Editing Serotonin transporter (section)

==Genetics==
[[File:Slc6a4, ISH, mouse, dorsal raphe.jpg|thumbnail|[http://mouse.brain-map.org/experiment/show/79591679 Slc6a4] is expressed in median and dorsal raphe in the midbrain of the postnatal day 56 mouse.<ref name="pmid19179540">{{cite journal | vauthors = Dahlin A, Royall J, Hohmann JG, Wang J | title = Expression profiling of the solute carrier gene family in the mouse brain | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 329 | issue = 2 | pages = 558–570 | date = May 2009 | pmid = 19179540 | pmc = 2672879 | doi = 10.1124/jpet.108.149831 }}</ref> [[Allen Brain Atlas]]es]]

[[File:Serotonin transporter 1 in green, tyrosine hydoxylase in red and nuclear DNA in blue in a region of rat brain.jpg|thumb|Serotonin transporter 1 (Slc6a4) in green, [[tyrosine hydroxylase]] in red and nuclear DNA in blue in a region of rat brain stem. Antibody staining and imaging by [[EnCor Biotechnology Inc.]]]]|

[[File:Chromosome 17.svg|125px|thumb|[[Chromosome 17]]]]
The [[gene]] that encodes the serotonin transporter is called ''solute carrier family 6 (neurotransmitter transporter, serotonin), member 4'' (SLC6A4, see [[Solute carrier family]]).
In [[human]]s the gene is found on [[chromosome 17]] on location 17q11.1&ndash;q12.<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 = 32–38 | date = January 2000 | pmid = 10673766 | doi = 10.1038/sj.mp.4000698 | s2cid = 12459610 | doi-access =  }}</ref>

Mutations associated with the gene may result in changes in serotonin transporter function, and experiments with [[mouse|mice]] have identified more than 50 different phenotypic changes as a result of genetic variation.
These phenotypic changes may, e.g., be increased [[anxiety]] and [[Gut (zoology)|gut]] dysfunction.<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 }}</ref>
Some of the human genetic variations associated with the gene are:<ref name="MurphyD2008Targeting"/>
* Length variation in the serotonin-transporter-gene-linked polymorphic region ([[5-HTTLPR]])
* [[rs25531]] &mdash; a [[single nucleotide polymorphism]] (SNP) in the 5-HTTLPR
* [[rs25532]] &mdash; another SNP in the 5-HTTLPR
* STin2 &mdash; a [[variable number of tandem repeats]] (VNTR) in the functional [[intron]] 2
* G56A on the second [[exon]]
* I425V on the ninth exon

=== Length variation in 5-HTTLPR ===
{{main|5-HTTLPR}}

According to a 1996 article in ''The Journal of Neurochemistry'', the [[promoter (biology)|promoter]] region of the SLC6A4 gene contains a [[Polymorphism (biology)|polymorphism]] with "short" and "long" repeats in a region: 5-HTT-linked polymorphic region ([[5-HTTLPR]] or ''SERTPR'').<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 = 2621–2624 | date = June 1996 | pmid = 8632190 | doi = 10.1046/j.1471-4159.1996.66062621.x | s2cid = 42037860 }}</ref>
The short variation has 14 repeats of a sequence while the long variation has 16 repeats.<ref name="NakamuraM2000Human"/> A second 1996 article stated that the short variation leads to less [[transcription (genetics)|transcription]] for SLC6A4, and it has been found that it can partly account for anxiety-related [[personality trait]]s.<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 = 1527–1531 | date = November 1996 | pmid = 8929413 | doi = 10.1126/science.274.5292.1527 | s2cid = 35503987 | bibcode = 1996Sci...274.1527L }}</ref> This polymorphism has been extensively investigated in over 300 scientific studies (as of 2006).<ref>{{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 = 224–226 | date = March 2006 | pmid = 16402131 | doi = 10.1038/sj.mp.4001789 | s2cid = 26655014 | doi-access =  }}</ref> The 5-HTTLPR polymorphism may be subdivided further:
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 [[Caucasian race|Caucasian]] people.<ref name="NakamuraM2000Human"/>

