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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 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]

Alleles Edit

Chromosome 17

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

The polymorphism occurs in the promotor region of the gene. Researchers commonly report it with two variations: A short ("s") and a long ("l"), but it can be subdivided further.[4] In connection with the region are two single nucleotide polymorphisms (SNP): rs25531 and rs25532.[5]

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.[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. [6]

Neuropsychiatric disorders Edit

It has been speculated that the polymorphism might be related to affective disorders, and an initial study found such a link.[7] However, another large European study found no such link.[8]

Treatment response Edit

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.[9] Another antidepressant treatment response study did, however, rather point to the rs25531 SNP,[10] 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".[11]

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.[12]

Personality traits Edit

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.[13][14] 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,[15] and this result was replicated by the group with new data.[16] Some other studies have, however, failed to find this association,[17] nor with peer-rated neuroticism,[18] and a review from 2006 noted the "erratic success in replication" of the first finding.[19] 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".[13] 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.[20] 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.[21] 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.[22]

Another research group have given evidence for a modest association between shyness and the long form in grade school children.[23] This is, however, just a single report and the link is not investigated as intensive as for the anxiety-related traits.

Neuroimaging Edit

ECAT-Exact-HR--PET-Scanner

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.[24] Using the PET radioligand carbon-11-labeled McN 5652 another research team could neither find any difference in serotonin transporter binding between genotype groups.[25] 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.[6] Another study with similar radioligand and genotype comparison found higher binding in the midbrain.[26]

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.[27] Brain blood flow measurements with positron emission tomography brain scanners can show genotype-related changes.[28] Furthermore, the glucose metabolism in the brain has also been investigated with respect to the polymorphism,[29] and the functional magnetic resonance imaging (fMRI) brain scans have also been correlated to the polymorphism.[30][31]

