5-HTTLPR

Last updated
SNP: rs25531
Gene SLC6A4
Chromosome 17
External databases
Ensembl Human SNPView
dbSNP 25531
HapMap 25531
SNPedia 25531

5-HTTLPR (serotonin-transporter-linked promoter region) is a degenerate repeat (redundancy in the genetic code) polymorphic region in SLC6A4 , the gene that codes for the serotonin transporter. Since the polymorphism was identified in the middle of the 1990s, [1] [2] 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. [3] While often discussed as an example of gene-environment interaction, this contention is contested.

Contents

Alleles

The serotonin transporter gene (SLC6A4) with the 5-HTTLPR is located on chromosome 17. Chromosome 17.svg
The serotonin transporter gene (SLC6A4) with the 5-HTTLPR is located on chromosome 17.

The polymorphism occurs in the promoter region of the gene. Researchers commonly report it with two variations in humans: A short ("s") and a long ("l"), but it can be subdivided further. [4] The short (s)- and long (l)- alleles have been thought to be related to stress and psychiatric disorders. [5] In connection with the region are two single nucleotide polymorphisms (SNP): rs25531 and rs25532. [6]

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 Europeans. [4] The difference between 16-A and 16-D is the rs25531 SNP. It is also the difference between 14-A and 14-D. [3]

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. [7] 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. [8] It is argued that the population variation in the allele frequency is more likely due to neutral evolutionary processes than natural selection. [8]

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. [9] However, another large European study found no such link. [10] 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. [11] [12] [13] However, a 2017 meta-analysis found no such association. [14] Earlier, two 2009 meta-analyses found no overall GxE effect, [15] [16] while a 2011 meta-analysis, demonstrated a positive result. [17] In turn, the 2011 meta-analysis has been criticized as being overly inclusive (e.g. including hip fractures as outcomes), for deeming a study supportive of the GxE interaction which is actually in the opposite direction, and because of substantial evidence of publication bias and data mining in the literature. [18] This criticism points out that if the original finding were real, and not the result of publication bias, we would expect that those replication studies which are closest in design to the original are the most likely to replicate—instead we find the opposite. This suggests that authors may be data dredging for measures and analytic strategies which yield the results they want.

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 antidepressants. [19] Another antidepressant treatment response study did, however, rather point to the rs25531 SNP, [20] 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". [21]

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. [22]

Amygdala

The 5-HTTLPR has been thought to predispose individuals to affective disorders such as anxiety and depression. There have been some studies that test whether this association is due to the effects of variation in 5-HTTLPR on the reactivity of the human amygdala. In order to test this, researchers gathered a group of subjects and administered a harm avoidance (HA) subset of the Tridimensional Personality Questionnaire as an initial mood and personality assessment. [23] Subjects also had their DNA isolated and analyzed in order to be genotyped. Next, the amygdala was then engaged by having the subject match fearful facial expressions during an fMRI scan (by the 3-T GE Signa scanner). [23] The results of the study showed that there was bilateral activity in the amygdala for every subject when processing the fearful images, as expected. However, the activity in the right amygdala was much higher for subjects with the s-allele, which shows that the 5-HTTLPR has an effect on amygdala activity. There did not seem to be the same effect on the left amygdala.

Insomnia

There has been speculation that the 5-HTTLPR gene is associated with insomnia and sleep quality. Primary insomnia is one of the most common sleep disorders and is defined as having trouble falling or staying asleep, enough to cause distress in one's life. Serotonin (5-HT) has been associated with the regulation of sleep for a very long time now. [5] The 5-HT transporter (5-HTT) is the main regulator of serotonin and serotonergic energy and is therefore targeted by many antidepressants. [5] There also have been several family and twin studies that suggest that insomnia is heavily genetically influenced. Many of these studies have found that there is a genetic and environment dual-factor that influences insomnia. It has been hypothesized that the short 5-HTTLPR genotype is related to poor sleep quality and, therefore, also primary insomnia. It is important to note that research studies have found that this variation does not cause insomnia, but rather may predispose an individual to experience worse quality of sleep when faced with a stressful life event.

