View source for 5-HTTLPR

{{Short description|Genetic polymorphism}}
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{{Infobox single nucleotide polymorphism
 | rsid         = 25531
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 | gene         = SLC6A4
 | chromosome   = 17
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'''5-HTTLPR''' (serotonin-transporter-linked promoter region) is a [[degenerate repeat]] (redundancy in the genetic code) [[polymorphism (biology)|polymorphic]] region in ''[[SLC6A4]]'', the [[gene]] that codes for the [[serotonin transporter]].
Since the polymorphism was identified in the middle of the 1990s,<ref>{{cite journal | vauthors = Heils A, Teufel A, Petri S, Seemann M, Bengel D, Balling U, Riederer P, Lesch KP | title = Functional promoter and polyadenylation site mapping of the human serotonin (5-HT) transporter gene | journal = Journal of Neural Transmission. General Section | volume = 102 | issue = 3 | pages = 247–54 | year = 1995 | pmid = 8788073 | doi = 10.1007/BF01281159 | s2cid = 8474414 | author8-link = K. P. Lesch | author7-link = P. Riederer }}</ref><ref>{{cite journal | vauthors = Heils A, Teufel A, Petri S, Stöber G, Riederer P, Bengel D, Lesch KP | title = Allelic variation of human serotonin transporter gene expression | journal = Journal of Neurochemistry | volume = 66 | issue = 6 | pages = 2621–4 | date = June 1996 | pmid = 8632190 | doi = 10.1046/j.1471-4159.1996.66062621.x | s2cid = 42037860 | author7-link = Klaus-Peter Lesch | author5-link = P. Riederer }}</ref>
it has been extensively investigated, e.g., in connection with [[neuropsychiatric disorder]]s.
A 2006 scientific article stated that "over 300 behavioral, psychiatric, pharmacogenetic and other medical genetics papers" had analyzed the polymorphism.<ref name="WendlandJ2006Simultaneous">{{cite journal | vauthors = Wendland JR, Martin BJ, Kruse MR, Lesch KP, Murphy DL | title = Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531 | journal = Molecular Psychiatry | volume = 11 | issue = 3 | pages = 224–6 | date = March 2006 | pmid = 16402131 | doi = 10.1038/sj.mp.4001789 | author4-link = Klaus-Peter Lesch | doi-access =  | s2cid = 26655014 }}</ref> While often discussed as an example of [[gene-environment interaction]], this contention is contested.

== Alleles ==
[[image:Chromosome 17.svg|150px|thumb|The serotonin transporter gene (''SLC6A4'') with the 5-HTTLPR is located on [[Chromosome 17 (human)|chromosome&nbsp;17]].]]
The polymorphism occurs in the [[promoter (biology)|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.<ref name="NakamuraM2000Human">{{cite journal | vauthors = Nakamura M, Ueno S, Sano A, Tanabe H | title = The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants | journal = Molecular Psychiatry | volume = 5 | issue = 1 | pages = 32–8 | date = January 2000 | pmid = 10673766 | doi = 10.1038/sj.mp.4000698 | doi-access =  | s2cid = 12459610 }}</ref> The short (s)- and long (l)- alleles have been thought to be related to stress and [[psychiatric disorders]].<ref name=":0">{{Cite journal|last=Deuschle|first=Michael|title=Association between a Serotonin Transporter Length Polymorphism and Primary Insomnia|journal=Sleep|volume=33|issue=3|pages=343–347|doi=10.1093/sleep/33.3.343|pmid=20337192|pmc=2831428|year=2010}}</ref>
In connection with the region are two [[single nucleotide polymorphism]]s (SNP): [[rs25531]] and [[rs25532]].<ref name="MurphyD2008Targeting">{{cite journal | vauthors = Murphy DL, Lesch KP | title = Targeting the murine serotonin transporter: insights into human neurobiology | journal = Nature Reviews. Neuroscience | volume = 9 | issue = 2 | pages = 85–96 | date = February 2008 | pmid = 18209729 | doi = 10.1038/nrn2284 | s2cid = 7563088 | url = https://zenodo.org/record/1233578 }}</ref>

