Serotonin… most of us think of the commercials with happy brain neurons bouncing serotonin between them. Turns out that there may be a lot more to this molecule that most of us realize. About 90% of serotonin is made in the gut and regulates motility there. Serotonin is also involved in various other bodily functions such as in bone mass regulation, cardiovascular health, the endocrine system, and appetite.
Serotonin, also known as 5-hydroxytrptamine, is made from tryptophan using tryptophan hydroxylase. In the brain, serotonin is involved in many different functions. Some researchers believe that imbalances in serotonin play a role in depression. 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. Here is an interesting article on SSRI’s: Five Reasons Not to Take SSRIs.
Below is a compilation of studies on polymorphisms that affect serotonin. It is not an exhaustive list, but it is a starting point for you to find out more about your genes.
Tryptophan Hydroxylase (TPH1 and TPH2)
Tryptophan hydroxylase is 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.
rs4570625 – T is the minor allele and has been studied in reference to a number of psychiatric conditions.[ref] A recent study found that those carrying the T allele were more susceptible to major depression even when not exposed to “high-negative life events”. [ref] A Chinese study in 2014 found that those with the T allele were more susceptible to paranoid schizophrenia. [ref] The T-allele is found less frequently in those with panic disorder [ref]. A 2013 study found: “The T allele of rs4570625 was associated with higher prefrontal GABA concentration in women”[ref]
rs4565946 – The T-allele is associated with a higher risk for tic disorders. “For rs4565946, individuals with the TT genotype showed a significantly higher risk of TD than those with TC plus CC genotypes [odds ratio (OR) =3.077″ [ref]
SLC6A4 is the gene that encodes the serotonin transporter. It is also called SERT or 5-HTT in some of the research. One polymorphism that has been studied extensively is the 5-HTTLPR variant which with a variable number tandem repeat. This means that there is a short version of the gene and a long version. There have been quite a few studied done on the short/short vs. long/long forms of this variant. Studies in 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.
According to SNPedia: “5-HTTLPR (serotonin-transporter-linked polymorphic region) is a degenerate repeat polymorphic region in SLC6A4, the gene that codes for the serotonin transporter. … The minor allele (G) of rs25531 is almost always in phase with the long (L) allele of 5-HTTLPR. ” and “”People with no-call for rs25531 may have one or two short-form alleles. “”
One interesting study in 2006 looked at the areas of the brain in a PET scan using 71 non-psychiatric subjects. For those with the short/short form, the study found: “Increased basal metabolism in fronto–limbic structures for the s/s group may be conceived as an “overactive metabolic state” of these structures, possibly related to an increased susceptibility for developing an anxiety–depression spectrum disorder.” [ref]
According to a 2011 study: “The best two-SNP proxy is …. the TA haplotype of rs2129785 and rs11867581 that tags the short allele.” [ref] So if you have a T for rs2129785 and an A on rs11867581, you most likely have a short allele.
DDC (dopa decarboxylase)
DDC is the gene that is involved in the conversion of DOPA to dopamine, L-tryptophan to tryptamine, l-histidine to histamine, and 5-HTP to serotonin. It uses pyridoxal phosphate (P5P, active B6) as a co-factor. Several polymorphisms have been studied in association with nicotine dependence.
rs6592961 (A is the minor allele) was found to be associated with autism in a 2013 study of over 600 subjects.[ref] Another study in Chinese children found no association.[ref] The A-allele was also found to be associated with adult ADHD. [ref]
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. This polymorphism has a number of studies associated with it including:
- A 2010 study showed that those homozygous for the minor allele had significantly higher impulsiveness scores. [ref]
- Another study shoed that rs6295 is associated with major depressive disorder. [ref]
- A 2014 study found that those with the minor allele were less likely to be in a romantic relationship. [ref]
- A 2013 looked at the connections between rs6295, panic disorder, and alterations of the cingulum bundle. [ref]
On the HTR1B gene that codes for another serotonin receptor, the rs6296 polymorphism has been extensively studied. Again, in the 23andMe orientation, G would be the minor allele. Most studies show the minus orientation with C as the minor allele. Studies have linked the minor allele to:
- A 2011 study found that rs6296 minor allele carriers were associated with higher depression and anxiety scores after stressful life events. [ref]
- A 2013 Finnish study found that the minor allele was associated with childhood aggressive behavior but not adult anger. [ref]
The serotonin 2A receptor also has several well studied polymorphisms including rs6314, also known as C1354T. In the plus (23andMe) orientation, A is the minor allele. Here are a few of the studies:
- In a study, paroxetine (antidepressant) therapy response was tied to rs6314 polymorphism. Those with the minor allele had a greater change of response than those without the minor allele. The OR for going into remission with paroxetine therapy was OR=7.5 for those with the minor allele. [ref]
- An interesting 2013 study looked at serotonin receptor polymorphisms in association with food reward. The study found that there was an association between rs6314 A allele and susceptibility towards food reinforcement. [ref]
On the HTR2C gene, the snp rs1414334 is associated with metabolic syndrome and weight gain for those with the C allele taking certain medications:
- A 2009 study found that those with the C allele had an OR=9.2 for metabolic syndrome on clozapine and an OR=5.35 for those on risperidone. [ref]
- Another 2007 study also found that those with the minor allele were at an increased risk for metabolic syndrome with atypical antipsychotics. [ref]
Environmental Aspects of Serotonin Levels:
While genes may have some effect on serotonin levels in the body, there are several environmental factors that also influence serotonin production. Exposure to bright light or sunlight is correlated to higher serotonin levels. 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] There are many studies showing the effect of supplementing with 5-HTP.
Here is a great research article on serotonin and the gut microbiome: Serotonin, tryptophan metabolism and the brain-gut-microbiome axis
Effects of Adult Exposure to Bisphenol A on Genes Involved in the Physiopathology of Rat Prefrontal Cortex. “In this study, BPA-treated rats showed an increase in Tph2 expression, a key isozyme in central 5-HT transmission . According to our results, it has been reported an increase of 5-HT ,  and Tph2  levels in rodent brain after BPA exposure. Given that estrogens can regulate 5-HT levels increasing Tph2 expression , BPA may affect Tph2 through P450arom induction. In view of our results, with BPA increasing in a greater manner Tph2 in females than in males and P450arom in males than in females, another molecular mechanism of BPA on Tph2 should be kept in mind.”