Brummett

The effect that the 5-HTTLPR gene had on sleep quality was tested by Brummett in a study conducted at Duke University Medical Center from 2001 to 2004. The sleep quality of 344 participants was measured using The Pittsburgh Sleep Quality Index. The study found that caregivers with the homozygous s-allele had poorer sleep quality, which shows that the stress of caregiving combined with the allele gave way to worse sleep quality. Although the study found that the 5-HTTLPR genotype did not directly affect sleep quality, the 5-HTTLPR polymorphism's effect on sleep quality was magnified by one's environmental stress. [24] It supports the notion that the 5-HTTLPR s-allele is what leads to hyperarousal when exposed to stress; hyperarousability is commonly associated with insomnia.

Deuschle

However, in a 2007 study conducted by a sleep laboratory in Germany, it was found that the 5-HTTLPR gene did have a strong association with both insomnia and depression both in participants with and without lifetime affective disorders. This study included 157 insomnia patients and a control group of 836 individuals that had no psychiatric disorders. The subjects were then genotyped through polymerase chain reaction (PCR) techniques. [5] The researchers found that the s-allele was greater represented in the vast majority of patients with insomnia compared to those who had no disorder. [5] This shows that there is an association between the 5-HTTPLR genotype and primary insomnia. However, it is important to consider the fact that there was a very limited number of subjects with insomnia tested in this study.

Personality traits

5-HTTLPR may be related to personality traits: Two 2004 meta-analyses found 26 research studies investigating the polymorphism in relation to anxiety-related traits. [25] [26] 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, [27] and this result was replicated by the group with new data. [28] Some other studies have, however, failed to find this association, [29] nor with peer-rated neuroticism, [30] and a 2006 review noted the "erratic success in replication" of the first finding. [31] 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". [25] 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. [32] However, based on over 4000 subjects, the largest study that used the NEO PI-R found no association between variants of the serotonin transporter gene (including 5-HTTLPR) and neuroticism, or its facets (Anxiety, Angry-Hostility, Depression, Self-Consciousness, Impulsiveness, and Vulnerability). [33]

In a study published in 2009, authors found that individuals homozygous for the long allele of 5-HTTLPR 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. [34] Other research indicates carriers of the short 5-HTTLPR allele have difficulty disengaging attention from emotional stimuli compared to long allele homozygotes. [35] Another study published in 2009 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, while long allele homozygotes viewed the emotion scenes in a more even-handed fashion. [36] 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. [37] This is, however, just a single report and the link is not investigated as intensively as for the anxiety-related traits.

Neuroimaging

Molecular neuroimaging studies may use PET scanners such as this type for examining the effect of the 5-HTTLPR genotypes on serotonin transporter binding in the human brain. ECAT-Exact-HR--PET-Scanner.jpg
Molecular neuroimaging studies may use PET scanners such as this type for examining the effect of the 5-HTTLPR genotypes on serotonin transporter binding in the human brain.

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. [38] Using the PET radioligand carbon-11-labeled McN 5652 another research team could neither find any difference in serotonin transporter binding between genotype groups. [39] 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. [7] Another study with similar radioligand and genotype comparison found higher binding in the midbrain. [40]

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. [41] 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. [23] Brain blood flow measurements with positron emission tomography brain scanners can show genotype-related changes. [42] The glucose metabolism in the brain has also been investigated with respect to the polymorphism, [43] and the functional magnetic resonance imaging (fMRI) brain scans have also been correlated to the polymorphism. [44] [45]

Especially the amygdala brain structure has been the focus of the functional neuroimaging studies.

Electrophysiology

The relationship between the Event Related Potentials P3a and P3b and the genetic variants of 5-HTTLPR were investigated using an auditory oddball paradigm and revealed short allele homozygotes mimicked those of COMT met/met homozygotes with an enhancement of the frontal, but not parietal P3a and P3b. This suggests a frontal-cortical dopaminergic and serotoninergic mechanism in bottom-up attentional capture. [46]

Other organisms

In rats (Rattus rattus) berberine increases 5-HTTLPR activity. [47]

Related Research Articles

<span class="mw-page-title-main">Serotonin transporter</span> Mammalian protein found in humans

The serotonin transporter also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein that in humans is encoded by the SLC6A4 gene. SERT is a type of monoamine transporter protein that transports the neurotransmitter serotonin from the synaptic cleft back to the presynaptic neuron, in a process known as serotonin reuptake.