One study published in 2000 found 14 [[allele|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 people|Japanese]] and [[Europeans]].<ref name="NakamuraM2000Human"/>
The difference between 16-A and 16-D is the rs25531 SNP.
It is also the difference between 14-A and 14-D.<ref name="WendlandJ2006Simultaneous"/>

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 L<sub>A</sub>) 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 L<sub>A</sub>/L<sub>A</sub> genotype against all other genotypes.<ref name="PraschakRiederN2007Novel">{{cite journal | vauthors = Praschak-Rieder N, Kennedy J, Wilson AA, Hussey D, Boovariwala A, Willeit M, Ginovart N, Tharmalingam S, Masellis M, Houle S, Meyer JH | title = Novel 5-HTTLPR allele associates with higher serotonin transporter binding in putamen: a [(11)C] DASB positron emission tomography study | journal = Biological Psychiatry | volume = 62 | issue = 4 | pages = 327–31 | date = August 2007 | pmid = 17210141 | doi = 10.1016/j.biopsych.2006.09.022 | s2cid = 46096787 | author11-link = Jeffrey H. Meyer | author7-link = Nathalie Ginovart }}</ref> 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.<ref name="rspb.2010.0714v1">{{cite journal | vauthors = Eisenberg DT, Hayes MG | title = Testing the null hypothesis: comments on 'Culture-gene coevolution of individualism-collectivism and the serotonin transporter gene' | journal = Proceedings: Biological Sciences | volume = 278 | issue = 1704 | pages = 329–32 | date = February 2011 | pmid = 20861042 | pmc = 3013402 | doi = 10.1098/rspb.2010.0714 }}</ref> It is argued that the population variation in the allele frequency is more likely due to neutral evolutionary processes than natural selection.<ref name="rspb.2010.0714v1" />

