Molecular Neurobiology

, Volume 53, Issue 8, pp 5510–5526 | Cite as

Role of the 5-HTTLPR and SNP Promoter Polymorphisms on Serotonin Transporter Gene Expression: a Closer Look at Genetic Architecture and In Vitro Functional Studies of Common and Uncommon Allelic Variants

  • Sandra IuresciaEmail author
  • Davide Seripa
  • Monica RinaldiEmail author


The serotonin (5-hydroxytriptamine (5-HT)) transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) is a variable number tandem repeats (VNTR) located in the promoter region of the human 5-HTT-encoding gene SLC6A4. This length polymorphism gives rise to different promoter variants, variously influencing SLC6A4 expression. Over the years, an extensive literature has investigated the relationships between these promoter variants and SLC6A4 gene expression, since these variants have been variously associated to complex neuropsychiatric conditions and traits. In this review, we detail the genetic architecture of the 5-HTTLPR allelic variants reported so far, with a closer look at the two single nucleotide polymorphisms (SNPs) rs25531 and rs25532 that lies in the VNTR and thus increase genetic variability of the SLC6A4 promoter. We summarize the hypothesized molecular mechanisms underlying this variation. We also provide an update on common and uncommon 5-HTTLPR allelic variants reviewing the available data on functional in vitro analysis of their regulatory effect on SLC6A4 gene transcription. Controversial findings are highlighted and critically discussed. A deeper knowledge of the “5-HTTLPR universe” will be useful to better understand the molecular basis of serotonin homeostasis and the pathological basis underlying serotonin-related neuropsychiatric conditions and traits.


5-HTT promoter polymorphism Serotonin transporter 5-HTTLPR Allelic variants In vitro functional studies SNPs 



We are particularly grateful to D. Fioretti for helping us with nucleotide sequence alignment and statistical analysis and to I. Condò for helpful and constructive comments on our in vitro functional studies. We thank Mrs C. Gravina and M. Urbano, Geriatric Unit and Gerontology-Geriatrics Research Laboratory, I.R.C.C.S. “Casa Sollievo della Sofferenza” for their skilled technical works.

We also thank Dr. N. Di Simone, Università Cattolica del Sacro Cuore, Rome, Italy, for providing us with the JAR cell line.

Results described in this review were included in a thesis entitled “Identification and functional characterization of promoter allelic variants of the human serotonin transporter gene” submitted for fulfilment of the Master of Science in Human Biology and Evolution by Elena De Dominicis at the University of Rome Tor Vergata.

This work was supported by “Ministero della Salute”, I.R.C.C.S. Research Program, Ricerca Corrente 2015–2017, Linea n. 2 “Malattie complesse e terapie innovative” and by the “5 × 1000” voluntary contribution.

Conflict of Interest

The authors declare that they have no conflict of interest to disclose.

Supplementary material

12035_2015_9409_MOESM1_ESM.docx (24 kb)
ESM 1 (DOCX 24 kb)