<span class="mw-page-title-main">Venlafaxine</span> Antidepressant medication

Venlafaxine, sold under the brand name Effexor among others, is an antidepressant medication of the serotonin–norepinephrine reuptake inhibitor (SNRI) class. It is used to treat major depressive disorder, generalized anxiety disorder, panic disorder, and social anxiety disorder. Studies have shown that venlafaxine improves post-traumatic stress disorder (PTSD). It may also be used for chronic pain. It is taken orally. It is also available as the salt venlafaxine besylate in an extended-release formulation.

Catechol-<i>O</i>-methyltransferase Class of enzymes

Catechol-O-methyltransferase is one of several enzymes that degrade catecholamines, catecholestrogens, and various drugs and substances having a catechol structure. In humans, catechol-O-methyltransferase protein is encoded by the COMT gene. Two isoforms of COMT are produced: the soluble short form (S-COMT) and the membrane bound long form (MB-COMT). As the regulation of catecholamines is impaired in a number of medical conditions, several pharmaceutical drugs target COMT to alter its activity and therefore the availability of catecholamines. COMT was first discovered by the biochemist Julius Axelrod in 1957.

Generalized anxiety disorder (GAD) is a mental and behavioral disorder, specifically an anxiety disorder characterized by excessive, uncontrollable and often irrational worry about events or activities. Worry often interferes with daily functioning, and individuals with GAD are often overly concerned about everyday matters such as health, finances, death, family, relationship concerns, or work difficulties. Symptoms may include excessive worry, restlessness, trouble sleeping, exhaustion, irritability, sweating, and trembling.

The candidate gene approach to conducting genetic association studies focuses on associations between genetic variation within pre-specified genes of interest, and phenotypes or disease states. This is in contrast to genome-wide association studies (GWAS), which is a hypothesis-free approach that scans the entire genome for associations between common genetic variants and traits of interest. Candidate genes are most often selected for study based on a priori knowledge of the gene's biological functional impact on the trait or disease in question. The rationale behind focusing on allelic variation in specific, biologically relevant regions of the genome is that certain alleles within a gene may directly impact the function of the gene in question and lead to variation in the phenotype or disease state being investigated. This approach often uses the case-control study design to try to answer the question, "Is one allele of a candidate gene more frequently seen in subjects with the disease than in subjects without the disease?" Candidate genes hypothesized to be associated with complex traits have generally not been replicated by subsequent GWASs or highly powered replication attempts. The failure of candidate gene studies to shed light on the specific genes underlying such traits has been ascribed to insufficient statistical power, low prior probability that scientists can correctly guess a specific allele within a specific gene that is related to a trait, poor methodological practices, and data dredging.

<span class="mw-page-title-main">Beck's cognitive triad</span> Three key elements of depression

Beck's cognitive triad, also known as the negative triad, is a cognitive-therapeutic view of the three key elements of a person's belief system present in depression. It was proposed by Aaron Beck in 1967. The triad forms part of his cognitive theory of depression and the concept is used as part of CBT, particularly in Beck's "Treatment of Negative Automatic Thoughts" (TNAT) approach.

<span class="mw-page-title-main">Trazodone</span> Antidepressant medication

Trazodone, sold under many brand names, is an antidepressant medication. It is used to treat major depressive disorder, anxiety disorders, and insomnia. The medication is taken orally.

<span class="mw-page-title-main">Gene–environment interaction</span> Response to the same environmental variation differently by different genotypes

Gene–environment interaction is when two different genotypes respond to environmental variation in different ways. A norm of reaction is a graph that shows the relationship between genes and environmental factors when phenotypic differences are continuous. They can help illustrate GxE interactions. When the norm of reaction is not parallel, as shown in the figure below, there is a gene by environment interaction. This indicates that each genotype responds to environmental variation in a different way. Environmental variation can be physical, chemical, biological, behavior patterns or life events.

<span class="mw-page-title-main">Monoamine oxidase A</span> Endogenous enzyme

Monoamine oxidase A, also known as MAO-A, is an enzyme that in humans is encoded by the MAOA gene. This gene is one of two neighboring gene family members that encode mitochondrial enzymes which catalyze the oxidative deamination of amines, such as dopamine, norepinephrine, and serotonin. A mutation of this gene results in Brunner syndrome. This gene has also been associated with a variety of other psychiatric disorders, including antisocial behavior. Alternatively spliced transcript variants encoding multiple isoforms have been observed.

