Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Research Article
  • Published:

Serotonin transporter gene promoter variants do not explain the hyperserotoninemia in autistic children

Molecular Psychiatry volume 7, pages 795–800 (2002)Cite this article

Abstract

Autism is a biologically-heterogeneous disease. Distinct subgroups of autistic patients may be marked by intermediate phenotypes, such as elevated serotonin (5-HT) blood levels, potentially associated with different underlying disease mechanisms. This could lead to inconsistent genetic association results, such as those of prior studies on serotonin transporter (5-HTT) gene promoter variants and autistic disorder. Contributions of 5-HTT gene promoter alleles to 5-HT blood levels were thus investigated in 134 autistic patients and 291 first-degree relatives. Mean 5-HT blood levels are 11% higher in autistic patients carrying the L/L genotype, compared to patients with the S/S or S/L genotype; this trend is not observed in first-degree relatives. The probability of inheriting L or S alleles is significantly enhanced in patients with 5-HT blood levels above or below the mean, respectively (P < 0.05), but quantitative TDT analyses yield a non-significant trend (P = 0.10), as this polymorphism explains only 2.5% of the variance in 5-HT blood levels of autistic patients. In conclusion, 5-HTT gene promoter variants seemingly exert a small effect on 5-HT blood levels in autistic children, which largely does not account for hyperserotoninemia. Nonetheless, the inconsistent outcome of prior association studies could partly stem from a selection bias of hyper- or hypo-serotoninemic probands.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Cook EH Jr, 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 

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

    Article  CAS  Google Scholar 

  3. Tordjman S, Gutneckt L, Carlier M, Spitz E, Antoine C, Slama F et al. Role of the serotonin transporter in the behavioral expression of autism Mol Psychiatry 2001; 6: 434–439

    Article  CAS  Google Scholar 

  4. Yirmiya N, Pilowsky T, Nemanov L, Arbelle S, Feinsilver T, Fried I et al. Evidence for an association with the serotonin transporter promoter region polymorphism and autism Am J Med Genet 2001; 105: 381–386

    Article  CAS  Google Scholar 

  5. Maestrini E, Lai C, Marlow A, Matthews N, Wallace S, Bailey A et al. Serotonin transporter (5-HTT) and γ-aminobutyric acid receptor subunit γ3 (GABRB3) gene polymorphisms are not associated with autism in the IMGSA families Am J Med Genet 1999; 88: 492–496

    Article  CAS  Google Scholar 

  6. Persico AM, Militerni R, Bravaccio C, Schneider C, Melmed R, Conciatori M et al. Lack of association between serotonin transporter gene promoter variants and autistic disorder in two ethnically-distinct samples Am J Med Genet 2000; 96: 123–127

    Article  CAS  Google Scholar 

  7. Cook EH Jr, Leventhal B . The serotonin system in autism Curr Opin Pediat 1996; 8: 348–354

    Article  CAS  Google Scholar 

  8. Piven J, Tsai G, Nehme E, Coyle JT, Chase GA, Folstein SE . Platelet serotonin, a possible marker for familial autism J Autism DevDisord 1991; 21: 51–59

    Article  CAS  Google Scholar 

  9. Katsui T, Okuda M, Usuda S, Koizumi T . Kinetics of 3H-serotonin uptake by platelets in infantile autism and developmental language disorder (including five pairs of twins) J Autism Dev Disord 1986; 16: 69–76

    Article  CAS  Google Scholar 

  10. Marazziti D, Muratori F, Cesari A, Masala I, Baroni S, Giannaccini G et al. Increased density of the platelet serotonin transporter in autism Pharmacopsychiatry 2000; 33: 165–168

    Article  CAS  Google Scholar 

  11. Cook EH Jr, Leventhal BL, Freedman DX . Free serotonin in plasma: autistic children and their first-degree relatives Biol Psychiatry 1988; 24: 488–491

    Article  Google Scholar 

  12. 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

    Article  CAS  Google Scholar 

  13. Greenberg BD, Tolliver TJ, Huang S-J, Li Q, Bengel D, Murphy DL . Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets Am J Med Genet 1999; 88: 83–87

    Article  CAS  Google Scholar 

  14. Nobile M, Begni B, Giorda R, Frigerio A, Marino C, Molteni M et al. Effects of serotonin transporter promoter genotype on platelet serotonin transporter functionality in depressed children and adolescents J Am Acad Child Adolesc Psychiatry 1999; 38: 1396–1402

    Article  CAS  Google Scholar 

  15. Hérault J, Petit E, Martineau J, Cherpi C, Perrot A, Barthélémy C et al. Serotonin and autism: biochemical and molecular biology features Psychiatry Res 1996; 65: 33–43

    Article  Google Scholar 

  16. Yang Q, Rabinowitz D, Isasi C, Shea S . Adjusting for confounding due to population admixture when estimating the effect of candidate genes on quantitative traits Hum Hered 2000; 50: 227–233

    Article  CAS  Google Scholar 

  17. McBride PA, Anderson G, Hertzig ME, Snow ME, Thompson SM, Khait VD et al. Effects of diagnosis, race, and puberty on platelet serotonin levels in autism and mental retardation J Am Acad Child Adolesc Psychiatry 1998; 37: 767–776

    Article  CAS  Google Scholar 

  18. Leboyer M, Philippe A, Bouvard M, Guilloud-Bataille M, Bondoux D, Tabuteau F et al. Whole blood serotonin and plasma beta-endorphin in autistic probands and their first-degree relatives Biol Psychiatry 1999; 45: 158–163