In addition to altering the expression of SERT protein and concentrations of extracellular serotonin in the brain, the 5-HTTLPR variation is associated with changes in brain structure.  One 2005 study found less [[grey matter]] in perigenual [[anterior cingulate cortex]] and [[amygdala]] for short allele carriers of the [[5-HTTLPR]] polymorphism compared to subjects with the long/long genotype.<ref name="Pezawas2005">{{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 = 828–834 | date = June 2005 | pmid = 15880108 | doi = 10.1038/nn1463 | s2cid = 1864631 }}</ref>

In contrast, a 2008 meta-analysis found no significant overall association between the 5-HTTLPR polymorphism and autism.<ref name=Huang-Santangelo>{{cite journal | vauthors = Huang CH, Santangelo SL | title = Autism and serotonin transporter gene polymorphisms: a systematic review and meta-analysis | journal = American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics | volume = 147B | issue = 6 | pages = 903–913 | date = September 2008 | pmid = 18286633 | doi = 10.1002/ajmg.b.30720 | s2cid = 9491697 }}</ref> A hypothesized [[gene–environment interaction]] between the short/short allele of the 5-HTTLPR and life stress as predictor for [[major depressive disorder|major depression]] has suffered a similar fate: after an influential<ref>{{cite journal | vauthors = Nierenberg AA | title = The long tale of the short arm of the promoter region for the gene that encodes the serotonin uptake protein | journal = CNS Spectrums | volume = 14 | issue = 9 | pages = 462–463 | date = September 2009 | pmid = 19890228 | doi = 10.1017/s1092852900023506 | s2cid = 24236284 }}</ref> initial report in 2003<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 = 386–389 | date = July 2003 | pmid = 12869766 | doi = 10.1126/science.1083968 | s2cid = 146500484 | bibcode = 2003Sci...301..386C }}</ref> there were mixed results in replication in 2008,<ref>{{cite journal | vauthors = Uher R, McGuffin P | title = The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis | journal = Molecular Psychiatry | volume = 13 | issue = 2 | pages = 131–146 | date = February 2008 | pmid = 17700575 | doi = 10.1038/sj.mp.4002067 | s2cid = 24432263 | doi-access =  }}</ref> and a 2009 meta-analysis was negative.<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 = 2462–2471 | date = June 2009 | pmid = 19531786 | pmc = 2938776 | doi = 10.1001/jama.2009.878 }}</ref> See [[5-HTTLPR]] for more information.

=== rs25532 ===
rs25532 is a SNP (C>T) close to the site of 5-HTTLPR.
It has been examined in connection with [[obsessive compulsive disorder]] (OCD).<ref>{{cite journal | vauthors = Wendland JR, Moya PR, Kruse MR, Ren-Patterson RF, Jensen CL, Timpano KR, Murphy DL | title = A novel, putative gain-of-function haplotype at SLC6A4 associates with obsessive-compulsive disorder | journal = Human Molecular Genetics | volume = 17 | issue = 5 | pages = 717–723 | date = March 2008 | pmid = 18055562 | doi = 10.1093/hmg/ddm343 | doi-access = free }}</ref>

