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Variants of the serotonin transporter gene (SLC6A4) significantly contribute to hyperserotonemia in autism

Abstract

The role of the serotonin system in the etiology and pathogenesis of autism spectrum disorders (ASD) is not clearly defined. High levels of platelet serotonin (5-HT) have been consistently found in a proportion of patients, and it is known that specific 5-HT transporter gene (SLC6A4) variants modulate transporter reuptake function, therefore possibly influencing the occurrence of hyperserotonemia in a subset of autistic patients. We have examined the association of platelet serotonin levels with two SLC6A4 polymorphisms, 5-HTT gene-linked polymorphic region (HTTLPR) in the promoter and intron 2 variable number of tandem repeats (VNTR), in a sample of 105 ASD patients, their parents, and 52 control children. Quantitative transmission disequilibrium test (QTDT) results showed a significant effect on 5-HT levels of each SLC6A4 marker (P=0.017 for HTTLPR; P=0.047 for intron 2 VNTR) and of haplotypes of the two markers (P=0.017), with a major contribution of the L.Stin2.10 haplotype (P=0.0013). A 5-HT mean value in the range of hyperserotonemia was associated with the homozygous L.Stin2.10 haplotype (H (1,N=97)=7.76, P=0.0054), which occurred in 33% of hyperserotonemic patients against 6% of patients with normal 5-HT levels (Fisher's exact test: P=0.013, OR=8). Allele interaction at the HTTLPR locus was found, with a significant dominance variance effect on 5-HT levels. We found no transmission disequilibrium of any of the SLC6A4 variants in ASD. Our results show that the SLC6A4 gene is a significant factor in the determination of 5-HT levels, and that specific SLC6A4 variants are associated with an increased risk for hyperserotonemia in our sample of autistic patients. The biological mechanism, however, is unlikely to involve the SLC6A4 gene solely. The associated SLC6A4 alleles likely interact with other genes or environmental factors to produce the abnormally high 5-HT levels observed in this subset of autistic patients, who possibly represent a separate etiological group.

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References

  1. Piven J . The biological basis of autism. Curr Opin Neurobiol 1997; 7: 708–712.

    Article  CAS  Google Scholar 

  2. Lamb JA, Moore J, Bailey A, Monaco AP . Autism: recent molecular genetic advances. Hum Mol Genet 2000; 9: 861–868.

    Article  CAS  Google Scholar 

  3. Folstein SE, Rosen-Sheidley B . Genetics of autism: complex aetiology for a heterogeneous disorder. Nat Rev Genet 2001; 2: 943–955.

    Article  CAS  Google Scholar 

  4. Newbury DF, Bonora E, Lamb JA, Fisher SE, Lai CSL, Baird G et al. FOXP2 is not a major susceptibility gene for autism or specific language impairment. Am J Hum Genet 2002; 70: 1318–1327.

    Article  CAS  Google Scholar 

  5. Buxbaum JD, Silverman JM, Smith CJ, Kilifarski M, Reichert J, Hollander E et al. Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity. Am J Hum Genet 2001; 68: 1514–1520.

    Article  CAS  Google Scholar 

  6. Shao Y, Raiford KL, Wolpert CM, Cope HA, Ravan SA, Ashley-Koch AA et al. Phenotypic homogeneity provides increased support for linkage on chromosome 2 in autistic disorder. Am J Hum Genet 2002; 70: 1058–1061.

    Article  CAS  Google Scholar 

  7. Abramson RK, Wright HH, Carpenter R, Brennan W, Lumpuy O, Cole E et al. Elevated blood serotonin in autistic probands and their first-degree relatives. J Autism Dev Disord 1989; 19: 397–407.

    Article  CAS  Google Scholar 

  8. Cook Jr EH, Leventhal BL, Heller W, Metz J, Wainwright M, Freedman DX . Autistic children and their first-degree relatives: relationships between serotonin and norepinephrine levels and intelligence. J Neuropsychiatry Clin Neurosci 1990; 2: 268–274.

    Article  Google Scholar 

  9. Leventhal BL, Cook Jr EH, Morford M, Ravitz A, Freedman DX . Relationships of whole blood serotonin and plasma norepinephrine within families. J Autism Dev Disord 1990; 20: 499–511.

    Article  CAS  Google Scholar 

  10. Piven J, Tsai G, Nehme E, Coyle JT . Platelet serotonin, a possible marker for familial autism. J Autism Dev Disord 1991; 1: 51–59.

    Article  Google Scholar 

  11. 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 

  12. Veenstra-VanderWeele J, Anderson GM, Cook Jr EH . Pharmacogenetics and the serotonin system: initial studies and future directions. Eur J Pharmacol 2000; 410: 165–181.

    Article  CAS  Google Scholar 

  13. Hariri AR, Mattay VS, Tessitore A, Kolachana B, Fera F, Goldman D et al. Serotonin transporter genetic variation and the response to human amygdala. Science 2002; 297: 400–403.

    Article  CAS  Google Scholar 

  14. Meltzer HY, Arora RC . Genetic control of serotonin uptake in blood platelets: a twin study. Psychiatry Res 1988; 24: 263–269.

    Article  CAS  Google Scholar 

  15. Lesch K-P, 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 

  16. 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 

  17. Cook Jr 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 

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

    Article  CAS  Google Scholar 

  19. 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 

  20. Kim S-J, Cox N, Courchesne R, Lord C, Corsello C, Akshoomoff N et al. Transmission disequilibrium mapping at the serotonin transporter gene (SLC6A4) region in autistic disorder. Mol Psychiatry 2002; 7: 278–288.