  1. 1.
    Murphy DL, Lerner A, Rudnick G, Lesch KP (2004) Serotonin transporter: gene, genetic disorders, and pharmacogenetics. Mol Interv 4:109–123CrossRefPubMedGoogle Scholar
  2. 2.
    Murphy DL, Lesch KP (2008) Targeting the murine serotonin transporter: insights into human neurobiology. Nat Rev Neurosci 9:85–96CrossRefPubMedGoogle Scholar
  3. 3.
    Rudnick G, Clark J (1993) From synapse to vesicle: the reuptake and storage of biogenic amine neurotransmitters. Biochim Biophys Acta 1144:249–263CrossRefPubMedGoogle Scholar
  4. 4.
    Daws LC, Toney GM (2007) High-speed chronoamperometry to study kinetics and mechanisms for serotonin clearance in vivo. In: Michael AC, Borland LM (eds) Electrochemical methods for neuroscience. CRC Press, Boca RatonGoogle Scholar
  5. 5.
    Gelernter J (2014) SLC6A4 polymorphism, population genetics, and psychiatric traits. Hum Genet 133:459–461CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Owens MJ, Morgan WN, Plott SJ, Nemeroff CB (1997) Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites. J Pharmacol Exp Ther 283:1305–1322PubMedGoogle Scholar
  7. 7.
    Preskorn SH (2004) Tianeptine: a facilitator of the reuptake of serotonin and norepinephrine as an antidepressant? J Psychiatr Pract 10:323–330CrossRefPubMedGoogle Scholar
  8. 8.
    Preskorn SH (2004) Milnacipran: a dual norepinephrine and serotonin reuptake pump inhibitor. J Psychiatr Pract 10:119–126CrossRefPubMedGoogle Scholar
  9. 9.
    Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, Watanabe N, Nakagawa A et al (2009) Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet 373:746–758CrossRefPubMedGoogle Scholar
  10. 10.
    Cipriani A, Purgato M, Furukawa TA, Trespidi C, Imperadore G, Signoretti A, Churchill R, Watanabe N et al (2012) Citalopram versus other anti-depressive agents for depression. Cochrane Database Syst Rev 7:CD006534PubMedPubMedCentralGoogle Scholar
  11. 11.
    Eyding D, Lelgemann M, Grouven U, Harter M, Kromp M, Kaiser T, Kerekes MF, Gerken M et al (2010) Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials. BMJ 341:c4737CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Linde K, Kriston L, Rucker G, Jamil S, Schumann I, Meissner K, Sigterman K, Schneider A (2015) Efficacy and acceptability of pharmacological treatments for depressive disorders in primary care: systematic review and network meta-analysis. Ann Fam Med 13:69–79CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Pizarro M, Fontenelle LF, Paravidino DC, Yucel M, Miguel EC, de Menezes GB (2014) An updated review of antidepressants with marked serotonergic effects in obsessive-compulsive disorder. Expert Opin Pharmacother 15:1391–1401CrossRefPubMedGoogle Scholar
  14. 14.
    Seripa D, Pilotto A, Paroni GH, Fontana A, D’Onofrio G, Gravina C, Urbano M, Cascavilla L, Paris F, Panza F, Padovani A (2015) Role of the serotonin transporter gene locus in the response to SSRI treatment of major depressive disorder in late life. J PsychopharmacolGoogle Scholar
  15. 15.
    Ramamoorthy S, Bauman AL, Moore KR, Han H, Yang-Feng T, Chang AS, Ganapathy V, Blakely RD (1993) Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization. Proc Natl Acad Sci U S A 90:2542–2546CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Gelernter J, Pakstis AJ, Kidd KK (1995) Linkage mapping of serotonin transporter protein gene SLC6A4 on chromosome 17. Hum Genet 95:677–680CrossRefPubMedGoogle Scholar
  17. 17.
    Hornung JP (2003) The human raphe nuclei and the serotonergic system. J Chem Neuroanat 26:331–343CrossRefPubMedGoogle Scholar
  18. 18.
    Lesch KP, Wolozin BL, Murphy DL, Reiderer P (1993) Primary structure of the human platelet serotonin uptake site: identity with the brain serotonin transporter. J Neurochem 60:2319–2322CrossRefPubMedGoogle Scholar
  19. 19.
    Faraj BA, Olkowski ZL, Jackson RT (1994) Expression of a high-affinity serotonin transporter in human lymphocytes. Int J Immunopharmacol 16:561–567CrossRefPubMedGoogle Scholar
  20. 20.
