5-HTTLPR
Encyclopedia
5-HTTLPR is a degenerate repeat polymorphic
region in SLC6A4, the gene
that codes for the serotonin transporter
.
Since the polymorphism was identified in the middle of the 1990s,
it has been extensively investigated, e.g., in connection with neuropsychiatric disorders.
A 2006 scientific article stated that "over 300 behavioral, psychiatric, pharmacogenetic and other medical genetics papers" had analyzed the polymorphism.
The polymorphism occurs in the promoter region of the gene.
Researchers commonly report it with two variations: A short ("s") and a long ("l"), but it can be subdivided further.
In connection with the region are two single nucleotide polymorphism
s (SNP): rs25531 and rs25532.
One study published in 2000 found 14 allelic
variants (14-A, 14-B, 14-C, 14-D, 15, 16-A, 16-B, 16-C, 16-D, 16-E, 16-F, 19, 20 and 22) in a group of around 200 Japanese
and Caucasian
people.
The difference between 16-A and 16-D is the rs25531 SNP.
It is also the difference between 14-A and 14-D.
Some studies have found that long allele results in higher serotonin transporter mRNA transcription in human cell lines.
The higher level may be due to the A-allele of rs25531, such that subjects with the long-rs25531(A) allelic combination (sometimes written LA) have higher levels while long-rs25531(G) carriers have levels more similar to short-allele carriers.
Newer studies examining the effects of genotype may compare the LA/LA genotype against all other genotypes. The allele frequency of this polymorphism seems to vary considerably across populations, with a higher frequency of the long allele in Europe and lower frequency in Asia. Despite speculation to the contrary, the population variation in the allele frequency is more likely due to neutral evolutionary processes than natural selection.
and an initial study found such a link.
However, another large European study found no such link. A decade later two studies found that 5-HTT polymorphism influences depressive responses to life stress; an example of gene-environment interaction
(GxE) not considered in the previous studies. Until 2007 there were 11 replications, 3 partial replication and 3 non-replications of this GxE. However, two of the largest studies were negative. A 2009 meta-analysis
was also negative.
s.
Another antidepressant treatment response study did, however, rather point to the rs25531 SNP,
and a large study by the group of investigators found a "lack of association between response to an SSRI and variation at the SLC6A4 locus".
One study could find a treatment response effect for repetitive transcranial magnetic stimulation to drug-resistant depression with long/long homozygotes benefitting more than short-allele carriers.
The researchers found a similar effect for the Val66Met polymorphism in the BDNF gene.
Two 2004 meta-analyses
found 26 research studies investigating the polymorphism in relation to anxiety-related traits.
The initial and classic 1996 study found s-allele carriers to on average have slightly higher neuroticism
score with the NEO PI-R personality questionnaire,
and this result was replicated by the group with new data.
Some other studies have, however, failed to find this association,
nor with peer-rated neuroticism,
and a review from 2006 noted the "erratic success in replication" of the first finding.
A meta-analysis
published in 2004 stated that the lack of replicability was "largely due to small sample size and the use of different inventories".
They found that neuroticism
as measured with the NEO
-family of personality inventories had quite significant association with 5-HTTLPR while the trait harm avoidance
from the Temperament and Character Inventory
family did not have any significant association.
A similar conclusion was reached in an updated 2008 meta-analysis.
However, a 2005 meta-analysis came to the opposite conclusion: That NEO neuroticism and 5-HTTLPR were not associated while TCI/TPQ harm avoidance and 5-HTTLPR were.
The largest (as of 2004) individual study on the personality genetics of anxiety-related traits is Australian involving 759 subjects.
It used the Eysenck Personality Questionnaire
and could not detect any difference between the short and long allele subjects with respect to neuroticism.
In a recent study, authors found that individuals homozygous for the long allele of 5-HTLPR paid more attention on average to positive affective pictures while selectively avoiding negative affective pictures presented alongside the positive pictures compared to their heterozygous and short-allele-homozygous peers. This biased attention of positive emotional stimuli suggests they may tend to be more optimistic. Other research indicates carriers of the short 5-HTTLPR allele have difficulty disengaging attention from emotional stimuli compared to long allele homozygotes. Another recent study using an eye tracking assessment of information processing found that short 5-HTTLPR allele carriers displayed an eye gaze bias to view positive scenes and avoid negative scenes. Long allele homozygotes viewed the emotion scenes in a more even-handed fashion. This research suggests that short 5-HTTLPR allele carriers may be more sensitive to emotional information in the environment than long allele homozygotes.