    Article  CAS  Google Scholar 

  21. Lesch K-P, Balling U, Gross J, Strauss K, Wolozin BL, Murphy DL et al. Organization of the human serotonin transporter gene. J Neural Transm Gen Sect 1994; 95: 157–162.

    Article  CAS  Google Scholar 

  22. Mackenzie A, Quinn J . A serotonin transporter gene intron 2 polymorphic region, correlated with affective disorders, has allele-dependent differential enhancer-like properties in the mouse embryo. Proc Natl Acad Sci USA 1999; 96: 15251–15255.

    Article  CAS  Google Scholar 

  23. Lesch K-P, Wolozin BL, Murphy DL, Riederer P . Primary structure of the human platelet serotonin uptake site: identity with the brain serotonin transporter. J Neurochem 1993; 60: 2319–2322.

    Article  CAS  Google Scholar 

  24. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, (4th edn). American Psychiatric Association Press: Washington, DC, 1994.

  25. Lord C, Rutter M, Couteur A . Autism Diagnostic Interview-Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord 1994; 24: 659–685.

    Article  CAS  Google Scholar 

  26. Schopler E, Reichler RJ, Renner BR . The Childhood Autism Rating Scale (CARS). Western Psychological Services: Los Angeles, 1988.

    Google Scholar 

  27. Griffiths R . The Abilities of Young Children. University of London Press: London, 1984.

    Google Scholar 

  28. Flachaire E, Beney C, Berthier A, Salandre J, Quincy C, Renaud B . Determination of reference values for serotonin concentration in platelets of healthy newborns, children, adults, and elderly subjects by HPLC with electrochemical detection. Clin Chem 1990; 36: 2117–2120.

    CAS  PubMed  Google Scholar 

  29. Lahiri DK, Nurnberger Jr JI . A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP analysis. Nucleic Acids Res 1991; 19: 5444.

    Article  CAS  Google Scholar 

  30. Abecasis GR, Cardon LR, Cookson WOC . A general test of association for quantitative traits in nuclear families. Am J Hum Genet 2000; 66: 279–292.

    Article  CAS  Google Scholar 

  31. Sham PC . The analysis of continuous and quasi-continuous characters. In: Everitt B (ed). Statistics in Human Genetics. Arnold Publishers: London, 1998, pp 187–267.

  32. Sham PC, Curtis D . An extended transmission/disequilibrium test (TDT) for multi-allelic marker loci. Ann Hum Genet 1995; 59: 323–336.

    Article  CAS  Google Scholar 

  33. Cook Jr EH, Arora RC, Anderson GM, Berry-Kravis EM, Yan S, Yeoh HC et al. Platelet serotonin studies in hyperserotonemic relatives of children with autistic disorder. Life Sci 1993; 52: 2005–2015.

    Article  Google Scholar 

  34. Maestrini E, Lai C, Marlow A, Matthews N, Wallace S, Bailey A et al. Serotonin transporter (5-HTT) and gamma-aminobutyric acid receptor subunit beta3 (GABRB3) gene polymorphisms are not associated with autism in the IMGSA families. Am J Med Genet 1999; 88: 492–496.

    Article  CAS  Google Scholar 

  35. 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 

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

    Article  CAS  Google Scholar 

  37. Betancur C, Corbex M, Spielewoy C, Philippe A, Laplanche J-L, Launay J-M et al. Serotonin transporter gene polymorphisms and hyperserotonemia in autistic disorder. Mol Psychiatry 2002; 7: 67–71.

    Article  CAS  Google Scholar 

  38. Persico AM, Pascucci T, Puglisi-Allegra S, Militerni R, Bravaccio C, Schneider C et al. Serotonin transporter gene promoter variants do not explain the hyperserotonemia in autistic children. Mol Psychiatry 2002; 7: 795–800.

    Article  CAS  Google Scholar 

  39. Anderson GM, Gutknecht L, Cohen DJ, Brailly-Tabard S, Cohen JHM, Ferrari P et al. Serotonin transporter promoter variants in autism: functional effects and relationship to platelet hyperserotonemia. Mol Psychiatry 2002; 7: 831–836.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  41. Ober C, Abney M, McPeek MS . The genetic dissection of complex traits in a founder population. Am J Hum Genet 2001; 69: 1068–1079.

    Article  CAS  Google Scholar 

  42. Abney M, McPeek MS, Ober C . Broad and narrow heritabilities of quantitative traits in a founder population. Am J Hum Genet 2001; 68: 1302–1307.

    Article  CAS  Google Scholar 

  43. Little KY, McLaughlin DP, Zhang L, Livermore CS, Dalack GW, Mc Finton PR et al. Cocaine, ethanol and genotype effects on human midbrain serotonin transporter binding sites and mRNA levels. Am J Psychiatry 1998; 155: 207–213.

    Article  CAS  Google Scholar 

  44. Comings DE, MacMurray JP . Molecular heterosis: a review. Mol Genet Metab 2000; 71: 19–31.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Gonçalo Abecasis for advice in statistical analysis and Luisa Mota-Vieira for critical reading of the manuscript. This work was supported by the Fundação Calouste Gulbenkian and by the Fundação para a Ciência e Tecnologia (POCTI/39636/ESP/2001).

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Correspondence to A M Vicente.

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Coutinho, A., Oliveira, G., Morgadinho, T. et al. Variants of the serotonin transporter gene (SLC6A4) significantly contribute to hyperserotonemia in autism. Mol Psychiatry 9, 264–271 (2004). https://doi.org/10.1038/sj.mp.4001409

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