    Iken K, Chheng S, Fargin A, Goulet AC, Kouassi E (1995) Serotonin upregulates mitogen-stimulated B lymphocyte proliferation through 5-HT1A receptors. Cell Immunol 163:1–9CrossRefPubMedGoogle Scholar
  21. 21.
    Gill RK, Pant N, Saksena S, Singla A, Nazir TM, Vohwinkel L, Turner JR, Goldstein J et al (2008) Function, expression, and characterization of the serotonin transporter in the native human intestine. Am J Physiol Gastrointest Liver Physiol 294:G254–G262CrossRefPubMedGoogle Scholar
  22. 22.
    Murphy DL, Moya PR (2011) Human serotonin transporter gene (SLC6A4) variants: their contributions to understanding pharmacogenomic and other functional GxG and GxE differences in health and disease. Curr Opin Pharmacol 11:3–10CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Heils A, Teufel A, Petri S, Stober G, Riederer P, Bengel D, Lesch KP (1996) Allelic variation of human serotonin transporter gene expression. J Neurochem 66:2621–2624CrossRefPubMedGoogle Scholar
  24. 24.
    Goldman N, Glei DA, Lin YH, Weinstein M (2010) The serotonin transporter polymorphism (5-HTTLPR): allelic variation and links with depressive symptoms. Depress Anxiety 27:260–269CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Serretti A, Kato M, Kennedy JL (2008) Pharmacogenetic studies in depression: a proposal for methodologic guidelines. Pharmacogenomics J 8:90–100CrossRefPubMedGoogle Scholar
  26. 26.
    Delbruck SJ, Wendel B, Grunewald I, Sander T, Morris-Rosendahl D, Crocq MA, Berrettini WH, Hoehe MR (1997) A novel allelic variant of the human serotonin transporter gene regulatory polymorphism. Cytogenet Cell Genet 79:214–220CrossRefPubMedGoogle Scholar
  27. 27.
    Frisch A, Finkel B, Michaelovsky E, Sigal M, Laor N, Weizman R (2000) A rare short allele of the serotonin transporter promoter region (5-HTTLPR) found in an aggressive schizophrenic patient of Jewish Libyan origin. Psychiatr Genet 10:179–183CrossRefPubMedGoogle Scholar
  28. 28.
    Gelernter J, Kranzler H, Cubells JF (1997) Serotonin transporter protein (SLC6A4) allele and haplotype frequencies and linkage disequilibria in African- and European-American and Japanese populations and in alcohol-dependent subjects. Hum Genet 101:243–246CrossRefPubMedGoogle Scholar
  29. 29.
    Kunugi H, Hattori M, Kato T, Tatsumi M, Sakai T, Sasaki T, Hirose T, Nanko S (1997) Serotonin transporter gene polymorphisms: ethnic difference and possible association with bipolar affective disorder. Mol Psychiatry 2:457–462CrossRefPubMedGoogle Scholar
  30. 30.
    Michaelovsky E, Frisch A, Rockah R, Peleg L, Magal N, Shohat M, Weizman R (1999) A novel allele in the promoter region of the human serotonin transporter gene. Mol Psychiatry 4:97–99CrossRefPubMedGoogle Scholar
  31. 31.
    Murdoch JD, Speed WC, Pakstis AJ, Heffelfinger CE, Kidd KK (2013) Worldwide population variation and haplotype analysis at the serotonin transporter gene SLC6A4 and implications for association studies. Biol Psychiatry 74:879–889CrossRefPubMedGoogle Scholar
  32. 32.
    Nakamura M, Ueno S, Sano A, Tanabe H (2000) The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants. Mol Psychiatry 5:32–38CrossRefPubMedGoogle Scholar
  33. 33.
    Vijayendran M, Cutrona C, Beach SR, Brody GH, Russell D, Philibert RA (2012) The relationship of the serotonin transporter (SLC6A4) extra long variant to gene expression in an African American sample. Am J Med Genet B Neuropsychiatr Genet 159B:611–612CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Zhang X, Cheng X, Hu YB, Lai JM, You H, Hu PL, Zou M, Zhu JH (2014) Serotonin transporter polymorphic region 5-HTTLPR modulates risk for Parkinson’s disease. Neurobiol Aging 35: 1957 e1959-1957 e1914Google Scholar
  35. 35.
    Ehli EA, Hu Y, Lengyel-Nelson T, Hudziak JJ, Davies GE (2012) Identification and functional characterization of three novel alleles for the serotonin transporter-linked polymorphic region. Mol Psychiatry 17:185–192CrossRefPubMedGoogle Scholar
  36. 36.
