Serotonin: How your genes affect this neurotransmitter

Serotonin… a word that brings to mind a commercial that might show our happy brain neurons bouncing serotonin between them.

There is a lot more to this molecule than most of us realize! This article covers how the body makes and transports serotonin and the needed receptors to complete its pathway. I’ll explain the genetic variants that impact the serotonergic system and then go through diet, supplement, and lifestyle changes that impact serotonin.

What does serotonin do?

In the brain, serotonin acts in several ways:

  • as a neurotransmitter, sending a chemical message between neurons.
  • as the precursor molecule for melatonin
  • in sleep quality, including sleep hallucinations[ref][ref]

But there is more to serotonin than just its impact on the brain.

About 90% of serotonin is made in the gut and helps to regulate motility.[ref] Serotonin also regulates other functions such as; bone mass, cardiovascular health, the endocrine system, and appetite.

Serotonin is also important in energy metabolism, heart rate, cell growth, and immunity.[ref]

 

Depression:

Some researchers believe that imbalances in serotonin may play a role in depression or anxiety. Common antidepressants include SSRIs (selective serotonin reuptake inhibitors) and are thought to increase serotonin levels in the brain. However, the method through which they work is still not completely understood.[ref]

Another link between serotonin and depression is that serotonin modulates immune function.[ref] Increased inflammation is implicated in causing major depressive disorder for some.

Recent animal research shows that one reason that SSRIs may not work for everyone is due to increased inflammation. The study showed that in inflammatory situations, histamine is upregulated and SSRIs act in off-target actions on histamine instead of increasing serotonin. In this study, decreasing histamine levels increased the SSRI effectiveness.[ref]  (Read more about histamine and check your histamine intolerance genes.)

Serotonin Synthesis and Transport:

Like most signaling molecules and neurotransmitters, serotonin first needs to be created (synthesized), then it needs to be transported, and finally the signal needs to be received by a cellular receptor.

Synthesis: Serotonin, also known as 5-hydroxytryptamine or 5-HT, is synthesized from the amino acid tryptophan using tryptophan hydroxylase. The TPH1 and TPH2 genes encode the tryptophan hydroxylase enzymes.

Transport: Serotonin is transported by SLC6A4, which is also known as SERT or sodium-dependent serotonin transporter.

Receptors: Serotonin receptors on the cell membrane, HTR1A, HTR1B, and HTR2A receive the serotonin signal.

All of these work in concert: from the creation of serotonin from amino acids to the transport of serotonin to the receptors that are necessary to receive this chemical messenger.

Serotonin Syndrome: Too much serotonin

Ultimately, balance is the key to serotonin. Too much serotonin can result in serotonin syndrome. Symptoms include restlessness, confusion, shivering, diarrhea, and, potentially, death.[ref]

Serotonin syndrome is usually caused by drugs such as MAOIs or SSRIs that affect the rate of serotonin break down.[ref]


Genetic Variants that Change Serotonin Levels:

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Below is a compilation of studies on genetic variants that affect serotonin synthesis, transport, and receptors. Please treat this as a starting point for learning more about your genes and serotonin. Talk with your doctor if you have any medical questions.

Serotonin Synthesis: Tryptophan Hydroxylase (TPH1 and TPH2)

Tryptophan hydroxylase is an enzyme that catalyzes the reaction that produces serotonin from the amino acid tryptophan. Iron is a co-factor, and BH4 is also used in the reaction.

There are two genes that code for tryptophan hydroxylase:

  • TPH1 is found mainly in the gut, skin, and pineal gland.
  • TPH2 works in the central nervous system.

(Learn more about tryptophan and how it converts to serotonin or kynurenine.)

Several TPH2 genetic variants have links to psychiatric issues such as obsessive-compulsive disorder, depression, and bipolar disorder. These variants affect the production rate of serotonin in the brain.

Check your genetic data for  rs4570625 (23andMe v4, v5; AncestryDNA):

  • G/G: typical
  • G/T: decreased risk of depression[ref], less anxiety, and aggression[ref][ref]
  • T/T: decreased risk of depression, less anxiety, and aggression, more likely to be honest[ref]

Members: Your genotype for rs4570625 is .

Interactions between different genetic variants can be important as well. There are a couple of interesting studies that look at the combination of carrying the rs4570625 genotypes with the BNDF Val66Met (rs6265) genotypes. Those with rs4570625 G/G and rs6265 T/T were more likely to have “impaired inhibition of negative emotional content”.[ref] (The next time you start yelling at someone, be sure to think about your “impaired inhibition of negative emotional content“!)

Serotonin Receptors: HTR1A, HTR1B, HTR2A

While there is still debate among researchers on this topic, one recent paper explains that the function of the brain serotonin receptors is to moderate stress and anxiety through patience and coping.

  • The HTR1 receptors seem to mediate the ability to tolerate a source of stress, ‘passive coping’.
  • The HTR2 receptors mediate the ability to actively cope and improve one’s ability to change due to adversity.

The HTR1A gene codes for a serotonin receptor.

Check your genetic data for rs6295 C1019G (23andMe v4, v5):

  • C/C: higher impulsiveness, increased risk for depression[ref][ref]
  • C/G: typical impulsiveness
  • G/G: typical
    *All alleles are given in the plus orientation to match 23andMe and AncestryDNA data

Members: Your genotype for rs6295 is .

The HTR1B gene codes for another serotonin receptor.

Check your genetic data for rs6296 (23andMe v4, v5; AncestryDNA):

  • G/G: increased risk of depression, anxiety after stressful life events, increased risk of childhood aggressive behavior, ADHD[ref][ref]
  • C/G: somewhat increased risk of depression, anxiety after stressful life events, increased risk of childhood aggressive behavior, ADHD
  • C/C: typical
    *All alleles are given in the plus orientation to match 23andMe and AncestryDNA data

Members: Your genotype for rs6296 is .

HTR2A gene: The serotonin 2A receptor (HTR2A) also has several well-studied variants including rs6314, also known as C1354T.

Check your genetic data for rs6314 C1354T(23andMe v4, v5; AncestryDNA):

  • A/A: reduced serotonin 2A receptors in the prefrontal cortex, increased risk of social withdrawal[ref][ref]
  • A/G: reduced serotonin 2A receptors in the prefrontal cortex, increased risk of social withdrawal
  • G/G: typical

Members: Your genotype for rs6314 is .

Other studies on rs6314 show:

  • In a study, paroxetine (Paxil) therapy response has ties to rs6314 polymorphism. Those with the minor allele (A) had a 7.5 times greater chance of response than those with G/G.[ref]
  • An interesting 2013 study looked at serotonin receptor polymorphisms in association with a food reward. The study found that there was an association between the rs6314 A allele and susceptibility towards food reinforcement.[ref]
  • A study found that those with the minor allele may not improve as much on olanzapine (an antipsychotic).[ref]

 

Check your genetic data for rs6311 (23andMe v4, v5; AncestryDNA):

  • C/C:  more empathy for happiness, more speed-dating success for women[ref], increased risk of sexual dysfunction with SSRI[ref][ref], increased risk of aggression in adults. [ref]
  • C/T: more empathy for happiness,
  • T/T: typical

Members: Your genotype for rs6311 is .

 

Serotonin Transporter:  5-HTTLPR Short and Long

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Related Genes 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.

Tryptophan
Tryptophan is an amino acid that the body uses to make serotonin and melatonin. Genetic variants can impact the amount of tryptophan that is used for serotonin. This can influence mood, sleep, neurotransmitters, and immune response.

 

 


About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.