== Neuropsychiatric disorders ==
{{See also|Biology of depression#Gene candidates}}
In the 1990s it has been speculated that the polymorphism might be related to [[affective disorder]]s, 
and an initial study found such a link.<ref>{{cite journal | vauthors = 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 | title = A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders | journal = Molecular Psychiatry | volume = 1 | issue = 6 | pages = 453–60 | date = December 1996 | pmid = 9154246 | author15-link = K. P. Lesch }} Comment:
{{cite journal | vauthors = Craddock N, Owen MJ | title = Candidate gene association studies in psychiatric genetics: a SERTain future? | journal = Molecular Psychiatry | volume = 1 | issue = 6 | pages = 434–6 | date = December 1996 | pmid = 9154242 }}</ref>
However, another large European study found no such link.<ref>{{cite journal | vauthors = 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 | title = Serotonin transporter 5HTTLPR polymorphism and affective disorders: no evidence of association in a large European multicenter study | journal = European Journal of Human Genetics | volume = 12 | issue = 5 | pages = 377–82 | date = May 2004 | pmid = 14735161 | doi = 10.1038/sj.ejhg.5201149 | author4-link = Jurgen Del-Favero | author20-link = Christine Van Broeckhoven | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R | title = Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene | journal = Science | volume = 301 | issue = 5631 | pages = 386–9 | date = July 2003 | pmid = 12869766 | doi = 10.1126/science.1083968 | bibcode = 2003Sci...301..386C | s2cid = 146500484 }}</ref><ref>{{cite journal | vauthors = Kendler KS, Kuhn JW, Vittum J, Prescott CA, Riley B | title = The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: a replication | journal = Archives of General Psychiatry | volume = 62 | issue = 5 | pages = 529–35 | date = May 2005 | pmid = 15867106 | doi = 10.1001/archpsyc.62.5.529 | doi-access = free }}</ref><ref>{{cite web | url=http://www.esi-topics.com/nhp/2006/september-06-KennethSKendler.html | title=Essential Science Indicators }}</ref> However, a 2017 meta-analysis found no such association.<ref>{{Cite journal|last1=Culverhouse|first1=R. C.|last2=Saccone|first2=N. L.|last3=Horton|first3=A. C.|last4=Ma|first4=Y.|last5=Anstey|first5=K. J.|last6=Banaschewski|first6=T.|last7=Burmeister|first7=M.|last8=Cohen-Woods|first8=S.|last9=Etain|first9=B.|date=2017-04-04|title=Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression|journal=Molecular Psychiatry|volume=23|issue=1|pages=133–142|language=en|doi=10.1038/mp.2017.44|pmid=28373689|pmc=5628077|issn=1476-5578}}</ref> Earlier, two 2009 [[meta-analyses]] found no overall GxE effect,<ref>{{cite journal | vauthors = Risch N, Herrell R, Lehner T, Liang KY, Eaves L, Hoh J, Griem A, Kovacs M, Ott J, Merikangas KR | title = Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis | journal = JAMA | volume = 301 | issue = 23 | pages = 2462–71 | date = June 2009 | pmid = 19531786 | pmc = 2938776 | doi = 10.1001/jama.2009.878 }}</ref><ref>{{cite journal | vauthors = Munafò MR, Durrant C, Lewis G, Flint J | title = Gene X environment interactions at the serotonin transporter locus | journal = Biological Psychiatry | volume = 65 | issue = 3 | pages = 211–9 | date = February 2009 | pmid = 18691701 | doi = 10.1016/j.biopsych.2008.06.009 | s2cid = 5780325 }}</ref> while a 2011 meta-analysis, demonstrated a positive result.<ref>{{cite journal | vauthors = Karg K, Burmeister M, Shedden K, Sen S | title = The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation | journal = Archives of General Psychiatry | volume = 68 | issue = 5 | pages = 444–54 | date = May 2011 | pmid = 21199959 | doi = 10.1001/archgenpsychiatry.2010.189 | pmc = 3740203 }}</ref> 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.<ref>{{cite journal | vauthors = Duncan LE, Keller MC | title = A critical review of the first 10 years of candidate gene-by-environment interaction research in psychiatry | journal = The American Journal of Psychiatry | volume = 168 | issue = 10 | pages = 1041–9 | date = October 2011 | pmid = 21890791 | pmc = 3222234 | doi = 10.1176/appi.ajp.2011.11020191 }}</ref> 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 [[antidepressant]]s.<ref>{{cite journal | vauthors = Durham LK, Webb SM, Milos PM, Clary CM, Seymour AB | title = The serotonin transporter polymorphism, 5HTTLPR, is associated with a faster response time to sertraline in an elderly population with major depressive disorder | journal = Psychopharmacology | volume = 174 | issue = 4 | pages = 525–9 | date = August 2004 | pmid = 12955294 | doi = 10.1007/s00213-003-1562-3 | s2cid = 23798209 }}</ref>
Another antidepressant treatment response study did, however, rather point to the rs25531 SNP,<ref>{{cite journal | vauthors = Kraft JB, Slager SL, McGrath PJ, Hamilton SP | title = Sequence analysis of the serotonin transporter and associations with antidepressant response | journal = Biological Psychiatry | volume = 58 | issue = 5 | pages = 374–81 | date = September 2005 | pmid = 15993855 | doi = 10.1016/j.biopsych.2005.04.048 | s2cid = 22673688 }}</ref>
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".<ref>{{cite journal | vauthors = Kraft JB, Peters EJ, Slager SL, Jenkins GD, Reinalda MS, McGrath PJ, Hamilton SP | title = Analysis of association between the serotonin transporter and antidepressant response in a large clinical sample | journal = Biological Psychiatry | volume = 61 | issue = 6 | pages = 734–42 | date = March 2007 | pmid = 17123473 | doi = 10.1016/j.biopsych.2006.07.017 | s2cid = 11331100 }}</ref>

One study could find a treatment response effect for [[repetitive transcranial magnetic stimulation]] to drug-resistant [[major depression|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.<ref>{{cite journal | vauthors = Bocchio-Chiavetto L, Miniussi C, Zanardini R, Gazzoli A, Bignotti S, Specchia C, Gennarelli M | title = 5-HTTLPR and BDNF Val66Met polymorphisms and response to rTMS treatment in drug resistant depression | journal = Neuroscience Letters | volume = 437 | issue = 2 | pages = 130–4 | date = May 2008 | pmid = 18450378 | doi = 10.1016/j.neulet.2008.04.005 | hdl = 11572/145667 | s2cid = 36187651 | url = https://iris.unitn.it/bitstream/11572/145667/1/NeuroscienceLetter_Bocchio-Chiavetto_08.pdf | hdl-access = free }}</ref>