Neuroticism is a personality trait associated with negative emotions. It is one of the Big Five traits. Individuals with high scores on neuroticism are more likely than average to experience such feelings as anxiety, worry, fear, anger, frustration, envy, jealousy, pessimism, guilt, depressed mood, and loneliness. Such people are thought to respond worse to stressors and are more likely to interpret ordinary situations, such as minor frustrations, as appearing hopelessly difficult. Their behavioral responses may include procrastination, substance use, and other maladaptive behaviors, which may aid in relieving negative emotions and generating positive ones.

<span class="mw-page-title-main">DASB</span> Chemical compound

DASB, also known as 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile, 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 (PET) since around year 2000. In this context it is regarded as one of the superior radioligands for PET study of the serotonin transporter in the brain, since it has high selectivity for the serotonin transporter.

In genetics, rs6313 also called T102C or C102T is a gene variation—a single nucleotide polymorphism (SNP)—in the human HTR2A gene that codes for the 5-HT2A receptor. The SNP is a synonymous substitution located in exon 1 of the gene where it is involved in coding the 34th amino acid as serine.

In genetics, rs6311 is a gene variation—a single nucleotide polymorphism (SNP)—in the human HTR2A gene that codes for the 5-HT2A receptor. 5-HT2A is a neuroreceptor, and several scientific studies have investigated the effect of the genetic variation on personality, e.g., personality traits measured with the Temperament and Character Inventory or with a psychological task measuring impulsive behavior. The SNP has also been investigated in rheumatology studies.

rs6295, also called C(-1019)G, is a gene variation—a single nucleotide polymorphism (SNP)—in the HTR1A gene. It is one of the most investigated SNPs of its gene. The C-allele is the most prevalent with 0.675 against the G-allele with 0.325 among Caucasian.

Rs6265, also called Val66Met or G196A, is a gene variation, a single nucleotide polymorphism (SNP) in the BDNF gene that codes for brain-derived neurotrophic factor.

<span class="mw-page-title-main">Klaus-Peter Lesch</span> German clinical psychiatrist

Klaus-Peter Lesch is a German clinical psychiatrist who has been investigating the neurobiological foundation of personality traits.

Scientific studies have found that different brain areas show altered activity in humans with major depressive disorder (MDD), and this has encouraged advocates of various theories that seek to identify a biochemical origin of the disease, as opposed to theories that emphasize psychological or situational causes. Factors spanning these causative groups include nutritional deficiencies in magnesium, vitamin D, and tryptophan with situational origin but biological impact. Several theories concerning the biologically based cause of depression have been suggested over the years, including theories revolving around monoamine neurotransmitters, neuroplasticity, neurogenesis, inflammation and the circadian rhythm. Physical illnesses, including hypothyroidism and mitochondrial disease, can also trigger depressive symptoms.

Terrie Edith Moffitt is an American-British clinical psychologist who is best known for her pioneering research on the development of antisocial behavior and for her collaboration with colleague and partner Avshalom Caspi in research on gene-environment interactions in mental disorders.

The genetic influences of post-traumatic stress disorder (PTSD) are not understood well due to the limitations of any genetic study of mental illness; in that, it cannot be ethically induced in selected groups. Because of this, all studies must use naturally occurring groups with genetic similarities and differences, thus the amount of data is limited. Still, genetics play some role in the development of PTSD.

<span class="mw-page-title-main">Biology of bipolar disorder</span> Biological Study Of Bipolar Disorder

Bipolar disorder is an affective disorder characterized by periods of elevated and depressed mood. The cause and mechanism of bipolar disorder is not yet known, and the study of its biological origins is ongoing. Although no single gene causes the disorder, a number of genes are linked to increase risk of the disorder, and various gene environment interactions may play a role in predisposing individuals to developing bipolar disorder. Neuroimaging and postmortem studies have found abnormalities in a variety of brain regions, and most commonly implicated regions include the ventral prefrontal cortex and amygdala. Dysfunction in emotional circuits located in these regions have been hypothesized as a mechanism for bipolar disorder. A number of lines of evidence suggests abnormalities in neurotransmission, intracellular signalling, and cellular functioning as possibly playing a role in bipolar disorder.