    Rasmussen HB, Werge TM (2007) Novel procedure for genotyping of the human serotonin transporter gene-linked polymorphic region (5-HTTLPR)--a region with a high level of allele diversity. Psychiatr Genet 17:287–291CrossRefPubMedGoogle Scholar
  37. 37.
    Iurescia S, Rinaldi M, Pilotto A, Paroni G, De Dominicis E, Gravina C, Urbano M, Borroni B et al (2012) Identification and functional characterization of novel functional alleles in the promoter region of the serotonin transporter gene. Neurol Sci 33:S401Google Scholar
  38. 38.
    Seripa D, Iurescia S, Rinaldi M, Pilotto A, Paroni G, Bazzano S, Antonelli A, Gravina C et al (2013) The serotonin transporter gene-linked polymorphic region: identification and functional characterization of novel alleles. Eur Geriatr Med 4(1):S100CrossRefGoogle Scholar
  39. 39.
    Canli T, Lesch KP (2007) Long story short: the serotonin transporter in emotion regulation and social cognition. Nat Neurosci 10:1103–1109CrossRefPubMedGoogle Scholar
  40. 40.
    Hu XZ, Lipsky RH, Zhu G, Akhtar LA, Taubman J, Greenberg BD, Xu K, Arnold PD et al (2006) Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. Am J Hum Genet 78:815–826CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Wendland JR, Moya PR, Kruse MR, Ren-Patterson RF, Jensen CL, Timpano KR, Murphy DL (2008) A novel, putative gain-of-function haplotype at SLC6A4 associates with obsessive-compulsive disorder. Hum Mol Genet 17:717–723CrossRefPubMedGoogle Scholar
  42. 42.
    Gatt JM, Burton KL, Williams LM, Schofield PR (2015) Specific and common genes implicated across major mental disorders: a review of meta-analysis studies. J Psychiatr Res 60:1–13CrossRefPubMedGoogle Scholar
  43. 43.
    Karg K, Burmeister M, Shedden K, Sen S (2011) The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation. Arch Gen Psychiatry 68:444–454CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Sharpley CF, Palanisamy SK, Glyde NS, Dillingham PW, Agnew LL (2014) An update on the interaction between the serotonin transporter promoter variant (5-HTTLPR), stress and depression, plus an exploration of non-confirming findings. Behav Brain Res 273:89–105CrossRefPubMedGoogle Scholar
  45. 45.
    Walitza S, Marinova Z, Grunblatt E, Lazic SE, Remschmidt H, Vloet TD, Wendland JR (2014) Trio study and meta-analysis support the association of genetic variation at the serotonin transporter with early-onset obsessive-compulsive disorder. Neurosci Lett 580:100–103CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Porcelli S, Fabbri C, Serretti A (2012) Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with antidepressant efficacy. Eur Neuropsychopharmacol 22:239–258CrossRefPubMedGoogle Scholar
  47. 47.
    Taylor MJ, Sen S, Bhagwagar Z (2010) Antidepressant response and the serotonin transporter gene-linked polymorphic region. Biol Psychiatry 68:536–543CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Gelernter J, Cubells JF, Kidd JR, Pakstis AJ, Kidd KK (1999) Population studies of polymorphisms of the serotonin transporter protein gene. Am J Med Genet 88:61–66CrossRefPubMedGoogle Scholar
  49. 49.
    Lesch KP, Balling U, Gross J, Strauss K, Wolozin BL, Murphy DL, Riederer P (1994) Organization of the human serotonin transporter gene. J Neural Transm Gen Sect 95:157–162CrossRefPubMedGoogle Scholar
  50. 50.
    Gelernter J, Freimer M (1994) PstI RFLP at the SERT locus. Hum Mol Genet 3:383CrossRefPubMedGoogle Scholar
  51. 51.
    Avula R, Rand A, Black JL, O’Kane DJ (2011) Simultaneous genotyping of multiple polymorphisms in human serotonin transporter gene and detection of novel allelic variants. Transl Psychiatry 1:e32Google Scholar
  52. 52.
    Flattem NL, Blakely RD (2000) Modified structure of the human serotonin transporter promoter. Mol Psychiatry 5:110–115Google Scholar
  53. 53.
    Delbruck SJ, Kidd KU, Hoehe MR (2001) Identification of an additional allelic variant (XLS) of the human serotonin transporter gene (SLC6A4): −1201Cins66. Hum Mutat 17:524Google Scholar
  54. 54.