===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.<ref name=":1" /> 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 [[Functional magnetic resonance imaging|fMRI]] scan (by the 3-T GE Signa scanner).<ref name=":1" /> 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.<ref name=":0" /> The 5-HT transporter (5-HTT) is the main regulator of serotonin and [[Serotonin|serotonergic]] energy and is therefore targeted by many [[antidepressant]]s.<ref name=":0" /> 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.<ref>{{Cite journal|last=Brummett|first=Beverly|title=Sleep Quality Varies as a Function of 5-HTTLPR Genotype and Stress|journal=Psychosom Med|volume=69|issue=7|pages=621–624|doi=10.1097/psy.0b013e31814b8de6|pmid=17766685|pmc=2758820|year=2007}}</ref> 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.<ref name=":0" /> 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.<ref name=":0" /> 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 trait]]s:
Two 2004 [[meta-analysis|meta-analyses]] found 26 research studies investigating the polymorphism in relation to anxiety-related traits.<ref name="SenS2004MetaAnalysis">{{cite journal | vauthors = Sen S, Burmeister M, Ghosh D | title = Meta-analysis of the association between a serotonin transporter promoter polymorphism (5-HTTLPR) and anxiety-related personality traits | journal = American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics | volume = 127B | issue = 1 | pages = 85–9 | date = May 2004 | pmid = 15108187 | doi = 10.1002/ajmg.b.20158 | hdl = 2027.42/34671 | s2cid = 18798250 | hdl-access = free }}</ref><ref>{{cite journal | vauthors = Schinka JA, Busch RM, Robichaux-Keene N | title = A meta-analysis of the association between the serotonin transporter gene polymorphism (5-HTTLPR) and trait anxiety | journal = Molecular Psychiatry | volume = 9 | issue = 2 | pages = 197–202 | date = February 2004 | pmid = 14966478 | doi = 10.1038/sj.mp.4001405 | doi-access =  | s2cid = 21326834 }}</ref>
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,<ref>{{cite journal | vauthors = Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Müller CR, Hamer DH, Murphy DL | title = Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region | journal = Science | volume = 274 | issue = 5292 | pages = 1527–31 | date = November 1996 | pmid = 8929413 | doi = 10.1126/science.274.5292.1527 | author-link = Klaus-Peter Lesch | bibcode = 1996Sci...274.1527L | s2cid = 35503987 }}</ref>
and this result was replicated by the group with new data.<ref>{{cite journal | vauthors = Greenberg BD, Li Q, Lucas FR, Hu S, Sirota LA, Benjamin J, Lesch KP, Hamer D, Murphy DL | title = Association between the serotonin transporter promoter polymorphism and personality traits in a primarily female population sample | journal = American Journal of Medical Genetics | volume = 96 | issue = 2 | pages = 202–16 | date = April 2000 | pmid = 10893498 | doi = 10.1002/(SICI)1096-8628(20000403)96:2<202::AID-AJMG16>3.0.CO;2-J | author7-link = K. P. Lesch | url = https://zenodo.org/record/1235472 }}</ref>
Some other studies have, however, failed to find this association,<ref>{{cite journal | vauthors = Flory JD, Manuck SB, Ferrell RE, Dent KM, Peters DG, Muldoon MF | title = Neuroticism is not associated with the serotonin transporter (5-HTTLPR) polymorphism | journal = Molecular Psychiatry | volume = 4 | issue = 1 | pages = 93–6 | date = January 1999 | pmid = 10089017 | doi = 10.1038/sj.mp.4000466 | doi-access = free }}</ref>
nor with peer-rated neuroticism,<ref>{{cite journal | vauthors = Ball D, Hill L, Freeman B, Eley TC, Strelau J, Riemann R, Spinath FM, Angleitner A, Plomin R | title = The serotonin transporter gene and peer-rated neuroticism | journal = NeuroReport | volume = 8 | issue = 5 | pages = 1301–4 | date = March 1997 | pmid = 9175133 | doi = 10.1097/00001756-199703240-00048 | s2cid = 32097570 }}</ref>
and a 2006 review   noted the "erratic success in replication" of the first finding.<ref>{{cite journal | vauthors = Ebstein RP | title = The molecular genetic architecture of human personality: beyond self-report questionnaires | journal = Molecular Psychiatry | volume = 11 | issue = 5 | pages = 427–45 | date = May 2006 | pmid = 16534505 | doi = 10.1038/sj.mp.4001814 | doi-access = free }}</ref>
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".<ref name="SenS2004MetaAnalysis"/>
They found that [[neuroticism]] as measured with the [[Revised NEO Personality Inventory|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.<ref>{{cite journal | vauthors = Munafò MR, Freimer NB, Ng W, Ophoff R, Veijola J, Miettunen J, Järvelin MR, Taanila A, Flint J | title = 5-HTTLPR genotype and anxiety-related personality traits: a meta-analysis and new data | journal = American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics | volume = 150B | issue = 2 | pages = 271–81 | date = March 2009 | pmid = 18546120 | pmc = 2819421 | doi = 10.1002/ajmg.b.30808 }}</ref>
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).<ref>{{cite journal | vauthors = 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 | title = Variants of the serotonin transporter gene and NEO-PI-R Neuroticism: No association in the BLSA and SardiNIA samples | journal = American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics | volume = 150B | issue = 8 | pages = 1070–7 | date = December 2009 | pmid = 19199283 | pmc = 2788669 | doi = 10.1002/ajmg.b.30932 }}</ref>

