[ref]

Neuronal firing:

GABAergic neurons are regulated and kept from being overstimulated by GABA, an inhibitory neurotransmitter within the brain. It’s commonly thought of like the brakes that keep neurons from firing too much. It is important in cognitive function, mood, and behavior.

Recent research shows that one form of ANK3 is important in how GABA binds to its receptor (GABARAP) in certain types of neurons. A rare mutation in ANK3 alters this binding and has strong links to causing bipolar disorder.[ref]

Additionally, the ANK3 protein is important in how the neurons fire in certain regions of the brain. The protein helps the way that sodium channels are structured in the axon of the neuron. Sodium channels are essential for changing the ion gradient so that a neuron fires.

CC Image PMC3492013

You may be wondering how the brain can even work if there is a problem with the neurons firing. There are different types of neurons and specific variations of sodium channels — the ANK3 protein is only important in specific neurons in certain parts of the brain and peripheral nervous system. Variants in ANK3 don’t affect all neurons.

Bipolar disorder and ANK3 variants:

Bipolar disease is reportedly 80% heritable, which means that the genetic component is very high.[ref] But there is not just one gene mutation that causes someone to have bipolar disorder. Instead, many different genetic variants come together to increase susceptibility to this mood disorder.

Executive function refers to the higher-order thinking that people use when making complex decisions or goal-oriented planning. Research shows that people with bipolar disorder are more likely to have executive function deficits, and it is one of the heritable features of bipolar.[ref]

Postmortem studies on the brains of people with bipolar disorder (BD) show that they have lower expression of ANK3. This association indicates that alterations in ANK3 may change how the neurons developed and/or the activity of neurons in specific brain regions, increasing susceptibility to BD.[ref]

Interestingly, new research shows that ANK3 interacts with GSK3B, the target of lithium, a commonly used medication for bipolar disorder.[ref]

Autism Spectrum Disorder:

Rare mutations in ANK3 have been identified in some patients with autism spectrum disorder. Autism is likely to have many different genetic causes, and ANK3 mutations are just one possibility. [ref]

Researchers believe that ANK3 mutations can cause autism or neurodevelopmental disorders by disrupting the proper formation of the axon during fetal development.[ref][ref]

Researchers have found that early stress during the prenatal or early postnatal period alters the interaction of ANK3 in the neuron. Common genetic variants in ANK3, when combined with prenatal stress, are linked to deficits in working memory. In this study, prenatal stress was determined by complications during the pregnancy or birth.[ref]

 


Genetic variants in ANK3:

Members: Log in and select your data file
Not a member? Join now to see your data below.

Check your genetic data for rs10994336 (23andMe v4, v5; AncestryDNA):

  • C/C: typical
  • C/T: increased risk of bipolar disorder, decreased executive function in bipolar patients
  • T/T: increased risk of bipolar disorder, decreased executive function[ref][ref][ref]; altered facial affect processing[ref] decreased working memory in schizophrenia patients[ref]

Members: Your genotype for rs10994336 is .

Check your genetic data for rs1938526 (23andMe v4; AncestryDNA):

  • G/G: increased relative risk of bipolar disorder; possibly decreased working memory[ref]
  • A/G: slightly increased relative risk of bipolar disorder[ref]
  • A/A: typical

Members: Your genotype for rs1938526 is .

Check your genetic data for rs9804190 (23andMe v4; AncestryDNA):

  • T/T: greater ANK3 expression and better working memory;[ref] lower relative risk of bipolar disorder[ref]
  • C/T: greater ANK3 expression; lower risk of bipolar disorder
  • C/C: typical

Members: Your genotype for rs9804190 is .

Check your genetic data for rs10761482 (23andMe v4, v5; AncestryDNA):

  • C/C: typical
  • C/T: increased relative risk of schizophrenia; slightly increased risk of bipolar disorder
  • T/T: increased relative risk of schizophrenia[ref]; increased relative risk of bipolar disorder[ref]; altered brain structure in BD.[ref]

Members: Your genotype for rs10761482 is .

 

Not all variants increase the risk of bipolar disorder. Researchers discovered that this uncommon variant significantly decreases the risk of psychiatric illness.[ref]

Check your genetic data for rs41283526 (23andMe v4):

  • C/C: significantly decreased risk of bipolar disorder and schizophrenia[ref][ref]
  • C/T: decreased risk of bipolar disorder and schizophrenia
  • T/T: typical risk

Members: Your genotype for rs41283526 is .

 


Lifehacks:

Variants in ANK3 physically affect how the brain works.

Animal studies show that lithium works well as a treatment for alterations in the ANK3 pathway.[ref][ref]. If you suspect you have a mood disorder, obviously, talk to your doctor first before trying any supplements. Lithium orotate, a low-dose supplement formula, is available online from supplement suppliers.

ANK3 acts in the axon of the neuron to help the sodium channels function correctly. A clinical trial is currently underway to see if dietary salt (sodium chloride) makes a difference in bipolar disorder.[ref] One way that lithium possibly works in bipolar disorder is that it has a higher conductance than sodium.[ref]

Dopamine receptor stimulation also increases intracellular sodium concentrations, and some researchers think this may interact with lithium in an ‘activity-dependent manner’.[ref] Our electronic world of tweets and likes is filled with dopamine stimulation. Perhaps taking a break from constant dopamine hits would help.

I don’t have all the answers here, but here’s a suggestion:
If you have mood issues and also carry the ANK3 variants that increase the risk of bipolar disorder, you may want to track your sodium intake and see if it impacts your mood. Potassium is on the other side of the ion equation for neurons to fire, so keeping track of potassium and how it balances with sodium may give you some clues.

Cronometer.com is a handy app for tracking what you eat. It will then break down your intake of different vitamins and minerals, including sodium and potassium. The web version is free, and the phone app is inexpensive.

If you think you have bipolar disorder, I encourage you to seek help from a medical professional and talk with your family or friends. If the first doctor you see isn’t the right fit for you, find another one. Mental health is essential, and the right professional help can make a difference. Diet, exercise, sleep – all are important as well.


Related articles and topics:

Bipolar Disorder, Depression, Circadian Clock Genes
New research shows that depression and bipolar disorder are linked to changes or disruption in circadian genes. Some people carry genetic variants in the circadian genes that make them more susceptible to circadian disruption.

Lithium Orotate + B12: Boosting mood and decreasing anxiety, for some people…
For some people, low-dose, supplemental lithium orotate is a game-changer for mood issues when combined with vitamin B12. But other people may have little to no response. The difference may be in your genes.

Is inflammation causing your depression or 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.

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Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering from Colorado School of Mines. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.