    Mortensen OV, Thomassen M, Larsen MB, Whittemore SR, Wiborg O (1999) Functional analysis of a novel human serotonin transporter gene promoter in immortalized raphe cells. Brain Res Mol Brain Res 68:141–148Google Scholar
  55. 55.
    Bennett ST, Todd JA (1996) Human type 1 diabetes and the insulin gene: principles of mapping polygenes. Annu Rev Genet 30:343–370CrossRefPubMedGoogle Scholar
  56. 56.
    Lalioti MD, Antonarakis SE, Scott HS (2003) The epilepsy, the protease inhibitor and the dodecamer: progressive myoclonus epilepsy, cystatin b and a 12-mer repeat expansion. Cytogenet Genome Res 100:213–223CrossRefPubMedGoogle Scholar
  57. 57.
    Lesch KP, Jatzke S, Meyer J, Stober G, Okladnova O, Mossner R, Riederer P (1999) Mosaicism for a serotonin transporter gene promoter-associated deletion: decreased recombination in depression. J Neural Transm 106:1223–1230CrossRefPubMedGoogle Scholar
  58. 58.
    Sen D, Gilbert W (1988) Formation of parallel four-stranded complexes by guanine-rich motifs in DNA and its implications for meiosis. Nature 334:364–366CrossRefPubMedGoogle Scholar
  59. 59.
    Bois PR (2003) Hypermutable minisatellites, a human affair? Genomics 81:349–355CrossRefPubMedGoogle Scholar
  60. 60.
    Jeffreys AJ, Barber R, Bois P, Buard J, Dubrova YE, Grant G, Hollies CR, May CA et al (1999) Human minisatellites, repeat DNA instability and meiotic recombination. Electrophoresis 20:1665–1675CrossRefPubMedGoogle Scholar
  61. 61.
    Bell GI, Selby MJ, Rutter WJ (1982) The highly polymorphic region near the human insulin gene is composed of simple tandemly repeating sequences. Nature 295:31–35CrossRefPubMedGoogle Scholar
  62. 62.
    Kobori JA, Strauss E, Minard K, Hood L (1986) Molecular analysis of the hotspot of recombination in the murine major histocompatibility complex. Science 234:173–179CrossRefPubMedGoogle Scholar
  63. 63.
    Stead JD, Jeffreys AJ (2000) Allele diversity and germline mutation at the insulin minisatellite. Hum Mol Genet 9:713–723CrossRefPubMedGoogle Scholar
  64. 64.
    Steinmetz M, Stephan D, Fischer Lindahl K (1986) Gene organization and recombinational hotspots in the murine major histocompatibility complex. Cell 44:895–904CrossRefPubMedGoogle Scholar
  65. 65.
    Jeffreys AJ, Neumann R (1997) Somatic mutation processes at a human minisatellite. Hum Mol Genet 6(129–132):134–126Google Scholar
  66. 66.
    Ellegren H (2004) Microsatellites: simple sequences with complex evolution. Nat Rev Genet 5:435–445CrossRefPubMedGoogle Scholar
  67. 67.
    Ali FR, Vasiliou SA, Haddley K, Paredes UM, Roberts JC, Miyajima F, Klenova E, Bubb VJ et al (2010) Combinatorial interaction between two human serotonin transporter gene variable number tandem repeats and their regulation by CTCF. J Neurochem 112:296–306CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    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. J Neural Transm Gen Sect 102:247–254CrossRefPubMedGoogle Scholar
  69. 69.
    Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR et al (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274:1527–1531CrossRefPubMedGoogle Scholar
  70. 70.
    Sakai K, Nakamura M, Ueno S, Sano A, Sakai N, Shirai Y, Saito N (2002) The silencer activity of the novel human serotonin transporter linked polymorphic regions. Neurosci Lett 327:13–16CrossRefPubMedGoogle Scholar
  71. 71.
    Prasansuklab A, Poovorawan Y, Tencomnao T (2011) Modulation of human serotonin transporter expression by 5-HTTLPR in colon cells. Int J Mol Sci 12:6619–6634CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Cool DR, Leibach FH, Bhalla VK, Mahesh VB, Ganapathy V (1991) Expression and cyclic AMP-dependent regulation of a high affinity serotonin transporter in the human placental choriocarcinoma cell line (JAR). J Biol Chem 266:15750–15757PubMedGoogle Scholar
  73. 73.
    McLaughlin DP, Little KY, Lopez JF, Watson SJ (1996) Expression of serotonin transporter mRNA in human brainstem raphe nuclei. Neuropsychopharmacology 15:523–529CrossRefPubMedGoogle Scholar
  74. 74.