References

  1. ↑ Heils A, Teufel A, Petri S, Seemann M, Bengel D, Balling U, Riederer P, Lesch KP (1995). "Functional promoter and polyadenylation site mapping of the human serotonin (5-HT) transporter gene". Journal of Neural Transmission. General Section. 102 (3): 247–54. doi:10.1007/BF01281159. PMID   8788073. S2CID   8474414.
  2. ↑ Heils A, Teufel A, Petri S, Stöber G, Riederer P, Bengel D, Lesch KP (June 1996). "Allelic variation of human serotonin transporter gene expression". Journal of Neurochemistry. 66 (6): 2621–4. doi:10.1046/j.1471-4159.1996.66062621.x. PMID   8632190. S2CID   42037860.
  3. 1 2 Wendland JR, Martin BJ, Kruse MR, Lesch KP, Murphy DL (March 2006). "Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531". Molecular Psychiatry. 11 (3): 224–6. doi:10.1038/sj.mp.4001789. PMID   16402131. S2CID   26655014.
  4. 1 2 Nakamura M, Ueno S, Sano A, Tanabe H (January 2000). "The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants". Molecular Psychiatry. 5 (1): 32–8. doi:10.1038/sj.mp.4000698. PMID   10673766. S2CID   12459610.
  5. 1 2 3 4 5 Deuschle M (2010). "Association between a Serotonin Transporter Length Polymorphism and Primary Insomnia". Sleep. 33 (3): 343–347. doi:10.1093/sleep/33.3.343. PMC   2831428 . PMID   20337192.
  6. ↑ Murphy DL, Lesch KP (February 2008). "Targeting the murine serotonin transporter: insights into human neurobiology". Nature Reviews. Neuroscience. 9 (2): 85–96. doi:10.1038/nrn2284. PMID   18209729. S2CID   7563088.
  7. 1 2 Praschak-Rieder N, Kennedy J, Wilson AA, Hussey D, Boovariwala A, Willeit M, Ginovart N, Tharmalingam S, Masellis M, Houle S, Meyer JH (August 2007). "Novel 5-HTTLPR allele associates with higher serotonin transporter binding in putamen: a [(11)C] DASB positron emission tomography study". Biological Psychiatry. 62 (4): 327–31. doi:10.1016/j.biopsych.2006.09.022. PMID   17210141. S2CID   46096787.
  8. 1 2 Eisenberg DT, Hayes MG (February 2011). "Testing the null hypothesis: comments on 'Culture-gene coevolution of individualism-collectivism and the serotonin transporter gene'". Proceedings: Biological Sciences. 278 (1704): 329–32. doi:10.1098/rspb.2010.0714. PMC   3013402 . PMID   20861042.
  9. ↑ Collier DA, Stöber G, Li T, Heils A, Catalano M, Di Bella D, Arranz MJ, Murray RM, Vallada HP, Bengel D, Müller CR, Roberts GW, Smeraldi E, Kirov G, Sham P, Lesch KP (December 1996). "A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders". Molecular Psychiatry. 1 (6): 453–60. PMID   9154246. Comment: Craddock N, Owen MJ (December 1996). "Candidate gene association studies in psychiatric genetics: a SERTain future?". Molecular Psychiatry. 1 (6): 434–6. PMID   9154242.
  10. ↑ Mendlewicz J, Massat I, Souery D, Del-Favero J, Oruc L, Nöthen MM, Blackwood D, Muir W, Battersby S, Lerer B, Segman RH, Kaneva R, Serretti A, Lilli R, Lorenzi C, Jakovljevic M, Ivezic S, Rietschel M, Milanova V, Van Broeckhoven C (May 2004). "Serotonin transporter 5HTTLPR polymorphism and affective disorders: no evidence of association in a large European multicenter study". European Journal of Human Genetics. 12 (5): 377–82. doi: 10.1038/sj.ejhg.5201149 . PMID   14735161.
  11. ↑ Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R (July 2003). "Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene". Science. 301 (5631): 386–9. Bibcode:2003Sci...301..386C. doi:10.1126/science.1083968. PMID   12869766. S2CID   146500484.
  12. ↑ Kendler KS, Kuhn JW, Vittum J, Prescott CA, Riley B (May 2005). "The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: a replication". Archives of General Psychiatry. 62 (5): 529–35. doi: 10.1001/archpsyc.62.5.529 . PMID   15867106.
