5-HTTLPR

5-HTTLPR (serotonin-transporter-linked polymorphic region) 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 1990's, [Cite journal
author = A. Heils, A. Teufel, S. Petri, M. Seemann, D. Bengel, U. Balling, P. Riederer & K. P. Lesch
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 = 247–244
year = 1995
pmid = 8788073
] [Cite journal
author = A. Heils, A. Teufel, S. Petri, G. Stober, P. Riederer, D. Bengel & Klaus-Peter Lesch
title = Allelic variation of human serotonin transporter gene expression
journal = Journal of Neurochemistry
volume = 66
issue = 6
pages = 2621–2624
year = 1996
month = June
pmid = 8632190
] 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.Cite journal
title = Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs255531
journal = Molecular Psychiatry
year = 2006
pages = 1–3
doi = 10.1038/sj.mp.4001789
author = J.R. Wendland, B.J. Martin, M.R. Kruse, Klaus-Peter Lesch, D.L. Murphy
volume = 274
url = http://www.psychobiologie.uni-wuerzburg.de/publications/pdf/2006-5.pdf
]

Alleles

The polymorphism occurs in the promotor region of the gene.Researchers commonly report it with two polymorphisms: A short ("s") and a long ("l"), but it can be subdivided further.Cite journal
author = M. Nakamura, S. Ueno, A. Sano & H. Tanabe
title = The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants
journal = Molecular Psychiatry
year = 2000
volume = 5
pages = 32–38
doi = 10.1038/sj.mp.4000698
] In connection with the region are two single nucleotide polymorphisms (SNP): rs25531 and rs25532.Cite journal
author = Dennis L. Murphy & Klaus-Peter Lesch
title = Targeting the murine serotonin transporter: insights into human neurobiology
journal = Nature Reviews Neuroscience
volume = 9
issue = 2
pages = 85–86
year = 2008
month = February
doi = 10.1038/nrn2284
pmid = 18209729
]

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. Cite journal
author = Nicole Praschak-Rieder, James Kennedy, Alan A. Wilson, Douglas Hussey, Anahita Boovariwala, Matthaeus Willeit, Nathalie Ginovart, Subi Tharmalingam, Mario Masellis, Sylvain Houle & Jeffrey H. Meyer
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 = 327–321
year = 2007
month = August
doi = 10.1016/j.biopsych.2006.09.022
pmid = 17210141
]

Neuropsychiatric disorders

It has been speculated that the polymorphism might be related to affective disorders, and an initial study found such a link. [Cite journal
author = D. A. Collier, G. Stober, T. Li, A. Heils, M. Catalano, D. Di Bella, M. J. Arranz, R. M. Murray, H. P. Vallada, D. Bengel, C. R. Muller, G. W. Roberts, E. Smeraldi, G. Kirov, P. Sham & K. P. Lesch
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 = 453–450
year = 1996
month = December
pmid = 9154246
Comment:
* Cite journal
author = N. Craddock & M. J. Owen
title = Candidate gene association studies in psychiatric genetics: a SERTain future?
journal = Molecular Psychiatry
volume = 1
issue = 6
pages = 434–436
year = 1996
month = December
pmid = 9154242
] However, another large European study found no such link. [Cite journal
author = Julien Mendlewicz, Isabelle Massat, Daniel Souery, Jurgen Del-Favero, Lilijana Oruc, Markus M. Nothen, Douglas Blackwood, Walter Muir, Sharon Battersby, Beny Lerer, Ronen H. Segman, Radka Kaneva, Alessandro Serretti, Roberta Lilli, Christian Lorenzi, Miro Jakovljevic, Sladana Ivezic, Marcella Rietschel, Vihra Milanova & Christine Van Broeckhoven
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 = 377–372
year = 2004
month = May
doi = 10.1038/sj.ejhg.5201149
pmid = 14735161
]

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. [Cite journal
author = L. Kathryn Durham, Suzin M. Webb, Patrice M. Milos, Cathryn M. Clary & Albert B. Seymour
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 = 525–529
year = 2004
month = August
doi = 10.1007/s00213-003-1562-3
pmid = 12955294
] Another antidepressant treatment response study did, however, rather point to the rs25531 SNP, [Cite journal
author = Jeffrey B. Kraft, Susan L. Slager, Patrick J. McGrath & Steven P. Hamilton
title = Sequence analysis of the serotonin transporter and associations with antidepressant response
journal = Biological psychiatry
volume = 58
issue = 5
pages = 374–371
year = 2005
month = September
doi = 10.1016/j.biopsych.2005.04.048
pmid = 15993855
] 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". [Cite journal
author = Jeffrey B. Kraft, Eric J. Peters, Susan L. Slager, Greg D. Jenkins, Megan S. Reinalda, Patrick J. McGrath & Steven P. Hamilton
title = Analysis of association between the serotonin transporter and antidepressant response in a large clinical sample
journal = Biological Psychiatry
volume = 61
issue = 6
pages = 734–732
year = 2007
month = March
doi = 10.1016/j.biopsych.2006.07.017
pmid = 17123473
]