Another research group have given evidence for a modest association between shyness
and the long form in grade school children.
This is, however, just a single report and the link is not investigated as intensive as for the anxiety-related traits.
Molecular neuroimaging studies have examined the association between genotype and serotonin transporter binding with positron emission tomography
(PET) and SPECT brain scanners.
Such studies use a radioligand
that binds—preferably selectively—to the serotonin transporter so an image can be formed that quantifies the distribution of the serotonin transporter in the brain.
One study could see no difference in serotonin transporter availability between long/long and short/short homozygotes subjects among 96 subjects scanned with SPECT using the iodine-123
β-CIT radioligand
.
Using the PET radioligand carbon-11-labeled McN 5652 another research team could neither find any difference in serotonin transporter binding between genotype groups.
Newer studies have used the radioligand carbon-11-labeled DASB
with one study finding higher serotonin transporter binding in the putamen
of LA homozygotes compared to other genotypes.
Another study with similar radioligand and genotype comparison found higher binding in the midbrain.
Associations between the polymorphism and the grey matter
in parts of the anterior cingulate brain region have also been reported based on magnetic resonance imaging
brain scannings and voxel-based morphometry analysis. 5-HTTLPR short allele–driven amygdala
hyperreactivity was confirmed in a large (by MRI study standards) cohort of healthy subjects with no history of psychiatric illness or treatment. Brain blood flow measurements with positron emission tomography
brain scanners can show genotype-related changes.
Furthermore, the glucose metabolism in the brain has also been investigated with respect to the polymorphism,
and the functional magnetic resonance imaging
(fMRI) brain scans have also been correlated to the polymorphism.
Especially the amygdala
brain structure has been the focus of the functional neuroimaging
studies.
Polymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
region in SLC6A4, the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
that codes for the serotonin transporter
Serotonin transporter
The serotonin transporter is a monoamine transporter protein.This protein is an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it...
.
Since the polymorphism was identified in the middle of the 1990s,
it has been extensively investigated, e.g., in connection with neuropsychiatric disorders.
A 2006 scientific article stated that "over 300 behavioral, psychiatric, pharmacogenetic and other medical genetics papers" had analyzed the polymorphism.
Alleles
Researchers commonly report it with two variations: A short ("s") and a long ("l"), but it can be subdivided further.
In connection with the region are two single nucleotide polymorphism
Single nucleotide polymorphism
A single-nucleotide polymorphism is a DNA sequence variation occurring when a single nucleotide — A, T, C or G — in the genome differs between members of a biological species or paired chromosomes in an individual...
s (SNP): rs25531 and rs25532.
One study published in 2000 found 14 allelic
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
variants (14-A, 14-B, 14-C, 14-D, 15, 16-A, 16-B, 16-C, 16-D, 16-E, 16-F, 19, 20 and 22) in a group of around 200 Japanese
Japanese people
The are an ethnic group originating in the Japanese archipelago and are the predominant ethnic group of Japan. Worldwide, approximately 130 million people are of Japanese descent; of these, approximately 127 million are residents of Japan. People of Japanese ancestry who live in other countries...
and Caucasian
Caucasian race
The term Caucasian race has been used to denote the general physical type of some or all of the populations of Europe, North Africa, the Horn of Africa, Western Asia , Central Asia and South Asia...
people.
The difference between 16-A and 16-D is the rs25531 SNP.
It is also the difference between 14-A and 14-D.
Some studies have found that long allele results in higher serotonin transporter mRNA transcription in human cell lines.
The higher level may be due to the A-allele of rs25531, such that subjects with the long-rs25531(A) allelic combination (sometimes written LA) have higher levels while long-rs25531(G) carriers have levels more similar to short-allele carriers.
Newer studies examining the effects of genotype may compare the LA/LA genotype against all other genotypes. The allele frequency of this polymorphism seems to vary considerably across populations, with a higher frequency of the long allele in Europe and lower frequency in Asia. Despite speculation to the contrary, the population variation in the allele frequency is more likely due to neutral evolutionary processes than natural selection.
Neuropsychiatric disorders
In the 1990s it has been speculated that the polymorphism might be related to affective disorders,and an initial study found such a link.