  13. ↑ "Essential Science Indicators".
  14. ↑ Culverhouse RC, Saccone NL, Horton AC, Ma Y, Anstey KJ, Banaschewski T, Burmeister M, Cohen-Woods S, Etain B (2017-04-04). "Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression". Molecular Psychiatry. 23 (1): 133–142. doi:10.1038/mp.2017.44. ISSN   1476-5578. PMC   5628077 . PMID   28373689.
  15. ↑ Risch N, Herrell R, Lehner T, Liang KY, Eaves L, Hoh J, Griem A, Kovacs M, Ott J, Merikangas KR (June 2009). "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis". JAMA. 301 (23): 2462–71. doi:10.1001/jama.2009.878. PMC   2938776 . PMID   19531786.
  16. ↑ Munafò MR, Durrant C, Lewis G, Flint J (February 2009). "Gene X environment interactions at the serotonin transporter locus". Biological Psychiatry. 65 (3): 211–9. doi:10.1016/j.biopsych.2008.06.009. PMID   18691701. S2CID   5780325.
  17. ↑ Karg K, Burmeister M, Shedden K, Sen S (May 2011). "The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation". Archives of General Psychiatry. 68 (5): 444–54. doi:10.1001/archgenpsychiatry.2010.189. PMC   3740203 . PMID   21199959.
  18. ↑ Duncan LE, Keller MC (October 2011). "A critical review of the first 10 years of candidate gene-by-environment interaction research in psychiatry". The American Journal of Psychiatry. 168 (10): 1041–9. doi:10.1176/appi.ajp.2011.11020191. PMC   3222234 . PMID   21890791.
  19. ↑ Durham LK, Webb SM, Milos PM, Clary CM, Seymour AB (August 2004). "The serotonin transporter polymorphism, 5HTTLPR, is associated with a faster response time to sertraline in an elderly population with major depressive disorder". Psychopharmacology. 174 (4): 525–9. doi:10.1007/s00213-003-1562-3. PMID   12955294. S2CID   23798209.
  20. ↑ Kraft JB, Slager SL, McGrath PJ, Hamilton SP (September 2005). "Sequence analysis of the serotonin transporter and associations with antidepressant response". Biological Psychiatry. 58 (5): 374–81. doi:10.1016/j.biopsych.2005.04.048. PMID   15993855. S2CID   22673688.
  21. ↑ Kraft JB, Peters EJ, Slager SL, Jenkins GD, Reinalda MS, McGrath PJ, Hamilton SP (March 2007). "Analysis of association between the serotonin transporter and antidepressant response in a large clinical sample". Biological Psychiatry. 61 (6): 734–42. doi:10.1016/j.biopsych.2006.07.017. PMID   17123473. S2CID   11331100.
  22. ↑ Bocchio-Chiavetto L, Miniussi C, Zanardini R, Gazzoli A, Bignotti S, Specchia C, Gennarelli M (May 2008). "5-HTTLPR and BDNF Val66Met polymorphisms and response to rTMS treatment in drug resistant depression" (PDF). Neuroscience Letters. 437 (2): 130–4. doi:10.1016/j.neulet.2008.04.005. hdl: 11572/145667 . PMID   18450378. S2CID   36187651.
  23. 1 2 3 Hariri AR, Drabant EM, Munoz KE, Kolachana BS, Mattay VS, Egan MF, Weinberger DR (February 2005). "A susceptibility gene for affective disorders and the response of the human amygdala". Archives of General Psychiatry. 62 (2): 146–52. doi:10.1001/archpsyc.62.2.146. PMID   15699291.
  24. ↑ Brummett B (2007). "Sleep Quality Varies as a Function of 5-HTTLPR Genotype and Stress". Psychosom Med. 69 (7): 621–624. doi:10.1097/psy.0b013e31814b8de6. PMC   2758820 . PMID   17766685.
  25. 1 2 Sen S, Burmeister M, Ghosh D (May 2004). "Meta-analysis of the association between a serotonin transporter promoter polymorphism (5-HTTLPR) and anxiety-related personality traits". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics. 127B (1): 85–9. doi:10.1002/ajmg.b.20158. hdl: 2027.42/34671 . PMID   15108187. S2CID   18798250.