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. [Cite journal
author = Luisella Bocchio-Chiavetto, Carlo Miniussi, Roberta Zanardini, Anna Gazzoli, Stefano Bignotti, Claudia Specchia & Massimo Gennarelli
title = 5-HTTLPR and BDNF Val66Met polymorphisms and response to rTMS treatment in drug resistant depression
journal = Neuroscience Letters
volume = 437
issue = 2
pages = 130–134
year = 2008
month = May
doi = 10.1016/j.neulet.2008.04.005
pmid = 18450378
]

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.Cite journal
author = Srijan Sen, Margit Burmeister & Debashis Ghosh
title = Meta-analysis of the association between a serotonin transporter promoter polymorphism (5-HTTLPR) and anxiety-related personality traits
journal =
volume = 127B
issue = 1
pages = 85–89
year = 2004
month = May
doi = 10.1002/ajmg.b.20158
pmid = 15108187
] [Cite journal
author = J. A. Schinka, R. M. Busch & N. Robichaux-Keene
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 = 197–192
year = 2004
month = February
doi = 10.1038/sj.mp.4001405
pmid = 14966478
] The initial and classic 1996 study found s-allele carriers to on average have slightly higher neuroticism score with the NEO PI-R personality questionaire, [Cite journal
author = Klaus-Peter Lesch, D. Bengel, A. Heils, S. Z. Sabol, B. D. Greenberg, S. Petri, J. Benjamin, C. R. Muller, D. H. Hamer & D. L. Murphy
title = Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region
journal = Science
volume = 274
issue = 5292
pages = 1527–1521
year = 1996
month = November
pmid = 8929413
] and this result was replicated by the group with new data. [Cite journal
author = B. D. Greenberg, Q. Li, F. R. Lucas, S. Hu, L. A. Sirota, J. Benjamin, K. P. Lesch, D. Hamer & D. L. Murphy
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 = 202–206
year = 2000
month = April
pmid = 10893498
] Some other studies have, however, failed to find this association, [Cite journal
author = J. D. Flory, S. B. Manuck, R. E. Ferrell, K. M. Dent, D. G. Peters & M. F. Muldoon
title = Neuroticism is not associated with the serotonin transporter (5-HTTLPR) polymorphism
journal = Molecular psychiatry
volume = 4
issue = 1
pages = 93–96
year = 1999
month = January
pmid = 10089017
] nor with peer-rated neuroticism, [Cite journal
author = D. Ball, L. Hill, B. Freeman, T. C. Eley, J. Strelau, R. Riemann, F. M. Spinath, A. Angleitner & R. Plomin
title = The serotonin transporter gene and peer-rated neuroticism
journal = NeuroReport
volume = 8
issue = 5
pages = 1301–1304
year = 1997
month = March
pmid = 9175133
] and a review from 2006 noted the "erratic success in replication" of the first finding. [Cite journal
author = R. P. Ebstein
title = The molecular genetic architecture of human personality: beyond self-report questionnaires
journal = Molecular Psychiatry
year = 2006
volume = 11
pages = 427–445
doi = 10.1038/sj.mp.4001814
] 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. [Cite journal
author = 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
year = 2008
month = June
doi = 10.1002/ajmg.b.30808
pmid = 18546120
] 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. [Cite journal
author = Marcus R. Munafò, T. Clark & Jonathan Flint
title = Does measurement instrument moderate the association between the serotonin transporter gene and anxiety-related personality traits? A meta-analysis
journal = Molecular Psychiatry
volume = 10
issue = 4
pages = 415–419
year = 2005
month = April
doi = 10.1038/sj.mp.4001627
pmid = 15599377
] In this meta-analysis a so-called mixed effect analysis was used that modeled the variation between studies. 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. [Cite journal
author = A. F. Jorm, A. S. Henderson, P. A. Jacomb, H. Christensen, A. E. Korten, B. Rodgers, X. Tan & S. Easteal
title = An association study of a functional polymorphism of the serotonin transporter gene with personality and psychiatric symptoms
journal = Molecular Psychiatry
volume = 3
issue = 5
pages = 449–441
year = 1998
month = September
pmid = 9774781
]

Another research group have given evidence for a modest association between shyness and the long form in grade school children. [Cite journal
author = Shoshana Arbelle, Jonathan Benjamin, Moshe Golin, Ilana Kremer, Robert H. Belmaker & Richard P. Ebstein
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 = 671–676
year = 2003
month = April
pmid = 12668354
] This is, however, just a single report and the link is not investigated as intensive as for the anxiety-related traits.