However, another large European study found no such link. A decade later two studies found that 5-HTT polymorphism influences depressive responses to life stress; an example of gene-environment interaction
Gene-environment interaction
Gene–environment interaction is the phenotypic effect of interactions between genes and the environment....
(GxE) not considered in the previous studies. Until 2007 there were 11 replications, 3 partial replication and 3 non-replications of this GxE. However, two of the largest studies were negative. A 2009 meta-analysis
Meta-analysis
In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...
was also negative.
Treatment response
With the results from one study the polymorphism was thought to be related to treatment response so that long-allele patients respond better to antidepressantAntidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
s.
Another antidepressant treatment response study did, however, rather point to the rs25531 SNP,
and a large study by the group of investigators found a "lack of association between response to an SSRI and variation at the SLC6A4 locus".
One study could find a treatment response effect for repetitive transcranial magnetic stimulation to drug-resistant depression with long/long homozygotes benefitting more than short-allele carriers.
The researchers found a similar effect for the Val66Met polymorphism in the BDNF gene.
Personality traits
5-HTTLPR may be related to personality traits:Two 2004 meta-analyses
Meta-analysis
In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...
found 26 research studies investigating the polymorphism in relation to anxiety-related traits.
The initial and classic 1996 study found s-allele carriers to on average have slightly higher neuroticism
Neuroticism
Neuroticism is a fundamental personality trait in the study of psychology. It is an enduring tendency to experience negative emotional states. Individuals who score high on neuroticism are more likely than the average to experience such feelings as anxiety, anger, guilt, and depressed mood...
score with the NEO PI-R personality questionnaire,
and this result was replicated by the group with new data.
Some other studies have, however, failed to find this association,
nor with peer-rated neuroticism,
and a review from 2006 noted the "erratic success in replication" of the first finding.
A meta-analysis
Meta-analysis
In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...
published in 2004 stated that the lack of replicability was "largely due to small sample size and the use of different inventories".
They found that neuroticism
Neuroticism
Neuroticism is a fundamental personality trait in the study of psychology. It is an enduring tendency to experience negative emotional states. Individuals who score high on neuroticism are more likely than the average to experience such feelings as anxiety, anger, guilt, and depressed mood...
as measured with the NEO
Revised NEO Personality Inventory
The Revised NEO Personality Inventory, or NEO PI-R, is a psychological personality inventory; a 240-item measure of the Five Factor Model: Extraversion, Agreeableness, Conscientiousness, Neuroticism, and Openness to Experience. Additionally, the test measures six subordinate dimensions of each of...
-family of personality inventories had quite significant association with 5-HTTLPR while the trait harm avoidance
Harm avoidance
In psychology, harm avoidance is a personality trait characterized by excessive worrying; pessimism; shyness; and being fearful, doubtful, and easily fatigued...
from the Temperament and Character Inventory
Temperament and Character Inventory
Temperament and Character Inventory is an inventory for personality traits devised by Cloninger et al.It is closely related to and an outgrowth of Tridimensional Personality Questionnaire ,...
family did not have any significant association.
A similar conclusion was reached in an updated 2008 meta-analysis.
However, a 2005 meta-analysis came to the opposite conclusion: That NEO neuroticism and 5-HTTLPR were not associated while TCI/TPQ harm avoidance and 5-HTTLPR were.
The largest (as of 2004) individual study on the personality genetics of anxiety-related traits is Australian involving 759 subjects.
It used the Eysenck Personality Questionnaire
Eysenck Personality Questionnaire
In psychology, Eysenck Personality Questionnaire is a questionnaire to assess the personality traits of a person.It was devised by the psychologists Hans Jürgen Eysenck and his wife Sybil B. G. Eysenck....
and could not detect any difference between the short and long allele subjects with respect to neuroticism.
In a recent study, authors found that individuals homozygous for the long allele of 5-HTLPR paid more attention on average to positive affective pictures while selectively avoiding negative affective pictures presented alongside the positive pictures compared to their heterozygous and short-allele-homozygous peers. This biased attention of positive emotional stimuli suggests they may tend to be more optimistic. Other research indicates carriers of the short 5-HTTLPR allele have difficulty disengaging attention from emotional stimuli compared to long allele homozygotes. Another recent study using an eye tracking assessment of information processing found that short 5-HTTLPR allele carriers displayed an eye gaze bias to view positive scenes and avoid negative scenes. Long allele homozygotes viewed the emotion scenes in a more even-handed fashion. This research suggests that short 5-HTTLPR allele carriers may be more sensitive to emotional information in the environment than long allele homozygotes.