  26. ↑ Schinka JA, Busch RM, Robichaux-Keene N (February 2004). "A meta-analysis of the association between the serotonin transporter gene polymorphism (5-HTTLPR) and trait anxiety". Molecular Psychiatry. 9 (2): 197–202. doi:10.1038/sj.mp.4001405. PMID   14966478. S2CID   21326834.
  27. ↑ Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Müller CR, Hamer DH, Murphy DL (November 1996). "Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region". Science. 274 (5292): 1527–31. Bibcode:1996Sci...274.1527L. doi:10.1126/science.274.5292.1527. PMID   8929413. S2CID   35503987.
  28. ↑ Greenberg BD, Li Q, Lucas FR, Hu S, Sirota LA, Benjamin J, Lesch KP, Hamer D, Murphy DL (April 2000). "Association between the serotonin transporter promoter polymorphism and personality traits in a primarily female population sample". American Journal of Medical Genetics. 96 (2): 202–16. doi:10.1002/(SICI)1096-8628(20000403)96:2<202::AID-AJMG16>3.0.CO;2-J. PMID   10893498.
  29. ↑ Flory JD, Manuck SB, Ferrell RE, Dent KM, Peters DG, Muldoon MF (January 1999). "Neuroticism is not associated with the serotonin transporter (5-HTTLPR) polymorphism". Molecular Psychiatry. 4 (1): 93–6. doi: 10.1038/sj.mp.4000466 . PMID   10089017.
  30. ↑ Ball D, Hill L, Freeman B, Eley TC, Strelau J, Riemann R, Spinath FM, Angleitner A, Plomin R (March 1997). "The serotonin transporter gene and peer-rated neuroticism". NeuroReport. 8 (5): 1301–4. doi:10.1097/00001756-199703240-00048. PMID   9175133. S2CID   32097570.
  31. ↑ Ebstein RP (May 2006). "The molecular genetic architecture of human personality: beyond self-report questionnaires". Molecular Psychiatry. 11 (5): 427–45. doi: 10.1038/sj.mp.4001814 . PMID   16534505.
  32. ↑ Munafò MR, Freimer NB, Ng W, Ophoff R, Veijola J, Miettunen J, Järvelin MR, Taanila A, Flint J (March 2009). "5-HTTLPR genotype and anxiety-related personality traits: a meta-analysis and new data". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics. 150B (2): 271–81. doi:10.1002/ajmg.b.30808. PMC   2819421 . PMID   18546120.
  33. ↑ Terracciano A, Balaci L, Thayer J, Scally M, Kokinos S, Ferrucci L, Tanaka T, Zonderman AB, Sanna S, Olla N, Zuncheddu MA, Naitza S, Busonero F, Uda M, Schlessinger D, Abecasis GR, Costa PT (December 2009). "Variants of the serotonin transporter gene and NEO-PI-R Neuroticism: No association in the BLSA and SardiNIA samples". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics. 150B (8): 1070–7. doi:10.1002/ajmg.b.30932. PMC   2788669 . PMID   19199283.
  34. ↑ Fox E, Ridgewell A, Ashwin C (May 2009). "Looking on the bright side: biased attention and the human serotonin transporter gene". Proceedings: Biological Sciences. 276 (1663): 1747–51. doi:10.1098/rspb.2008.1788. PMC   2674488 . PMID   19324793.
  35. ↑ Beevers CG, Wells TT, Ellis AJ, McGeary JE (August 2009). "Association of the serotonin transporter gene promoter region (5-HTTLPR) polymorphism with biased attention for emotional stimuli". Journal of Abnormal Psychology. 118 (3): 670–81. doi:10.1037/a0016198. PMC   2841741 . PMID   19685963.
  36. ↑ Beevers CG, Ellis AJ, Wells TT, McGeary JE (March 2010). "Serotonin transporter gene promoter region polymorphism and selective processing of emotional images". Biological Psychology. 83 (3): 260–5. doi:10.1016/j.biopsycho.2009.08.007. PMC   2834869 . PMID   19715738.
  37. ↑ Arbelle S, Benjamin J, Golin M, Kremer I, Belmaker RH, Ebstein RP (April 2003). "Relation of shyness in grade school children to the genotype for the long form of the serotonin transporter promoter region polymorphism". The American Journal of Psychiatry. 160 (4): 671–6. doi:10.1176/appi.ajp.160.4.671. PMID   12668354.