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.<ref>{{cite journal | vauthors = Fox E, Ridgewell A, Ashwin C | title = Looking on the bright side: biased attention and the human serotonin transporter gene | journal = Proceedings: Biological Sciences | volume = 276 | issue = 1663 | pages = 1747–51 | date = May 2009 | pmid = 19324793 | pmc = 2674488 | doi = 10.1098/rspb.2008.1788 }}</ref> Other research indicates carriers of the short 5-HTTLPR allele have difficulty disengaging attention from emotional stimuli compared to long allele homozygotes.<ref>{{cite journal | vauthors = Beevers CG, Wells TT, Ellis AJ, McGeary JE | title = Association of the serotonin transporter gene promoter region (5-HTTLPR) polymorphism with biased attention for emotional stimuli | journal = Journal of Abnormal Psychology | volume = 118 | issue = 3 | pages = 670–81 | date = August 2009 | pmid = 19685963 | pmc = 2841741 | doi = 10.1037/a0016198 }}</ref> 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.<ref>{{cite journal | vauthors = Beevers CG, Ellis AJ, Wells TT, McGeary JE | title = Serotonin transporter gene promoter region polymorphism and selective processing of emotional images | journal = Biological Psychology | volume = 83 | issue = 3 | pages = 260–5 | date = March 2010 | pmid = 19715738 | pmc = 2834869 | doi = 10.1016/j.biopsycho.2009.08.007 }}</ref> 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.<ref>{{cite journal | vauthors = Arbelle S, Benjamin J, Golin M, Kremer I, Belmaker RH, Ebstein RP | title = Relation of shyness in grade school children to the genotype for the long form of the serotonin transporter promoter region polymorphism | journal = The American Journal of Psychiatry | volume = 160 | issue = 4 | pages = 671–6 | date = April 2003 | pmid = 12668354 | doi = 10.1176/appi.ajp.160.4.671 }}</ref>
This is, however, just a single report and the link is not investigated as intensively as for the anxiety-related traits.