Another research group have given evidence for a modest association between shyness
Shyness
In humans, shyness is a social psychology term used to describe the feeling of apprehension, lack of comfort, or awkwardness experienced when a person is in proximity to, approaching, or being approached by other people, especially in new situations or with unfamiliar people...
and the long form in grade school children.
This is, however, just a single report and the link is not investigated as intensive as for the anxiety-related traits.
Neuroimaging
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...
(PET) and SPECT brain scanners.
Such studies use a radioligand
Radioligand
A radioligand is a radioactive biochemical substance that is used for diagnosis or for research-oriented study of the receptor systems of the body....
that binds—preferably selectively—to the serotonin transporter so an image can be formed that quantifies the distribution of the serotonin transporter in the brain.
One study could see no difference in serotonin transporter availability between long/long and short/short homozygotes subjects among 96 subjects scanned with SPECT using the iodine-123
Iodine-123
Iodine-123 is a radioactive isotope of iodine used in nuclear medicine imaging, including single photon emission computed tomography . The isotope's half-life is 13.22 hours; the decay by electron capture to tellurium-123 emits gamma radiation with predominant energies of 159 keV and 127 keV...
β-CIT radioligand
Radioligand
A radioligand is a radioactive biochemical substance that is used for diagnosis or for research-oriented study of the receptor systems of the body....
.
Using the PET radioligand carbon-11-labeled McN 5652 another research team could neither find any difference in serotonin transporter binding between genotype groups.
Newer studies have used the radioligand carbon-11-labeled DASB
DASB
DASB is a compound that binds to the serotonin transporter.Labeled with carbon-11 — a radioactive isotope — it has been used as a radioligand in neuroimaging with positron emission tomography since around year 2000....
with one study finding higher serotonin transporter binding in the putamen
Putamen
The putamen is a round structure located at the base of the forebrain . The putamen and caudate nucleus together form the dorsal striatum. It is also one of the structures that comprises the basal ganglia. Through various pathways, the putamen is connected to the substantia nigra and globus pallidus...
of LA homozygotes compared to other genotypes.
Another study with similar radioligand and genotype comparison found higher binding in the midbrain.
Associations between the polymorphism and the grey matter
Grey matter
Grey matter is a major component of the central nervous system, consisting of neuronal cell bodies, neuropil , glial cells and capillaries. Grey matter contains neural cell bodies, in contrast to white matter, which does not and mostly contains myelinated axon tracts...
in parts of the anterior cingulate brain region have also been reported based on magnetic resonance imaging
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
brain scannings and voxel-based morphometry analysis. 5-HTTLPR short allele–driven amygdala
Amygdala
The ' are almond-shaped groups of nuclei located deep within the medial temporal lobes of the brain in complex vertebrates, including humans. Shown in research to perform a primary role in the processing and memory of emotional reactions, the amygdalae are considered part of the limbic system.-...
hyperreactivity was confirmed in a large (by MRI study standards) cohort of healthy subjects with no history of psychiatric illness or treatment. Brain blood flow measurements with positron emission tomography
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...
brain scanners can show genotype-related changes.
Furthermore, the glucose metabolism in the brain has also been investigated with respect to the polymorphism,
and the functional magnetic resonance imaging
Functional magnetic resonance imaging
Functional magnetic resonance imaging or functional MRI is a type of specialized MRI scan used to measure the hemodynamic response related to neural activity in the brain or spinal cord of humans or other animals. It is one of the most recently developed forms of neuroimaging...
(fMRI) brain scans have also been correlated to the polymorphism.
Especially the amygdala
Amygdala
The ' are almond-shaped groups of nuclei located deep within the medial temporal lobes of the brain in complex vertebrates, including humans. Shown in research to perform a primary role in the processing and memory of emotional reactions, the amygdalae are considered part of the limbic system.-...
brain structure has been the focus of the functional neuroimaging
Functional neuroimaging
Functional neuroimaging is the use of neuroimaging technology to measure an aspect of brain function, often with a view to understanding the relationship between activity in certain brain areas and specific mental functions...
studies.