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


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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  1. Maes M, Meltzer HY . The serotonin hypothesis of major depression. In: Bloom FE, Kupfer DE (eds) Psychopharmacology: The Fourth Generation of Progress Raven Press: New York 1995 pp?933–944

    Google Scholar 

  2. Newman ME, Lerer B, Shapira B . 5-HT-1a receptor mediated effects of antidepressants Prog Neuropsychopharmacol Biol Psychiatry 1993 17: 1–19

    Article  CAS  Google Scholar 

  3. Price LH, Charney DS, Delgado PL, Heninger GR . Lithium and serotonergic function: implications for the serotonergic hypothesis of depression Psychopharmacology 1990 100: 3–12

    Article  CAS  Google Scholar 

  4. Barnes NM, Sharp T . A review of central 5-HT receptors and their function Neuropharmacology 1999 38: 1083–1152

    Article  CAS  Google Scholar 

  5. Lappalainen J, Zhang L, Dean M, Oz M, Ozaki N, Yu D-H et al. Identification, expression, and pharmacology of a Cys23-Ser23 substitution in the human 5-HT2C receptor gene (HTR2C) Genomics 1995 27: 174–279

    Article  Google Scholar 

  6. Segman RH, Lerer B . Genetic factors in the etiology of bipolar disorder. In: Soares J, Gershon S (eds). Bipolar Disorders: Basic Mechanisms and Therapeutic Implications Marcel Dekker: New York 2000

    Google Scholar 

  7. Tsuang MT, Faraone SSV . The Genetics of Mood Disorders Johns Hopkins University Press: Baltimore 1990

    Google Scholar 

  8. Souery D, Lipp O, Mahieu B, Serretti A, Cavallini C, Ackenheil M et al. European collaborative project on affective disorders: interactions between genetic and psychosocial vulnerability factors Psychiatr Genet 1998 8: 197–205

    Article  CAS  Google Scholar 

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

    Google Scholar 

  10. Oruc L, Verheyen GR, Furac I, Jakovljevic M, Ivezic S, Raeymaekers P et al. Association analysis of the 5-HT2C receptor and 5-HT transporter genes in bipolar disorder Am J Med Genetics (Neuropsychiat Genet) 1997 74: 504–506

    Article  CAS  Google Scholar 

  11. Gutierrez B, Fananas L, Arranz MJ, Valles V, Guillamat R, van Os J et al. Allelic association analysis of the 5-HT2C receptor gene in bipolar affective disorder Neurosci Lett 1996 212: 65–67

    Article  CAS  Google Scholar 

  12. Frisch A, Postilnick D, Rockah R, Michaelovsky E, Postilnick S, Birman E et al. Association of unipolar major depressive disorder with genes of the serotonergic and dopaminergic pathways Mol Psychiatry 1999 4: 389–392

    Article  CAS  Google Scholar 

  13. Vincent JB, Masellis M, Lawrence J, Choi V, Gurling H, Phil M et al. Genetic association analysis of serotonin system genes in bipolar affective disorder Am J Psychiatry 1999 156: 136–138

    Article  CAS  Google Scholar 

  14. Malhotra AK, Goldman D . Benefits and pitfalls encountered in psychiatric genetic association studies Biol Psychiatry 1999 45: 544–550

    Article  CAS  Google Scholar 

  15. Jorm AF, Easteal S . Assessing candidate genes as risk factors for mental disorders: the value of population-based epidemiological studies Soc Psychiatry Psychiatr Epidemiol 2000 35: 1–4

    Article  CAS  Google Scholar 

  16. Hamer D, Sirota L . Beware the chopsticks gene Mol Psychiatry 2000 5: 11–13

    Article  CAS  Google Scholar 

  17. Wacholder S, Silverman DT, McLaughlin JK, Mandel JS . Selection of controls in case-control studies. II. Types of controls Am J Epidemiol 1992 135: 1029–1041

    Article  CAS  Google Scholar 

  18. Risch NJ . Searching for genetic determinants in the new millenium Nature 2000 405: 847–856

    Article  CAS  Google Scholar 

  19. Devlin B, Roeder K . Genomic control for association studies Biometrics 1999 55: 997–1004

    Article  CAS  Google Scholar 

  20. Prazos A, Probst A, Palacios JM . Serotonin receptors in the human brain. III. Autoradiographic mapping of serotonin-1 receptors Neuroscience 1987 21: 97–122

    Article  Google Scholar 

  21. Marazziti D, Rossi A, Giannaccini G, Zavaglia KM, Dell'Osso L, Lucacchini A et al. Distribution and characterization of [3H]mesulergine binding in human brain postmortem Eur Neuropsychopharmacol 1999 10: 21–26

    Article  CAS  Google Scholar 

  22. Tecott LH, Sun LM, Akana SF, Strack AM, Lowenstein DH, Dallman MF et al. Eating disorder and epilepsy in mice lacking 5-HT2C serotonin receptors Nature 1995 374: 542–546

    Article  CAS  Google Scholar 

  23. Brennan TJ, Seeley WW, Kilgard M, Schreiner CE, Tecott LH . Sound-induced seizures in serotonin 5-HT2C receptor mutant mice Nature Genet 1997 16: 387–390

    Article  CAS  Google Scholar 

  24. Lerer B, Moore N, Meyendorff E, Cho SR, Gershon S . Carbamazepine versus lithium in mania: a double blind study J Clin Psychiatry 1987 48: 89–93

    PubMed  CAS  Google Scholar 

  25. Bowden CL . New concepts in mood stabilization: evidence for the effectiveness of valproate and lamotrigine Neuropsychopharmacology 1998 19: 194–199

    Article  CAS  Google Scholar 

  26. Pigott TA, Zohar J, Hill JL, Bernstein EB, Grover GN, Zohar-Kadouch R et al. Metergoline blocks the behavioral and neuroendocrine effects of orally administered m-chlorophenlypiperazine in patients with obesessive-compulsive disorder Biol Psychiatry 1991 29: 418–426

    Article  CAS  Google Scholar 

  27. Newman ME, Shapira B, Lerer B . Evaluation of central serotonergic function in affective and related disorders by the fenfluramine challenge test: a critical review Int J Neuropsychopharmacol 1998 1: 49–70

    Article  CAS  Google Scholar 

  28. Coccaro EF, Kavoussi RJ, Oakes M, Cooper TB, Hauger R . 5-HT-2a/2c receptor blockade by amesergide fully attenuates prolactin response to d-fenfluramine challenge in physically healthy human subjects Psychopharmacology 1996 126: 24–30

    Article  CAS  Google Scholar 

  29. Quested DJ, Whale R, Sharpley AL, McGavin CL, Crossland N, Harrison PJ et al. Allelic variation in the 5-HT2C receptor and functional response to the 5-HT2c receptor antagonist mCPP Psychopharmacol (Berl) 1999 144: 306–307

    Article  CAS  Google Scholar 

  30. Xie E, Zhu L, Zhao L, Chang LS . The human serotonin 5-HT2C receptor: complete cDNA, genomic structure, and alternatively spliced variants Genomics 1996 35: 551–561

    Article  CAS  Google Scholar 

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

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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).

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  • bipolar disorder
  • major depression
  • unipolar disorder
  • affective disorder
  • 5-HT2C receptor gene
  • HT2CR
  • genetic polymorphism
  • genetic association
  • population genetics

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