  38. ↑ van Dyck CH, Malison RT, Staley JK, Jacobsen LK, Seibyl JP, Laruelle M, Baldwin RM, Innis RB, Gelernter J (March 2004). "Central serotonin transporter availability measured with [123I]beta-CIT SPECT in relation to serotonin transporter genotype". The American Journal of Psychiatry. 161 (3): 525–31. doi:10.1176/appi.ajp.161.3.525. PMID   14992979.
  39. ↑ Parsey RV, Hastings RS, Oquendo MA, Hu X, Goldman D, Huang YY, Simpson N, Arcement J, Huang Y, Ogden RT, Van Heertum RL, Arango V, Mann JJ (January 2006). "Effect of a triallelic functional polymorphism of the serotonin-transporter-linked promoter region on expression of serotonin transporter in the human brain". The American Journal of Psychiatry. 163 (1): 48–51. doi:10.1176/appi.ajp.163.1.48. PMID   16390888.
  40. ↑ Reimold M, Smolka MN, Schumann G, Zimmer A, Wrase J, Mann K, Hu XZ, Goldman D, Reischl G, Solbach C, Machulla HJ, Bares R, Heinz A (2007). "Midbrain serotonin transporter binding potential measured with [11C]DASB is affected by serotonin transporter genotype". Journal of Neural Transmission. 114 (5): 635–9. doi:10.1007/s00702-006-0609-0. PMID   17225932. S2CID   9369923.
  41. ↑ Pezawas L, Meyer-Lindenberg A, Drabant EM, Verchinski BA, Munoz KE, Kolachana BS, Egan MF, Mattay VS, Hariri AR, Weinberger DR (June 2005). "5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression". Nature Neuroscience. 8 (6): 828–34. doi:10.1038/nn1463. PMID   15880108. S2CID   1864631.
  42. ↑ Furmark T, Tillfors M, Garpenstrand H, Marteinsdottir I, Långström B, Oreland L, Fredrikson M (May 2004). "Serotonin transporter polymorphism related to amygdala excitability and symptom severity in patients with social phobia". Neuroscience Letters. 362 (3): 189–92. doi:10.1016/j.neulet.2004.02.070. PMID   15158011. S2CID   5638054.
  43. ↑ Graff-Guerrero A, De la Fuente-Sandoval C, Camarena B, Gómez-Martin D, Apiquián R, Fresán A, Aguilar A, Méndez-Núñez JC, Escalona-Huerta C, Drucker-Colín R, Nicolini H (May 2005). "Frontal and limbic metabolic differences in subjects selected according to genetic variation of the SLC6A4 gene polymorphism". NeuroImage. 25 (4): 1197–204. doi:10.1016/j.neuroimage.2004.12.020. PMID   15850737. S2CID   20402303.
  44. ↑ Hariri AR, Mattay VS, Tessitore A, Kolachana B, Fera F, Goldman D, Egan MF, Weinberger DR (July 2002). "Serotonin transporter genetic variation and the response of the human amygdala". Science. 297 (5580): 400–3. Bibcode:2002Sci...297..400H. doi:10.1126/science.1071829. PMID   12130784. S2CID   29315003. Comment: Miller G (July 2002). "Neuroscience. Gene's effect seen in brain's fear response". Science. 297 (5580): 319a–319. doi:10.1126/science.297.5580.319a. PMID   12130759. S2CID   28337659.
  45. ↑ Dannlowski U, Ohrmann P, Bauer J, Deckert J, Hohoff C, Kugel H, Arolt V, Heindel W, Kersting A, Baune BT, Suslow T (January 2008). "5-HTTLPR biases amygdala activity in response to masked facial expressions in major depression". Neuropsychopharmacology. 33 (2): 418–24. doi: 10.1038/sj.npp.1301411 . PMID   17406646.
  46. ↑ Heitland I, Kenemans JL, Oosting RS, Baas JM, Böcker KB (July 2013). "Auditory event-related potentials (P3a, P3b) and genetic variants within the dopamine and serotonin system in healthy females". Behavioural Brain Research. 249: 55–64. doi:10.1016/j.bbr.2013.04.013. PMID   23619133. S2CID   22589525.
  47. ↑

Further reading

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.