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The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants


The serotonin transporter (5-HTT) gene is a promising candidate for introducing the heritability of interindividual variation in personality and the genetic susceptibility for various psychiatric diseases. Transcription of the gene is modulated by a common polymorphism in its upstream regulatory region (5-HTT gene-linked polymorphic region: 5-HTTLPR). The 5-HTTLPR consists of variation of the repetitive sequence containing GC-rich, 20-23-bp-long repeat elements. A deletion/insertion in the 5-HTTLPR was first reported to create a short (S) allele and a long (L) allele (14- and 16-repeats, respectively). Three other kinds of alleles (18-, 19- and 20-repeats) in addition to the S and L alleles in 5-HTTLPR have been reported. In the present study, we examined the 5-HTTLPR polymorphism in detail and identified ten novel sequence variants, concluding that the alleles reported as S and L are divided into four and six kinds of allelic variant, respectively. Subsequently, we developed a method for genotyping. The total number of alleles (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 the 5-HTTLPR was 14 in our populations (Japanese: n = 131; Caucasian: n = 74) in the present study. In addition, a significant ethnic difference between Japanese and Caucasian populations was observed for distributions of alleles and genotypes (P < 0.0001 and P < 0.0001, respectively). Our results suggest that the analyses of the 5-httlpr should be revised by genotyping with a more complete subdivision of alleles.

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  1. Ramamoorthy S, Bauman AL, Moore KR, Han H, Yang-Feng T, Cheng A et al. Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization Proc Natl Acad Sci USA 1993; 90: 2542–2546

    CAS  Article  Google Scholar 

  2. Heils A, Teufel A, Petri S, Stober G, Riederer P, Bengel D et al. Allelic variation of human serotonin transporter gene expression J Neurochem 1996; 66: 1–4

    Google Scholar 

  3. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region Science 1996; 274: 1527–1531

    CAS  Article  Google Scholar 

  4. Collier DA, Stöber G, Li T, Heils A, Catalan M, Di Bella D et al. A promoter of the serotonin gene: possible role in susceptibility to affective disorder Mol Psychiatry 1996; 1: 453–460

    CAS  Google Scholar 

  5. Mortensen OV, Thomassen M, Larsen MB, Whittemore SR, Wiborg O . Functional analysis of a novel human serotonin transporter gene promoter in immortalized raphe cells Brain Res Mol Brain Res 1999; 68: 141–148

    CAS  Article  Google Scholar 

  6. Kunugi H, Hattori M, Kato T, Tatsumi M, Saki T, Sasaki T et al. Serotonin transporter gene polymorphisms: ethnic difference and possible association with bipolar affective disorder Mol Psychiatry 1997; 2: 457–462

    CAS  Article  Google Scholar 

  7. Malhotra AK, Goldman D, Mazzanti C, Clifton A, Breier A, Pickar D . A functional serotonin transporter (5-HTT) polymorphism is associated with psychosis in neuroleptic-free schizophrenics Mol Psychiatry 1998; 3: 328–332

    CAS  Article  Google Scholar 

  8. Mendes de Oliveira JR, Otto PA, Vallada H, Lauriano V, Elkis H, Lafer B et al. Analysis of a novel functional polymorphism within the promoter region of the serotonin transporter gene (5-HTT) in Brazilian patients affected by bipolar disorder and schizophrenia Am J Med Genet 1998; 81: 225–227

    CAS  Article  Google Scholar 

  9. Matsushita S, Muramatsu T, Kimura M, Shirakawa O, Mita T, Nakai T et al. Serotonin transporter gene regulatory region polymorphism and panic disorder Mol Psychiatry 1997; 2: 390–392

    CAS  Article  Google Scholar 

  10. Cook EH, Courchesne R, Lord C, Cox NJ, Yan S, Lincoln A et al. Evidence of linkage between the serotonin transporter and autistic disorder Mol Psychiatry 1997; 2: 247–250

    Article  Google Scholar 

  11. Klauck SM, Poustka F, Benner A, Lesch KP, Poustka A . Serotonin transporter (5-HTT) gene variants associated with autism? Hum Mol Genet 1997; 6: 2233–2238

    CAS  Article  Google Scholar 

  12. Flory JD, Manuck SB, Ferrell RE, Dent KM, Peters DG, Muldoon MF . Neuroticism is not associated with the serotonin transporter (5-HTTLPR) polymorphism Mol Psychiatry 1999; 4: 93–96

    CAS  Article  Google Scholar 

  13. Michaelovsky E, Frisch A, Rockah R, Peleg L, Magal N, Shohat M et al. A novel allele in the promoter region of the human serotonin transporter gene Mol Psychiatry 1999; 4: 97–99

    CAS  Article  Google Scholar 

  14. Delbrück SJ, Wendel B, Grunewald I, Sander T, Morris-Rosendahl D, Crocq MA et al. A novel allelic variant of the human serotonin transporter gene regulatory polymorphism Cytogenet Cell Genet 1997; 79: 214–220

    Article  Google Scholar 

  15. Stefan S, Jean-Marc K, David R, Laurent E . Arlequin: a Software for Population Genetic Data Analysis Genetics and Biometry Laboratory, University of Geneva: Switzerland 1997

    Google Scholar 

  16. Guo SW, Thompson EA . Performing the exact test of Hardy–Weinberg proportion for multiple alleles Biometrics 1992; 48: 361–372

    CAS  Article  Google Scholar 

  17. Raymond M, Rousset F . An exact test for population differentiation Evolution 1995; 49: 1280–1283

    Article  Google Scholar 

  18. Cooper DN, Krawczak M, Antonorakis SE . The Metabolic and Molecular Bases of Inherited Disease 7th edn. McGraw-Hill: New York 1995; pp259–291

    Google Scholar 

  19. Cooper DN, Krawczak M . Human Gene Mutation Bios Scientific: Oxford 1993

    Google Scholar 

  20. Bell GI, Selby MJ, Rutter WJ . The highly polymorphic region near the human insulin gene is composed of simple tandemly repeating sequences Nature 1982; 295: 286–292

    Google Scholar 

  21. Gelernter J, Cubells JF, Kidd JR, Pakstis AJ, Kidd KK . Population studies of polymorphisms of the serotonin transporter protein gene Am J Med Genet 1999; 88: 61–66

    CAS  Article  Google Scholar 

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We would like to express our thanks to the subjects who participated in this study, to Miss Y Maruki for her technical assistance, and to Dr Y Nakamura of the University of Tokyo for providing genomic DNAs of the CEPH family members. This work was supported in part by a Grant-in-Aid for Co-operative Research from the Ministry of Education, Science, Sports and Culture of Japan.

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Correspondence to A Sano.

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Nakamura, M., Ueno, S., Sano, A. et al. The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants. Mol Psychiatry 5, 32–38 (2000).

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  • serotonin transporter
  • functional polymorphism
  • novel alleles
  • ethnic difference

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