Serotonin: How your genes affect this neurotransmitter

serotoninSerotonin… most of us think of the commercials with happy brain neurons bouncing the serotonin molecule between them. Turns out that there is a lot more to this molecule than most of us realize.

About 90% of serotonin is made in the gut and regulates motility there.[ref] Serotonin is also involved in various other bodily functions such as in bone mass regulation, cardiovascular health, the endocrine system, and appetite.

In the brain, serotonin is involved in many different functions. It acts as a neurotransmitter, sending a chemical message between neurons. It is also the precursor molecule for melatonin, which is vital to our circadian rhythm and sleep.[ref]

Some researchers believe that imbalances in serotonin may play a role in depression or anxiety. Common anti-depressants include SSRI’s which are thought to increase serotonin levels in the brain, although the method through which they work is still not completely understood.[ref]

Balance seems to be a key word with serotonin. Too much serotonin is known as serotonin syndrome. Symptoms include restlessness, confusion, shivering, diarrhea, and more.[ref]


Genetic Variants that Could Change Serotonin Levels:
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, and there are several receptors for serotonin, 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.

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

1.) Serotonin Synthesis: Tryptophan Hydroxylase (TPH1 and TPH2)
Tryptophan hydroxylase is an enzyme that acts as a catalyst for 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 mainly in the gut, skin, and pineal gland, while TPH2 is 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.

TPH2 has several polymorphisms that have been linked to psychiatric issues such as obsessive-compulsive disorder, depression, and bipolar disorder. These polymorphisms may be affecting the rate at which serotonin is being produced in the brain.

Check your 23andMe results for rs4570625 (v4, v5):

  • GG: most common form
  • GT: decreased risk of depression[ref], less anxiety and aggression[ref][ref]
  • TT: decreased risk of depression, less anxiety and aggression, more likely to be honest [ref]

There are a couple of interesting studies that combined the rs4570625 genotypes with the BNDF Val66Met (rs6265) genotypes. Those with rs4570625 GG and rs6265 Val/Val (TT on 23andMe) were more likely to have “impaired inhibition of negative emotional content”.[ref] This is a very good reminder that none of our genetic variants are acting alone, and, especially when it comes to psychiatric and brain-related issues, genes interact with other genes and the environment.

2.) 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. One variant that has been studied extensively is the 5-HTTLPR variant which is a variable number tandem repeat. This just means that there is a short version of the gene and a long version.  There have been quite a few studies done on the short/short vs. long/long forms of this variant.  Studies in the ’90’s and early 2000’s 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, but the linkage here isn’t 100% accurate.

A couple of studies have found that two SNPs predict the long or short version of 5-HTTPLPR fairly well – around 95+% of the time. [ref][ref][ref]  These are found in both v4 and v5 for 23andMe.

5HTTLPR rs2129785 rs11867581
 Probably Long  T  G
 Probably Long  C  A
 Probably Short  T  A

So why do we care about the long or short version of this serotonin transporter? There have been hundreds of studies done on this gene looking at the relationship between the long or short version and a variety of personality traits. The most replicated link seems to be between those carrying the short/short version and risk of anxiety disorders.[ref][ref]  [ref] Additional studies have shown that the short allele also increases the risk for major depressive disorder.[ref]

The short form of this gene is associated with lower 5-HTT activity. [ref]

Perhaps more interestingly, the long and short forms of this gene have been studied to see the interaction with prescription medications:

  • Escitalopram (Lexapro) was studied in a clinical trial of adults aged 60+ with generalized anxiety disorder. The study found that escitalopram had “no efficacy” for those with the low activity haplotype.[ref]
  • In a study of citalopram for depression after TBI, 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]

One more interesting correlation for this gene is found in irritable bowel syndrome.  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]

3.) 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’, while the HTR2 receptors mediate the ability to actively cope and improve one’s ability to change due to adversity.

On the serotonin receptor gene HTR1A, the polymorphism rs6295 is also known as C(-1019)G.  In the plus (23andMe) orientation, C is the minor allele, but most studies use the minus orientation and will note G as the minor allele. Note that this is a very common variant with almost half of most populations carrying the minor allele.

Check your 23andMe results for rs6295 (v4, v5)

  • CC: higher impulsiveness, increased risk for depression[ref][ref]
  • GG: normal

The HTR1B gene that codes for another serotonin receptor. One well studied genetic variant is rs6296.  Again, in the 23andMe orientation, G would be the risk allele, but when you read through the studies, it will refer to C as the minor allele.

Check your  23andMe results for rs6296 (v4, v5):

  • GG: increased risk of depression, anxiety after stressful life events, increased risk of childhood aggressive behavior, ADHD[ref][ref]
  • CG: somewhat increased risk of depression, anxiety after stressful life events, increased risk of childhood aggressive behavior, ADHD
  • CC: normal (most common type)

The serotonin 2A receptor (HTR2A) also has several well-studied variants including rs6314, also known as C1354T.  In the 23andMe orientation, A is the minor allele.

Check your 23andMe results for rs6314 (v4, v5):

  • AA: reduced serotonin 2A receptors in prefrontal cortex, increased risk of social withdrawal[ref][ref]
  • AG: reduced serotonin 2A receptors in prefrontal cortex, increased risk of social withdrawal
  • GG: normal (most common)

Here are a few other studies on rs6314:

  • 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 GG. [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]

Another HTR2A very common variant has also been well studied. The variant rs6311 (C allele) has been found to be associated with increased risk of aggression in adults. [ref]

Check your 23andMe results for rs6311 (v4, v5):

  • CC:  more empathy for happiness, more speed-dating success for women[ref], increased risk of sexual dysfunction with SSRI[ref][ref]
  • CT: more empathy for happiness,
  • TT: normal

 


Lifehacks

Get outside: While your genes have an effect on serotonin levels in the body, there are also several environmental factors that also influence serotonin production.  Exposure to bright light or sunlight is correlated to higher serotonin levels.[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: Don’t forget in all this talk about neurotransmitters that serotonin 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 mobility 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“.

There are quite a few clinical trials showing that 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]  One probiotic that has worked well for me is the Renew Life Ultimate Flora that combines several strains of Lactobacillus and Bifidobacterium.

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: There is a supplemental form of the precursor to serotonin, 5-HTP that is readily available. There are many studies showing the effect of supplementing with 5-HTP, but I would say that caution is always advised when taking supplements that can affect your neurotransmitters. 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]

 

 

 

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