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Variability of 5-HT2C receptor cys23ser polymorphism among European populations and vulnerability to affective disorder

Molecular Psychiatry volume 6, pages 579–585 (2001)Cite this article

Abstract

Substantial evidence supports a role for dysfunction of brain serotonergic (5-HT) systems in the pathogenesis of major affective disorder, both unipolar (recurrent major depression) and bipolar.1 Modification of serotonergic neurotransmission is pivotally implicated in the mechanism of action of antidepressant drugs2 and also in the action of mood stabilizing agents, particularly lithium carbonate.3 Accordingly, genes that code for the multiple subtypes of serotonin receptors that have been cloned and are expressed in brain,4 are strong candidates for a role in the genetic etiology of affective illness. We examined a structural variant of the serotonin 2C (5-HT2C) receptor gene (HTR2C) that gives rise to a cysteine to serine substitution in the N terminal extracellular domain of the receptor protein (cys23ser),5 in 513 patients with recurrent major depression (MDD-R), 649 patients with bipolar (BP) affective disorder and 901 normal controls. The subjects were drawn from nine European countries participating in the European Collaborative Project on Affective Disorders. There was significant variation in the frequency of the HT2CR ser23 allele among the 10 population groups included in the sample (from 24.6% in Greek control subjects to 9.2% in Scots, χ2?=?20.9, df 9, P?=?0.01). Logistic regression analysis demonstrated that over and above this inter-population variability, there was a significant excess of HT2CR ser23 allele carriers in patients compared to normal controls that was demonstrable for both the MDD (χ2?=?7.34, df 1, P?=?0.006) and BP (χ2?=?5.45, df 1, P?=?0.02) patients. These findings support a possible role for genetically based structural variation in 5-HT2C receptors in the pathogenesis of major affective disorder.

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Acknowledgements

This project was supported by the European Community Biomed 2 Grant (No. BMH4-97-2307).

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Authors and Affiliations

  1. Biological Psychiatry Laboratory, Hadassah Medical Organization, Jerusalem, Israel

    B Lerer & R H Segman

  2. Clarke Division, Unit of Biostatistics and Genetic Epidemiology, Neurogenetics Section, CAMH, Toronto, Canada

    F Macciardi

  3. University of Umea, Dept of Psychiatry, Sweden

    R Adolfsson

  4. University Department of Psychiatry and MRC Human Genetic Unit, Edinburgh, UK

    D Blackwood & W Muir

  5. Dept of Psychiatry, University Clinics of Brussels, Erasme Hospital, Free University of Brussels, Belgium

    S Blairy, I Massat, D Souery & J Mendlewicz

  6. Department of Biochemistry, Neurogenetics Laboratory, Flanders Interuniversity Institute for Biotechnology (VIB), Born-Bunge Foundation (BBS), University of Antwerpen (UIA), Antwerp, Belgium

    J Del Favero, S Van Gestel & C Van Broeckhoven

  7. Department of Psychiatry and University Mental Health Research Institute, Athens University Medical School, Athens, Greece

    D G Dikeos & G N Papadimitriou

  8. Laboratory of Molecular Pathology, Maternity University Hospital of Obstetrics, Medical University, Sofia, Bulgaria

    R Kaneva, V Milanova & T Petrova

  9. Department of Neuropsychiatric Sciences, Instituto Scientifico Ospedale San Raffaele, University of Milan School of Medicine, Milan, Italy

    R Lilli & A Serretti

  10. Institute of Human Genetics, University of Bonn, Germany

    M Noethen & M Rietschel

  11. Department of Psychiatry, University Hospital ‘Rebro’, University of Zagreb, Zagreb, Croatia

    L Oruc

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  1. B Lerer
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  12. V Milanova
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  20. D Souery
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Correspondence to B Lerer.

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Lerer, B., Macciardi, F., Segman, R. et al. Variability of 5-HT2C receptor cys23ser polymorphism among European populations and vulnerability to affective disorder. Mol Psychiatry 6, 579–585 (2001). https://doi.org/10.1038/sj.mp.4000883

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