    Bradley SL, Dodelzon K, Sandhu HK, Philibert RA (2005) Relationship of serotonin transporter gene polymorphisms and haplotypes to mRNA transcription. Am J Med Genet B Neuropsychiatr Genet 136B:58–61CrossRefPubMedGoogle Scholar
  75. 75.
    Hranilovic D, Stefulj J, Schwab S, Borrmann-Hassenbach M, Albus M, Jernej B, Wildenauer D (2004) Serotonin transporter promoter and intron 2 polymorphisms: relationship between allelic variants and gene expression. Biol Psychiatry 55:1090–1094CrossRefPubMedGoogle Scholar
  76. 76.
    Lim JE, Papp A, Pinsonneault J, Sadee W, Saffen D (2006) Allelic expression of serotonin transporter (SERT) mRNA in human pons: lack of correlation with the polymorphism SERTLPR. Mol Psychiatry 11:649–662CrossRefPubMedGoogle Scholar
  77. 77.
    Philibert RA, Sandhu H, Hollenbeck N, Gunter T, Adams W, Madan A (2008) The relationship of 5HTT (SLC6A4) methylation and genotype on mRNA expression and liability to major depression and alcohol dependence in subjects from the Iowa Adoption Studies. Am J Med Genet B Neuropsychiatr Genet 147B:543–549CrossRefPubMedGoogle Scholar
  78. 78.
    Hanna GL, Himle JA, Curtis GC, Koram DQ, Veenstra-VanderWeele J, Leventhal BL, Cook EH Jr (1998) Serotonin transporter and seasonal variation in blood serotonin in families with obsessive-compulsive disorder. Neuropsychopharmacology 18:102–111CrossRefPubMedGoogle Scholar
  79. 79.
    Greenberg BD, Tolliver TJ, Huang SJ, Li Q, Bengel D, Murphy DL (1999) Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets. Am J Med Genet 88:83–87CrossRefPubMedGoogle Scholar
  80. 80.
    Greenberg BD, Li Q, Lucas FR, Hu S, Sirota LA, Benjamin J, Lesch KP, Hamer D et al (2000) Association between the serotonin transporter promoter polymorphism and personality traits in a primarily female population sample. Am J Med Genet 96:202–216CrossRefPubMedGoogle Scholar
  81. 81.
    Stoltenberg SF, Twitchell GR, Hanna GL, Cook EH, Fitzgerald HE, Zucker RA, Little KY (2002) Serotonin transporter promoter polymorphism, peripheral indexes of serotonin function, and personality measures in families with alcoholism. Am J Med Genet 114:230–234CrossRefPubMedGoogle Scholar
  82. 82.
    Mann JJ, Huang YY, Underwood MD, Kassir SA, Oppenheim S, Kelly TM, Dwork AJ, Arango V (2000) A serotonin transporter gene promoter polymorphism (5-HTTLPR) and prefrontal cortical binding in major depression and suicide. Arch Gen Psychiatry 57:729–738CrossRefPubMedGoogle Scholar
  83. 83.
    Willeit M, Stastny J, Pirker W, Praschak-Rieder N, Neumeister A, Asenbaum S, Tauscher J, Fuchs K et al (2001) No evidence for in vivo regulation of midbrain serotonin transporter availability by serotonin transporter promoter gene polymorphism. Biol Psychiatry 50:8–12CrossRefPubMedGoogle Scholar
  84. 84.
    Kaiser R, Muller-Oerlinghausen B, Filler D, Tremblay PB, Berghofer A, Roots I, Brockmoller J (2002) Correlation between serotonin uptake in human blood platelets with the 44-bp polymorphism and the 17-bp variable number of tandem repeat of the serotonin transporter. Am J Med Genet 114:323–328CrossRefPubMedGoogle Scholar
  85. 85.
    Shioe K, Ichimiya T, Suhara T, Takano A, Sudo Y, Yasuno F, Hirano M, Shinohara M et al (2003) No association between genotype of the promoter region of serotonin transporter gene and serotonin transporter binding in human brain measured by PET. Synapse 48:184–188CrossRefPubMedGoogle Scholar
  86. 86.
    van Dyck CH, Malison RT, Staley JK, Jacobsen LK, Seibyl JP, Laruelle M, Baldwin RM, Innis RB et al (2004) Central serotonin transporter availability measured with [123I] beta-CIT SPECT in relation to serotonin transporter genotype. Am J Psychiatry 161:525–531CrossRefPubMedGoogle Scholar
  87. 87.
    Patkar AA, Berrettini WH, Mannelli P, Gopalakrishnan R, Hoehe MR, Bilal L, Weinstein S, Vergare MJ (2004) Relationship between serotonin transporter gene polymorphisms and platelet serotonin transporter sites among African-American cocaine-dependent individuals and healthy volunteers. Psychiatr Genet 14:25–32CrossRefPubMedGoogle Scholar
  88. 88.