== Neuroimaging ==
[[Image:ECAT-Exact-HR--PET-Scanner.jpg|thumb|300px|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 scanner]]s.
Such studies use a [[radioligand]] that binds&mdash;preferably selectively&mdash;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]] [[beta-CIT|β-CIT]] [[radioligand]].<ref>{{cite journal | vauthors = van Dyck CH, Malison RT, Staley JK, Jacobsen LK, Seibyl JP, Laruelle M, Baldwin RM, Innis RB, Gelernter J | author-link1 =Christopher H. van Dyck | title = Central serotonin transporter availability measured with [123I]beta-CIT SPECT in relation to serotonin transporter genotype | journal = The American Journal of Psychiatry | volume = 161 | issue = 3 | pages = 525–31 | date = March 2004 | pmid = 14992979 | doi = 10.1176/appi.ajp.161.3.525 | url =https://zenodo.org/record/1038570 }}</ref>
Using the PET radioligand [[carbon-11]]-labeled [[McN 5652]] another research team could neither find any difference in serotonin transporter binding between genotype groups.<ref>{{cite journal | vauthors = 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 | title = Effect of a triallelic functional polymorphism of the serotonin-transporter-linked promoter region on expression of serotonin transporter in the human brain | journal = The American Journal of Psychiatry | volume = 163 | issue = 1 | pages = 48–51 | date = January 2006 | pmid = 16390888 | doi = 10.1176/appi.ajp.163.1.48 | author12-link = Victoria Arango }}</ref>
Newer studies have used the radioligand [[carbon-11]]-labeled [[DASB]] 
with one study finding higher serotonin transporter binding in the [[putamen]] of L<sub>A</sub> [[homozygote]]s compared to other genotypes.<ref name="PraschakRiederN2007Novel"/>
Another study with similar radioligand and genotype comparison found higher binding in the [[midbrain]].<ref>{{cite journal | vauthors = 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 | title = Midbrain serotonin transporter binding potential measured with [11C]DASB is affected by serotonin transporter genotype | journal = Journal of Neural Transmission | volume = 114 | issue = 5 | pages = 635–9 | year = 2007 | pmid = 17225932 | doi = 10.1007/s00702-006-0609-0 | s2cid = 9369923 }}</ref>

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.<ref>{{cite journal | vauthors = Pezawas L, Meyer-Lindenberg A, Drabant EM, Verchinski BA, Munoz KE, Kolachana BS, Egan MF, Mattay VS, Hariri AR, Weinberger DR | title = 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression | journal = Nature Neuroscience | volume = 8 | issue = 6 | pages = 828–34 | date = June 2005 | pmid = 15880108 | doi = 10.1038/nn1463 | s2cid = 1864631 }}</ref> 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.<ref name=":1">{{cite journal | vauthors = Hariri AR, Drabant EM, Munoz KE, Kolachana BS, Mattay VS, Egan MF, Weinberger DR | title = A susceptibility gene for affective disorders and the response of the human amygdala | journal = Archives of General Psychiatry | volume = 62 | issue = 2 | pages = 146–52 | date = February 2005 | pmid = 15699291 | doi = 10.1001/archpsyc.62.2.146 | doi-access =  }}</ref> [[Brain blood flow]] measurements with [[positron emission tomography]] brain scanners can show genotype-related changes.<ref>{{cite journal | vauthors = Furmark T, Tillfors M, Garpenstrand H, Marteinsdottir I, Långström B, Oreland L, Fredrikson M | title = Serotonin transporter polymorphism related to amygdala excitability and symptom severity in patients with social phobia | journal = Neuroscience Letters | volume = 362 | issue = 3 | pages = 189–92 | date = May 2004 | pmid = 15158011 | doi = 10.1016/j.neulet.2004.02.070 | s2cid = 5638054 }}</ref>
The [[glucose metabolism]] in the brain has also been investigated with respect to the polymorphism,<ref>{{cite journal | vauthors = 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 | title = Frontal and limbic metabolic differences in subjects selected according to genetic variation of the SLC6A4 gene polymorphism | journal = NeuroImage | volume = 25 | issue = 4 | pages = 1197–204 | date = May 2005 | pmid = 15850737 | doi = 10.1016/j.neuroimage.2004.12.020 | s2cid = 20402303 }}</ref>
and the [[functional magnetic resonance imaging]] (fMRI) brain scans have also been correlated to the polymorphism.<ref>{{cite journal | vauthors = Hariri AR, Mattay VS, Tessitore A, Kolachana B, Fera F, Goldman D, Egan MF, Weinberger DR | s2cid = 29315003 | title = Serotonin transporter genetic variation and the response of the human amygdala | journal = Science | volume = 297 | issue = 5580 | pages = 400–3 | date = July 2002 | pmid = 12130784 | doi = 10.1126/science.1071829 | bibcode = 2002Sci...297..400H }} Comment:  {{cite journal | vauthors = Miller G | title = Neuroscience. Gene's effect seen in brain's fear response | journal = Science | volume = 297 | issue = 5580 | pages = 319a–319 | date = July 2002 | pmid = 12130759 | doi = 10.1126/science.297.5580.319a | s2cid = 28337659 }}</ref><ref>{{cite journal | vauthors = Dannlowski U, Ohrmann P, Bauer J, Deckert J, Hohoff C, Kugel H, Arolt V, Heindel W, Kersting A, Baune BT, Suslow T | title = 5-HTTLPR biases amygdala activity in response to masked facial expressions in major depression | journal = Neuropsychopharmacology | volume = 33 | issue = 2 | pages = 418–24 | date = January 2008 | pmid = 17406646 | doi = 10.1038/sj.npp.1301411  | doi-access = free }}</ref>