Neuroimaging

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. [Cite journal
author = Christopher H. van Dyck, Robert T. Malison, Julie K. Staley, Leslie K. Jacobsen, John P. Seibyl, Marc Laruelle, Ronald M. Baldwin, Robert B. Innis & Joel Gelernter
title = Central serotonin transporter availability measured with 123Ibeta-CIT SPECT in relation to serotonin transporter genotype
journal = The American Journal of Psychiatry
volume = 161
issue = 3
pages = 525–521
year = 2004
month = March
pmid = 14992979
url = http://ajp.psychiatryonline.org/cgi/content/abstract/161/3/525
] Using the PET radioligand carbon-11-labeled McN 5652 another research team could neither find any difference in serotonin transporter binding between genotype groups. [Cite journal
author = Ramin V. Parsey, Ramin S. Hastings, Maria A. Oquendo, Xianzhang Hu, David Goldman, Yung-yu Huang, Norman Simpson, Julie Arcement, Yiyun Huang, R. Todd Ogden, Ronald L. Van Heertum, Victoria Arango & J. John Mann
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 = 48–41
year = 2006
month = January
doi = 10.1176/appi.ajp.163.1.48
pmid = 16390888
url = http://ajp.psychiatryonline.org/cgi/content/abstract/163/1/48
] 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. [Cite journal
author = M. Reimold, M. N. Smolka, G. Schumann, A. Zimmer, J. Wrase, K. Mann, X.-Z. Hu, D. Goldman, G. Reischl, C. Solbach, H.-J. Machulla, R. Bares & A. Heinz
title = Midbrain serotonin transporter binding potential measured with 11CDASB is affected by serotonin transporter genotype
journal = Journal of Neural Transmission
volume = 114
issue = 5
pages = 635–639
year = 2007
month =
doi = 10.1007/s00702-006-0609-0
pmid = 17225932
]

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. [Cite journal
author = Lukas Pezawas, Andreas Meyer-Lindenberg, Emily M. Drabant, Beth A. Verchinski, Karen E. Munoz, Bhaskar S. Kolachana, Michael F. Egan, Venkata S. Mattay, Ahmad R. Hariri & Daniel R. Weinberger
title = 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression
journal = Nature Neuroscience
volume = 8
issue = 6
pages = 828–824
year = 2005
month = June
doi = 10.1038/nn1463
pmid = 15880108
]
Brain blood flow measurements with positron emission tomography brain scanners can show genotype-related changes. [Cite journal
author = Tomas Furmark, Maria Tillfors, Hakan Garpenstrand, Ina Marteinsdottir, Bengt Langstrom, Lars Oreland & Mats Fredrikson
title = Serotonin transporter polymorphism related to amygdala excitability and symptom severity in patients with social phobia
journal = Neuroscience letters
volume = 362
issue = 3
pages = 189–182
year = 2004
month = May
doi = 10.1016/j.neulet.2004.02.070
pmid = 15158011
] Furthermore, the glucose metabolism in the brain has also been investigated with respect to the polymorphism, [Cite journal
author = A. Graff-Guerrero, C. De la Fuente-Sandoval, B. Camarena, D. Gómez-Martin, R. Apiquián, A. Fresán, A. Aguilar, J. C. Méndez-Núñez, C. Escalona-Huerta, R. Drucker-Colin & H. Nicolini
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 = 1197–1194
year = 2005
month = May
doi = 10.1016/j.neuroimage.2004.12.020
pmid = 15850737
] and the functional magnetic resonance imaging (fMRI) brain scans have also been correlated to the polymorphism. [Cite journal
author = Ahmad R. Hariri, Venkata S. Mattay, Alessandro Tessitore, Bhaskar Kolachana, Francesco Fera, David Goldman, Michael F. Egan & Daniel R. Weinberger
title = Serotonin transporter genetic variation and the response of the human amygdala
journal = Science
volume = 297
issue = 5580
pages = 400–403
year = 2002
month = July
doi = 10.1126/science.1071829
pmid = 12130784

* Cite journal
author = Greg Miller
title = Neuroscience. Gene's effect seen in brain's fear response
journal = Science
volume = 297
issue = 5580
pages = 319
year = 2002
month = July
doi = 10.1126/science.297.5580.319a
pmid = 12130759
] [Cite journal
author = Udo Dannlowski, Patricia Ohrmann, Jochen Bauer, Jurgen Deckert, Christa Hohoff, Harald Kugel, Volker Arolt, Walter Heindel, Anette Kersting, Bernhard T. Baune & Thomas Suslow
title = 5-HTTLPR biases amygdala activity in response to masked facial expressions in major depression
journal = Neuropsychopharmacology
volume = 33
issue = 2
pages = 418–414
year = 2008
month = January
doi = 10.1038/sj.npp.1301411
pmid = 17406646
]

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

References

Others

* Cite web
title = Serotonin Transporter-Linked Polymorphic Region (5HTTLPR) and rs25531 SNP (Mspl, LA/LG)
url = http://ibgwww.colorado.edu/genotyping_lab/pdf/5HTTLPR.pdf
accessdate = 2008-06-27


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