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:

The serotonin-2A receptor gene locus does not contain common polymorphism affecting mRNA levels in adult brain

Molecular Psychiatry volume 9, pages 109–114 (2004)Cite this article

Abstract

The serotonin-2A (HTR2A) receptor is a molecule of particular interest in biological psychiatry, as it is an important target for psychotropic drugs,1,2 and altered HTR2A expression has been found in several neuropsychiatric conditions, including depression3 and schizophrenia.4 Genetic association has been reported between a synonymous 102T/C polymorphism in the gene encoding HTR2A and a number of clinical phenotypes, including schizophrenia,5,6 clozapine response,7 psychotic symptoms in Alzheimer's disease8 and certain features of depression.9 Given that there are no known effects of the 102T/C polymorphism on the structure of the receptor, attention has switched to the possibility that the observations of both altered expression and genetic association point to functional sequence variants that alter expression of the HTR2A gene.10 Moreover, data have been presented recently suggesting that mRNAs containing the 102T- and C-alleles are differentially expressed.11 This suggests a direct effect of the variant itself on mRNA levels, or the influence of a distinct regulatory variant, such as the −1438A/G promoter polymorphism, with which it is in perfect linkage disequilibrium.12 The present study tested this hypothesis by employing a highly accurate quantitative allele- specific primer extension assay13 to measure the relative expression of brain mRNAs carrying each allele in 23 individuals heterozygous for the 102T/C polymorphism. Comparison between allele ratios derived from genomic DNA and mRNA from several cortical regions revealed that the 102C- and T-alleles are expressed identically. Furthermore, the absence of any interindividual variability in relative mRNA allele ratio suggests that the HTR2A locus is unlikely to contain common polymorphisms or epigenetic modification that alter HTR2A mRNA levels in adult brain, and essentially exclude such phenomena as a potential explanation for the altered expression and genetic associations that have been reported to date.

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

Similar content being viewed by others

References

  1. Meltzer HY . The role of serotonin in antipsychotic drug action. Neuropsychopharmacology 1999; 21: 106S–115S.

    Article  CAS  Google Scholar 

  2. Aghajanian GK, Marek GJ . Serotonin and hallucinogens. Neuropsychopharmacology 1999; 21: 16S–23S.

    Article  CAS  Google Scholar 

  3. Hrdina PD, Bakish D, Ravindran A, Chudzik J, Cavazzoni P, Lapierre YD . Platelet serotonergic indices in major depression: up-regulation of 5-HT2A receptors unchanged by antidepressant treatment. Psychiatry Res 1997; 66: 73–85.

    Article  CAS  Google Scholar 

  4. Burnet PW, Eastwood SL, Harrison PJ . 5-HT1A and 5-HT2A receptor mRNAs and binding site densities are differentially altered in schizophrenia. Neuropsychopharmacology 1996; 15: 442–455.

    Article  CAS  Google Scholar 

  5. Inayama Y, Yoneda H, Sakai T, Ishida T, Nonomura Y, Kono Y et al. Positive association between a DNA sequence variant in the serotonin 2A receptor gene and schizophrenia. Am J Med Genet 1996; 67: 103–105.

    Article  CAS  Google Scholar 

  6. Williams J, McGuffin P, Nothen M, Owen MJ . Meta-analysis of association between the 5-HT2a receptor T102C polymorphism and schizophrenia. EMASS Collaborative Group. European Multicentre Association Study of Schizophrenia. Lancet 1997; 349: 1221.

    Article  CAS  Google Scholar 

  7. Arranz MJ, Munro J, Sham P, Kirov G, Murray RM, Collier DA et al. Meta-analysis of studies on genetic variation in 5-HT2A receptors and clozapine response. Schizophr Res 1998; 32: 93–99.

    Article  CAS  Google Scholar 

  8. Holmes C, Arranz MJ, Powell JF, Collier DA, Lovestone S . 5-HT2A and 5-HT2C receptor polymorphisms and psychopathology in late onset Alzheimer's disease. Hum Mol Genet 1998; 7: 1507–1509.

    Article  CAS  Google Scholar 

  9. Arias B, Gutierrez B, Pintor L, Gasto C, Fananas L . Variability in the 5-HT(2A) receptor gene is associated with seasonal pattern in major depression. Mol Psychiatry 2001; 6: 239–242.

    Article  CAS  Google Scholar 

  10. O'Donovan MC, Owen MJ . Candidate-gene association studies of schizophrenia. Am J Hum Genet 1999; 65: 587–592.

    Article  CAS  Google Scholar 

  11. Polesskaya OO, Sokolov BP . Differential expression of the ‘C’ and ‘T’ alleles of the 5-HT2A receptor gene in the temporal cortex of normal individuals and schizophrenics. J Neurosci Res 2002; 67: 812–822.

