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 in 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 thought to increase serotonin levels in the brain. Although, 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 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"!)

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