    Zalsman G, Anderson GM, Peskin M, Frisch A, King RA, Vekslerchik M, Sommerfeld E, Michaelovsky E et al (2005) Relationships between serotonin transporter promoter polymorphism, platelet serotonin transporter binding and clinical phenotype in suicidal and non-suicidal adolescent inpatients. J Neural Transm 112:309–315CrossRefPubMedGoogle Scholar
  89. 89.
    Parsey RV, Hastings RS, Oquendo MA, Huang YY, Simpson N, Arcement J, Huang Y, Ogden RT et al (2006) Lower serotonin transporter binding potential in the human brain during major depressive episodes. Am J Psychiatry 163:52–58CrossRefPubMedGoogle Scholar
  90. 90.
    Praschak-Rieder N, Kennedy J, Wilson AA, Hussey D, Boovariwala A, Willeit M, Ginovart N, Tharmalingam S et al (2007) Novel 5-HTTLPR allele associates with higher serotonin transporter binding in putamen: a [(11)C] DASB positron emission tomography study. Biol Psychiatry 62:327–331CrossRefPubMedGoogle Scholar
  91. 91.
    Reimold M, Smolka MN, Schumann G, Zimmer A, Wrase J, Mann K, Hu XZ, Goldman D et al (2007) Midbrain serotonin transporter binding potential measured with [11C]DASB is affected by serotonin transporter genotype. J Neural Transm 114:635–639CrossRefPubMedGoogle Scholar
  92. 92.
    Bah J, Lindstrom M, Westberg L, Manneras L, Ryding E, Henningsson S, Melke J, Rosen I et al (2008) Serotonin transporter gene polymorphisms: effect on serotonin transporter availability in the brain of suicide attempters. Psychiatry Res 162:221–229CrossRefPubMedGoogle Scholar
  93. 93.
    Kalbitzer J, Frokjaer VG, Erritzoe D, Svarer C, Cumming P, Nielsen FA, Hashemi SH, Baare WF et al (2009) The personality trait openness is related to cerebral 5-HTT levels. Neuroimage 45:280–285CrossRefPubMedGoogle Scholar
  94. 94.
    Murthy NV, Selvaraj S, Cowen PJ, Bhagwagar Z, Riedel WJ, Peers P, Kennedy JL, Sahakian BJ et al (2010) Serotonin transporter polymorphisms (SLC6A4 insertion/deletion and rs25531) do not affect the availability of 5-HTT to [11C] DASB binding in the living human brain. Neuroimage 52:50–54CrossRefPubMedGoogle Scholar
  95. 95.
    Fisher PM, Holst KK, Mc Mahon B, Haahr ME, Madsen K, Gillings N, Baare WF, Jensen PS et al (2012) 5-HTTLPR status predictive of neocortical 5-HT4 binding assessed with [(11)C]SB207145 PET in humans. Neuroimage 62:130–136CrossRefPubMedGoogle Scholar
  96. 96.
    Kraft JB, Slager SL, McGrath PJ, Hamilton SP (2005) Sequence analysis of the serotonin transporter and associations with antidepressant response. Biol Psychiatry 58:374–381CrossRefPubMedGoogle Scholar
  97. 97.
    Perroud N, Salzmann A, Saiz PA, Baca-Garcia E, Sarchiapone M, Garcia-Portilla MP, Carli V, Vaquero-Lorenzo C et al (2010) Rare genotype combination of the serotonin transporter gene associated with treatment response in severe personality disorder. Am J Med Genet B Neuropsychiatr Genet 153B:1494–1497CrossRefPubMedGoogle Scholar
  98. 98.
    Martin J, Cleak J, Willis-Owen SA, Flint J, Shifman S (2007) Mapping regulatory variants for the serotonin transporter gene based on allelic expression imbalance. Mol Psychiatry 12:421–422CrossRefPubMedGoogle Scholar
  99. 99.
    Contreras-Sesvold CL, Abraham P, Devaney JM, Harmon BT, Deuster PA (2015) The association of 5-HTTLPR XLL genotype with higher cortisol levels in African Americans. Int J Med GenetGoogle Scholar
  100. 100.
    Murphy DL, Maile MS, Vogt NM (2013) 5HTTLPR: white knight or dark blight? ACS Chem Neurosci 4:13–15CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Premi E, Archetti S, Pilotto A, Seripa D, Paghera B, Padovani A, Borroni B (2015) Functional genetic variation in the serotonin 5-HTTLPR modulates brain damage in frontotemporal dementia. Neurobiol Aging 36:446–451CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.National Research Council (CNR)Institute of Translational Pharmacology (IFT)RomeItaly
  2. 2.Geriatric Unit and Gerontology-Geriatrics Research Laboratory, Department of Medical SciencesIRCCS Casa Sollievo della SofferenzaSan Giovanni RotondoItaly

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