=== I425V ===
I425V is a rare mutation on the ninth exon.
In 2003, researchers from Japan and the US reported that they had found this genetic variation in unrelated families with [[OCD]], and have found that it leads to faulty transporter function and regulation. A second variant in the same gene of some patients with this mutation suggests a genetic "double hit", resulting in greater biochemical effects and more severe symptoms.<ref>{{cite journal | vauthors = Ozaki N, Goldman D, Kaye WH, Plotnicov K, Greenberg BD, Lappalainen J, Rudnick G, Murphy DL | title = Serotonin transporter missense mutation associated with a complex neuropsychiatric phenotype | journal = Molecular Psychiatry | volume = 8 | issue = 11 | pages = 933–936 | date = November 2003 | pmid = 14593431 | doi = 10.1038/sj.mp.4001365 | s2cid = 2171955 | doi-access =  }}
News article:
* {{Cite news
 |agency       = Reuters
 |title        = Gene Found for Obsessive-Compulsive Disorder
 |publisher    = Mental Health E-News
 |date         = 27 October 2003
 |url          = http://www.nyaprs.org/Pages/View_ENews.cfm?ENewsID=2842
 |access-date   = 25 January 2008
 |archive-url  = https://web.archive.org/web/20061006182857/http://www.nyaprs.org/Pages/View_ENews.cfm?ENewsID=2842
 |archive-date = 6 October 2006
 |url-status     = dead
 |df           = dmy-all
}}</ref><ref>
{{cite journal | vauthors = Delorme R, Betancur C, Wagner M, Krebs MO, Gorwood P, Pearl P, Nygren G, Durand CM, Buhtz F, Pickering P, Melke J, Ruhrmann S, Anckarsäter H, Chabane N, Kipman A, Reck C, Millet B, Roy I, Mouren-Simeoni MC, Maier W, Råstam M, Gillberg C, Leboyer M, Bourgeron T | title = Support for the association between the rare functional variant I425V of the serotonin transporter gene and susceptibility to obsessive compulsive disorder | journal = Molecular Psychiatry | volume = 10 | issue = 12 | pages = 1059–1061 | date = December 2005 | pmid = 16088327 | pmc = 2547479 | doi = 10.1038/sj.mp.4001728 }}</ref><ref>{{Cite web
 | author = Stephen Wheless
 | title = "The OCD Gene" Popular Press v. Scientific Literature: Is SERT Responsible for Obsessive-Compulsive Disorder?
 | publisher = [[Davidson College]]
 | url = http://www.bio.davidson.edu/courses/genomics/2004/Wheless/SERT.html
 | access-date = 12 June 2008
}}</ref>

=== VNTR in STin2 ===
Another noncoding polymorphism is a [[VNTR]] in the second [[intron]] ([[STin2]]). In a 2005 study, it was found with three [[allele]]s: 9, 10 and 12 repeats.
A [[meta-analysis]] has found that the 12 repeat allele of the STin2 VNTR polymorphism had some minor (with [[odds ratio]] 1.24), but statistically significant, association with [[schizophrenia]].<ref>{{cite journal | vauthors = Fan JB, Sklar P | title = Meta-analysis reveals association between serotonin transporter gene STin2 VNTR polymorphism and schizophrenia | journal = Molecular Psychiatry | volume = 10 | issue = 10 | pages = 928–38, 891 | date = October 2005 | pmid = 15940296 | doi = 10.1038/sj.mp.4001690 | s2cid = 29240701 | doi-access =  }}</ref>
A 2008 meta-analysis found no significant overall association between the STin2 VNTR polymorphism and [[autism]].<ref name=Huang-Santangelo/>
Furthermore, a 2003 meta-analysis of [[affective disorder]]s, [[major depressive disorder]] and [[bipolar disorder]], found a minor association to the intron 2 VNTR polymorphism, but the results of the meta-analysis were dependent upon a large effect from one individual study.<ref>{{cite journal | vauthors = Anguelova M, Benkelfat C, Turecki G | title = A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: I. Affective disorders | journal = Molecular Psychiatry | volume = 8 | issue = 6 | pages = 574–591 | date = June 2003 | pmid = 12851635 | doi = 10.1038/sj.mp.4001328 | doi-access = free }}</ref>

The polymorphism has also been related to [[personality trait]]s with a 2008 Russian study finding individuals with the STin2.10 allele having lower [[neuroticism]] scores as measured with the [[Eysenck Personality Inventory]].<ref>{{cite journal | vauthors = Kazantseva AV, Gaysina DA, Faskhutdinova GG, Noskova T, Malykh SB, Khusnutdinova EK | title = Polymorphisms of the serotonin transporter gene (5-HTTLPR, A/G SNP in 5-HTTLPR, and STin2 VNTR) and their relation to personality traits in healthy individuals from Russia | journal = Psychiatric Genetics | volume = 18 | issue = 4 | pages = 167–176 | date = August 2008 | pmid = 18628678 | doi = 10.1097/YPG.0b013e328304deb8 | s2cid = 7423923 }}</ref>