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 the way that serotonin is made in the body, the transport of serotonin, and the receptors needed to complete the pathway.

What does serotonin do?

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.

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]

Depression:

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

Serotonin Syndrome:

Ultimately, balance is the key to serotonin. Too much serotonin is known as 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]

Serotonin Synthesis and Transport:

Serotonin, also known as 5-hydroxytryptamine or 5-HT, is synthesized from the amino acid tryptophan using tryptophan hydroxylase (TPH1 and TPH2 gene).

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

The serotonin signal is received by serotonin receptors on the cell membrane: HTR1A, HTR1B, and HTR2A.

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.


Genetic Variants that Change Serotonin Levels:

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Below is a compilation of studies on genetic variants that affect serotonin.  It is not an exhaustive list; instead, treat this as a starting point for you to find out more about your genes.

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.

A good overview of TPH2 can be found in the introduction of this study which also explains the link with GABA levels as well.

Several TPH2 genetic variants have been linked to psychiatric issues such as obsessive-compulsive disorder, depression, and bipolar disorder. These variants affect the rate at which serotonin is being produced 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 are thought 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 was tied 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 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

SLC6A4 is the gene that encodes the serotonin transporter. It is also called SERT or 5-HTT in some of the research. The 5-HTTLPR variant is a variable number tandem repeat. This just means there is a short version of the gene and a long version – due to repeated parts of the gene.

A lot of researchers have studied the 5-HTTLPR short/short and long/long forms. Initial studies in the ’90s and early 2000s found that those with the short version of the gene were more prone to depression due to stressful events. Here is a nice article summarizing the research that has been done on this gene:  Controversial Gene-Depression Link Confirmed in New Study.

Variable number tandem repeats are not included in 23andMe or AncestryDNA data, but there are SNPs that usually go along with the serotonin transporter repeats. So you can get a pretty good idea of whether you carry the long or short version. A couple of studies have found that two SNPs predict the long or short version of 5-HTTLPR fairly well – around 95+% of the time. [ref][ref][ref]  These are found in both v.4 and v.5 for 23andMe data.

5HTTLPR rs2129785
(23andMe v4, v5; AncestryDNA)
rs11867581
(23andMe v4, v5
; AncestryDNA)
 Long  T  G
 Long  C  A
 Short  T  A

The above table can be kind of confusing – here is an example: If your rs2129785 genotype is T/T and your rs11867581 genotype is A/G, you would carry one copy of the 5-HTTLPR short and one copy of the long version.

Studies on personality traits and genes tend to show all kinds of different results — with the results of one study often contradicting other studies. So take the following with a grain of salt:

  • The most replicated results for 5-HTTLPR show a link between carrying the short/short version and an increased risk of anxiety disorders.[ref][ref] [ref] 
  • The short form of this gene is associated with lower 5-HTT activity. [ref]

A recent study may explain some of the contradictory results from previous studies. [ref] The researchers found that people who carried two copies of the long allele were more affected by environmental influences on mood (e.g. good or bad life events).  Thus people who carried the long/long genotype were more likely to have a positive mood in a positive environment, but they were also more negative when bad things happened.

Studies show the long or short form may influence how well depression medications work for you:

  • Escitalopram (Lexapro) was studied in a clinical trial of adults aged 60+ with a generalized anxiety disorder. The study found that escitalopram had “no efficacy” for those with low activity haplotype. [ref] (The short/short genotype is associated with lower activity.)
  • In a study of citalopram for depression after TBI (traumatic brain injury), the results showed that those patients carrying the short/short genotype were more likely to have adverse events. (But honestly, with 84% of patients having adverse events, it doesn’t look like genotype plays a huge role here.)[ref]
  • In an analysis of studies on Caucasian populations, those with the long/long genotype had a better response rate to SSRI’s.  This didn’t hold true for Asian populations, though.[ref]

Serotonin plays a major role in the gut, and IBS patients with a short allele had worse symptoms than those with a long/long version of this gene.[ref]

The short/short genotype is also tied to an increased risk of gastrointestinal intolerance of metformin.[ref]


Lifehacks for Serotonin:

Below are research-supported ways of affecting your serotonin levels. If you are needing psychiatric help, please be sure to contact a health care provider!

Get outside, be active, and eat well:

While your genes have an effect on serotonin levels in the body, there are also several environmental factors that also influence serotonin production. There is a correlation between higher serotonin levels and exposure to bright light or sunlight.[ref]

Physical activity may also increase serotonin levels. Eating foods high in tryptophan may also increase serotonin levels, but it is hard to know how much of an effect it has on serotonin in the brain.[ref]

Gut health:

Serotonin also plays a big role in the gut. Here is a great research article on serotonin and the gut microbiome: Serotonin, tryptophan metabolism and the brain-gut-microbiome axis

There are quite a few studies (mostly animal studies) showing the effect of Lactobacillus species on serotonin production in the gut. This not only seems to have an effect on gut motility and gut issues, but it also has an effect, perhaps through the gut-brain axis, on anxiety and depression.[ref][ref][ref][ref]

A good overview of the gut-brain axis and the recent research on the effect of gut microbes on mood and anxiety can be found in the March 2018 journal article “Vagus Nerve as Modulator of the Brain-Gut Axis in Psychiatric and Inflammatory Disorders“.

Quite a few clinical trials show specific probiotics are effective for depression and anxiety (whether due to serotonin problems or other reasons).

  • One clinical trial for postpartum depression found that Lactobacillus rhamnosus was effective. [ref]
  • Another clinical trial in IBS patients with depression found that Bifidobacterium longum reduced depression but not anxiety.[ref] A
  • clinical trial using Lactobacillus casei, acidophilus, and Bifidobacterium bifidum found a significant decrease in depression scores. [ref]

Meditation:

Considering the intersection of so many studies between trauma, stress, serotonin and depression/anxiety, mindfulness meditation may be something to explore. [ref]

5-HTP:

A supplemental form of the precursor to serotonin, 5-HTP is readily available in most health food stores. Many studies show positive effects of supplementing with 5-HTP, but always use caution when taking supplements that can affect your neurotransmitters. With this in mind, if you are under a doctor’s care or on other medications, be sure to check with your doctor.  A case report shows that mixing MAOI prescription with over the counter 5-HTP supplement caused an adverse reaction (manic episode).[ref] [ref][ref]


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.

 

 



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. 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.