    Article  CAS  Google Scholar 

  19. Persico AM, Militerni R, Bravaccio C, Schneider C, Melmed R, Trillo S et al. Adenosine deaminase (ADA) alleles and autistic disorder: case-control and family-based association studies Am J Med Genet 2000; 96: 784–790

    Article  CAS  Google Scholar 

  20. Chugani DC, Muzik O . γ[11C]methyl-L-tryptophan PET maps brain serotonin synthesis and kynurenine pathway metabolism J Cereb Blood Flow Metab 2000; 20: 2–9

    Article  CAS  Google Scholar 

  21. Croonenberghs J, Delmerie L, Verkerk R, Lin A-H, Meskal A, Neels H et al. Peripheral markers of serotoninergic and noradrenergic function in post-pubertal, caucasian males with autistic disorder Neuropsychopharmacology 2000; 22: 275–283

    Article  CAS  Google Scholar 

  22. Pedersen OS, Liu Y, Reichelt KL . Serotonin uptake stimulating peptide found in plasma of normal individuals and in some autistic urines J Peptide Res 1999; 53: 641–646

    Article  CAS  Google Scholar 

  23. Keller F, Persico AM, Baldi A, Reichelt K-L, Gonzalez A . Serotonin uptake-stimulating peptides extracted from the urines of autistic patients: potential significance for the pathogenesis of autistic disorder Soc Neurosci Abs 1998; 24: 227

    Google Scholar 

  24. Militerni R, Bravaccio C, Falco C, Puglisi-Allegra S, Pascucci T, Fico C . Pain reactivity in children with autistic disorder J Headache Pain 2000; 1: 53–56

    Article  Google Scholar 

  25. Ramamoorthy S, Blakely RD . Phosphorylation and sequestration of serotonin transporters differentially modulated by psychostimulants Science 1999; 285: 763–766

    Article  CAS  Google Scholar 

  26. Marazziti D, Rossi A, Masala I, Rotondo A, Palego L, Mazzoni M et al. Regulation of the platelet serotonin transporter by protein kinase C in the young and elderly Biol Psychiatry 1999; 45: 443–447

    Article  CAS  Google Scholar 

  27. Barman AL, Apparsundaram S, Ramamoorthy S, Wadsinski BE, Vaughan RA, Blakely RD . Cocaine and antidepressant-sensitive biogenic amine transporters exist in regulated complexes with protein phosphatase 2A J Neurosci 2000; 20: 7571–7578

    Article  Google Scholar 

  28. Persico AM, D'Agruma L, Maiorano N, Totaro A, Militerni R, Bravaccio C et al. Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder Mol Psychiatry 2001; 6: 150–159

    Article  CAS  Google Scholar 

  29. Spielman RS, Ewens WJ . The TDT and other family-based tests for linkage disequilibrium and association Am J Hum Genet 1996; 59: 983–989

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Terwilliger JD, Ott J . A haplotype-based ‘haplotype relative risk’ approach to detecting allelic associations Hum Hered 1992; 42: 337–346

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors are very grateful to the families who participated in this study. We also thank Rossella Ventura for collaborating on HPLC analyses. This work was funded by the European Community (Biomed-2 grant BMH4-CT96–0730), and by the Italian Ministry of Health (grant ICS.190.1.RF99/90), and by a grant from the National Alliance for Autism Research (NAAR).

Author information

Authors and Affiliations

  1. Laboratory of Neuroscience, Interdisciplinary Center for Biomedical Research (CIR), Università ‘Campus Bio-Medico’, Via Longoni 83, Rome, I-00155, Italy

    A M Persico, M Conciatori, R Marino & F Keller

  2. Department of Psychology, University ‘La Sapienza’, Rome, Italy

    T Pascucci & S Puglisi-Allegra

  3. IRCCS ‘Fondazione Santa Lucia’, Rome, Italy

    T Pascucci & S Puglisi-Allegra

  4. Department of Child Neuropsychiatry, II University of Naples, Naples, Italy

    R Militerni & C Bravaccio

  5. Southwest Autism Research Center, Phoenix, AZ, USA

    C Schneider & R Melmed

  6. Division of Child Neuropsychiatry, IRCCS ‘Ospedale Bambino-Gesù’, Rome, Italy

    S Trillo & F Montecchi

  7. Clinic for Autism and Developmental Disabilities, Università ‘Campus Bio-Medico’, Rome, Italy

    M Palermo

  8. Columbia University, New York, NY, USA

    D Rabinowitz

  9. Department of Pediatric Research, Rikshospitalet, University of Oslo, Norway

    K-L Reichelt

Authors
  1. A M Persico
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T Pascucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Puglisi-Allegra
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R Militerni
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C Bravaccio
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C Schneider
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R Melmed
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S Trillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. F Montecchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M Palermo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. D Rabinowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. K-L Reichelt
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. M Conciatori
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. R Marino
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. F Keller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to F Keller.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Persico, A., Pascucci, T., Puglisi-Allegra, S. et al. Serotonin transporter gene promoter variants do not explain the hyperserotoninemia in autistic children. Mol Psychiatry 7, 795–800 (2002). https://doi.org/10.1038/sj.mp.4001069

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001069

Keywords

This article is cited by

Search

Advanced search

Quick links