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

References Edit

  1. A. Heils, A. Teufel, S. Petri, M. Seemann, D. Bengel, U. Balling, P. Riederer & K. P. Lesch (1995). Functional promoter and polyadenylation site mapping of the human serotonin (5-HT) transporter gene. Journal of Neural Transmission. General Section 102 (3): 247–244.
  2. A. Heils, A. Teufel, S. Petri, G. Stober, P. Riederer, D. Bengel & Klaus-Peter Lesch (June 1996). Allelic variation of human serotonin transporter gene expression. Journal of Neurochemistry 66 (6): 2621–2624.
  3. 3.0 3.1 J.R. Wendland, B.J. Martin, M.R. Kruse, Klaus-Peter Lesch, D.L. Murphy (2006). Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs255531. Molecular Psychiatry 274: 1–3.
  4. 4.0 4.1 M. Nakamura, S. Ueno, A. Sano & H. Tanabe (2000). The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants. Molecular Psychiatry 5: 32–38.
  5. Dennis L. Murphy & Klaus-Peter Lesch (February 2008). Targeting the murine serotonin transporter: insights into human neurobiology. Nature Reviews Neuroscience 9 (2): 85–86.
  6. 6.0 6.1 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 (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): 327–321.
  7. 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 (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): 453–450. Comment:
  8. 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 (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): 377–372.
  9. L. Kathryn Durham, Suzin M. Webb, Patrice M. Milos, Cathryn M. Clary & Albert B. Seymour (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): 525–529.
  10. Jeffrey B. Kraft, Susan L. Slager, Patrick J. McGrath & Steven P. Hamilton (September 2005). Sequence analysis of the serotonin transporter and associations with antidepressant response. Biological psychiatry 58 (5): 374–371.
  11. Jeffrey B. Kraft, Eric J. Peters, Susan L. Slager, Greg D. Jenkins, Megan S. Reinalda, Patrick J. McGrath & Steven P. Hamilton (March 2007). Analysis of association between the serotonin transporter and antidepressant response in a large clinical sample. Biological Psychiatry 61 (6): 734–732.
  12. Luisella Bocchio-Chiavetto, Carlo Miniussi, Roberta Zanardini, Anna Gazzoli, Stefano Bignotti, Claudia Specchia & Massimo Gennarelli (May 2008). 5-HTTLPR and BDNF Val66Met polymorphisms and response to rTMS treatment in drug resistant depression. Neuroscience Letters 437 (2): 130–134.
  13. 13.0 13.1 Srijan Sen, Margit Burmeister & Debashis Ghosh (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 : the official publication of the International Society of Psychiatric Genetics 127B (1): 85–89.
  14. J. A. Schinka, R. M. Busch & N. Robichaux-Keene (February 2004). A meta-analysis of the association between the serotonin transporter gene polymorphism (5-HTTLPR) and trait anxiety. Molecular Psychiatry 9 (2): 197–192.
  15. 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 (November 1996). Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274 (5292): 1527–1521.
  16. B. D. Greenberg, Q. Li, F. R. Lucas, S. Hu, L. A. Sirota, J. Benjamin, K. P. Lesch, D. Hamer & D. L. Murphy (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): 202–206.
  17. J. D. Flory, S. B. Manuck, R. E. Ferrell, K. M. Dent, D. G. Peters & M. F. Muldoon (January 1999). Neuroticism is not associated with the serotonin transporter (5-HTTLPR) polymorphism. Molecular psychiatry 4 (1): 93–96.
  18. D. Ball, L. Hill, B. Freeman, T. C. Eley, J. Strelau, R. Riemann, F. M. Spinath, A. Angleitner & R. Plomin (March 1997). The serotonin transporter gene and peer-rated neuroticism. NeuroReport 8 (5): 1301–1304.
  19. R. P. Ebstein (2006). The molecular genetic architecture of human personality: beyond self-report questionnaires. Molecular Psychiatry 11: 427–445.
  20. Munafò MR, Freimer NB, Ng W, Ophoff R, Veijola J, Miettunen J, Järvelin MR, Taanila A, Flint J. (June 2008). 5-HTTLPR genotype and anxiety-related personality traits: A meta-analysis and new data. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics.
  21. Marcus R. Munafò, T. Clark & Jonathan Flint (April 2005). Does measurement instrument moderate the association between the serotonin transporter gene and anxiety-related personality traits? A meta-analysis. Molecular Psychiatry 10 (4): 415–419.
  22. A. F. Jorm, A. S. Henderson, P. A. Jacomb, H. Christensen, A. E. Korten, B. Rodgers, X. Tan & S. Easteal (September 1998). An association study of a functional polymorphism of the serotonin transporter gene with personality and psychiatric symptoms. Molecular Psychiatry 3 (5): 449–441.
  23. Shoshana Arbelle, Jonathan Benjamin, Moshe Golin, Ilana Kremer, Robert H. Belmaker & Richard P. Ebstein (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): 671–676.
  24. 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 (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): 525–521.
  25. 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 (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): 48–41.
  26. 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 (2007). Midbrain serotonin transporter binding potential measured with [11C]DASB is affected by serotonin transporter genotype. Journal of Neural Transmission 114 (5): 635–639.
  27. 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 (June 2005). 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. Nature Neuroscience 8 (6): 828–824.
  28. Tomas Furmark, Maria Tillfors, Hakan Garpenstrand, Ina Marteinsdottir, Bengt Langstrom, Lars Oreland & Mats Fredrikson (May 2004). Serotonin transporter polymorphism related to amygdala excitability and symptom severity in patients with social phobia. Neuroscience letters 362 (3): 189–182.
  29. 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 (May 2005). Frontal and limbic metabolic differences in subjects selected according to genetic variation of the SLC6A4 gene polymorphism. NeuroImage 25 (4): 1197–1194.
  30. Ahmad R. Hariri, Venkata S. Mattay, Alessandro Tessitore, Bhaskar Kolachana, Francesco Fera, David Goldman, Michael F. Egan & Daniel R. Weinberger (July 2002). Serotonin transporter genetic variation and the response of the human amygdala. Science 297 (5580): 400–403.
    • Greg Miller (July 2002). Neuroscience. Gene's effect seen in brain's fear response. Science 297 (5580): 319.
  31. Udo Dannlowski, Patricia Ohrmann, Jochen Bauer, Jurgen Deckert, Christa Hohoff, Harald Kugel, Volker Arolt, Walter Heindel, Anette Kersting, Bernhard T. Baune & Thomas Suslow (January 2008). 5-HTTLPR biases amygdala activity in response to masked facial expressions in major depression. Neuropsychopharmacology 33 (2): 418–414.

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