    Article  CAS  Google Scholar 

  12. Spurlock G, Heils A, Holmans P, Williams J, D'Souza UM, Cardno A et al. A family based association study of T102C polymorphism in 5HT2A and schizophrenia plus identification of new polymorphisms in the promoter. Mol Psychiatry 1998; 3: 42–49.

    Article  CAS  Google Scholar 

  13. Norton N, Williams NM, Williams HJ, Spurlock G, Kirov G, Morris DW et al. Universal, robust, highly quantitative SNP allele frequency measurement in DNA pools. Hum Genet 2002;110: 471–478.

    Article  CAS  Google Scholar 

  14. Singer-Sam J, Chapman V, LeBon JM, Riggs AD . Parental imprinting studied by allele-specific primer extension after PCR: paternal X chromosome-linked genes are transcribed prior to preferential paternal X chromosome inactivation. Proc Natl Acad Sci USA 1992; 89: 10469–10473.

    Article  CAS  Google Scholar 

  15. Le Hellard S, Ballereau SJ, Visscher PM, Torrance HS, Pinson J, Morris SW et al. SNP genotyping on pooled DNAs: comparison of genotyping technologies and a semi automated method for data storage and analysis. Nucleic Acids Res 2002; 30: 74.

    Article  Google Scholar 

  16. Yan H, Yuan W, Velculescu VE, Vogelstein B, Kinzler KW . Allelic variation in human gene expression. Science 2002; 297: 1143.

    Article  CAS  Google Scholar 

  17. Bray NJ, Buckland PR, Owen MJ, O’Donovan MC . Cis-acting variation in the expression of a high proportion of genes in human brain. Hum Genet 2003; 113: 149–153.

    PubMed  Google Scholar 

  18. Hoogendoorn B, Norton N, Kirov G, Williams N, Hamshere ML, Spurlock G et al. Cheap, accurate and rapid allele frequency estimation of single nucleotide polymorphisms by primer extension and DHPLC in DNA pools. Hum Genet 2000; 107: 488–493.

    Article  CAS  Google Scholar 

  19. Breen G, Harold D, Ralston S, Shaw D, St Clair D . Determining SNP allele frequencies in DNA pools. Biotechniques 2000; 28: 464–466, 468, 470.

    Article  CAS  Google Scholar 

  20. Turecki G, Briere R, Dewar K, Antonetti T, Lesage AD, Segwin M et al. Prediction of level of serotonin 2A receptor binding by serotonin receptor 2A genetic variation in postmortem brain samples from subjects who did or did not commit suicide. Am J Psychiatry 1999; 156: 1456–1458.

    PubMed  CAS  Google Scholar 

  21. Kouzmenko AP, Hayes WL, Pereira AM, Dean B, Burnet PW, Harrison PJ . 5-HT2A receptor polymorphism and steady state receptor expression in schizophrenia. Lancet 1997; 349: 1815.

    Article  CAS  Google Scholar 

  22. Kouzmenko AP, Scaffidi A, Pereira AM, Hayes WL, Copolov DL, Dean B . No correlation between A(-1438)G polymorphism in 5-HT2A receptor gene promoter and the density of frontal cortical 5-HT2A receptors in schizophrenia. Hum Hered 1999; 49: 103–105.

    Article  CAS  Google Scholar 

  23. Kato MV, Shimizu T, Nagayoshi M, Kaneko A, Sasaki MS, Ikawa Y . Genomic imprinting of the human serotonin-receptor (HTR2) gene involved in development of retinoblastoma. Am J Hum Genet 1996; 59: 1084–1090.

    PubMed  PubMed Central  CAS  Google Scholar 

  24. Bunzel R, Blumcke I, Cichon S, Normann S, Schramm J et al. Polymorphic imprinting of the serotonin-2A (5-HT2A) receptor gene in human adult brain. Brain Res Mol Brain Res 1998; 59: 90–92.

    Article  CAS  Google Scholar 

  25. Enattah NS, Sahi T, Savilahti E, Terwilliger JD, Peltonen L, Jarvela I . Identification of a variant associated with adult-type hypolactasia. Nat Genet 2002; 30: 233–237.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to the Stanley Medical Research Institute (Bethesda, USA) and to the MRC London Neurodegenerative Diseases Brain Bank (UK) for donating brain tissue. This work was funded by the Medical Research Council (UK).

Author information

Authors and Affiliations

  1. Department of Psychological Medicine, University of Wales College of Medicine, Heath Park, Cardiff, UK

    N J Bray, P R Buckland, M J Owen & M C O'Donovan

  2. Department of Clinical Neuroscience, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden

    H Hall

Authors
  1. N J Bray
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P R Buckland
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H Hall
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M J Owen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M C O'Donovan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M C O'Donovan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bray, N., Buckland, P., Hall, H. et al. The serotonin-2A receptor gene locus does not contain common polymorphism affecting mRNA levels in adult brain. Mol Psychiatry 9, 109–114 (2004). https://doi.org/10.1038/sj.mp.4001366

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001366

Keywords

This article is cited by

Search

Advanced search

Quick links