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.<ref>{{cite journal | vauthors = Heitland I, Kenemans JL, Oosting RS, Baas JM, Böcker KB | title = Auditory event-related potentials (P3a, P3b) and genetic variants within the dopamine and serotonin system in healthy females | journal = Behavioural Brain Research | volume = 249 | pages = 55–64 | date = July 2013 | pmid = 23619133 | doi = 10.1016/j.bbr.2013.04.013 | s2cid = 22589525 }}</ref>

== Other organisms ==
In [[rat]]s (''Rattus rattus'') [[berberine]] increases 5-HTTLPR activity.<ref name="Berb">
   {{Unbulleted list citebundle
      |{{*}} {{cite journal | title=Pharmacological Actions of Multi-Target-Directed Evodiamine | doi=10.3390/molecules18021826 | pages=1826–1843 | last1=Yu | first1=Hui | last2=Jin | first2=Hongwei | last3=Gong | first3=Wuzhuang | last4=Wang | first4=Zhanli | last5=Liang | first5=Huaping | year=2013 | issue=2 | volume=18 | issn=1420-3049 | journal=[[Molecules (journal)|Molecules]] | publisher=[[MDPI AG]]| pmid=23434865 | pmc=6270287 | doi-access=free }}<!--- Published by MDPI but this review is very highly cited, including by Kaushik et al., 2013, Wang et al., 2015, and Cacabelos et al., 2014. --->
      |{{*}} {{cite journal | issn=1734-1140 | journal=[[Pharmacological Reports]] | publisher=[[Institute of Pharmacology, Polish Academy of Sciences]] ([[Elsevier Sp. z o.o.]]) | year=2015 | issue=5 | volume=67 | first6=Mohammad | first5=Seyed | first4=Maria | first3=Mohammad | first2=Anwar | last6=Nabavi | last5=Nabavi | last4=Daglia | first1=Touqeer | last3=Abdollahi | last2=Gilani | last1=Ahmed | pages=970–979 | doi=10.1016/j.pharep.2015.03.002 | title=Berberine and neurodegeneration: A review of literature| pmid=26398393 | s2cid=751303 }}

      |{{*}} {{cite journal | issn=1470-269X | journal=The Pharmacogenomics Journal | year=2011 | issue=5 | volume=12 | publisher=[[Macmillan Publishers Limited]] | first4=G. E. | first3=J. J. | first2=E. A. | first1=Y. | last4=Davies | last3=Hudziak | last2=Ehli | last1=Hu | pages=372–378 | doi=10.1038/tpj.2011.24 | title=Berberine and evodiamine influence serotonin transporter (5-HTT) expression via the 5-HTT-linked polymorphic region| pmid=21647174 | s2cid=11148104 }}
   }}
</ref>

== References ==
{{Reflist|2}}

== Further reading ==
* {{Cite web | title = Serotonin Transporter-Linked Polymorphic Region (5HTTLPR) and rs25531 SNP (Mspl, L<sub>A</sub>/L<sub>G</sub>) | url = http://tranquilene.com/5-HTTLPR-post.html | archive-url=https://web.archive.org/web/20170407054553/http://tranquilene.com/5-HTTLPR-post.html|archive-date=2017-04-07|access-date = 2015-05-04 }}
* {{cite journal | vauthors = Brown GW, Harris TO | title = Depression and the serotonin transporter 5-HTTLPR polymorphism: a review and a hypothesis concerning gene-environment interaction | journal = Journal of Affective Disorders | volume = 111 | issue = 1 | pages = 1–12 | date = November 2008 | pmid = 18534686 | doi = 10.1016/j.jad.2008.04.009 }}

== External links ==

* [https://slatestarcodex.com/2019/05/07/5-httlpr-a-pointed-review/ 5-HTTLPR: A Pointed Review] at [[Slate Star Codex]]
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