HTR2C Cys23Ser polymorphism in relation to CSF monoamine metabolite concentrations and DSM-III-R psychiatric diagnoses

Background: Heritable variation in brain monoaminergic activity has been su ggested to lead to interindividual differences in vulnerability to alcoholi sm, and many other behavioral disorders. We evaluated if a functional Cys23 Ser polymorphism in the 5-HT2C receptor gene, the principal serotonin recep tor in the brain, contributes to variation in serotonin, norepinephrine and dopamine activity, as indexed by their major metabolite concentrations in cerebrospinal fluid (CSF). Genotype-monoamine metabolite concentration asso ciations were subsequently correlated to risk for alcoholism. Methods: The study sample consisted of unrelated Finnish males, including 2 14 alcoholic, violent offenders and 222 population controls who were interv iewed using the Structured Clinical Interview for DSM-III-R, blind rated fo r psychiatric diagnoses and typed for the HTR2C Cys23Ser polymorphism. CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA) the major metabolite of serotonin, 3-methoxy4-hydroxyphenylethyleneglycol (MHPG) the major metab olite of norepinephrine, and homovanillic acid (HVA), the major metabolite of dopamine were available from 195 individuals. Results: The major finding in this study was that HTR2C CysSer23 significan tly contributed to CSF MHPG concentrations (p = .012), Higher concentration s of CSF MHPG were observed both in alcoholic violent offenders and populat ion controls with HTR2C Ser23 genotype. Despite the association of Cys23Ser to CSF MHPG, HTR2C genotype was not associated with alcoholism, nor with o ther psychiatric disorders present in this sample. Conclusions: We conclude that a functional HTR2C Cys23Ser polymorphism cont ributes to the interindividual generic variation of CSF MHPG explaining 3% of the total variance. This finding suggests that 5-HT2C receptors are invo lved in the regulation of norepinephrine turnover in humans; however, HTR2C Cys23Ser does not appear to contribute to the risk of alcoholism, or its c ontribution to this complex and heterogenous disorder is too small to be de tected by a sample of this size and structure. (C) 1999 Society of Biologic al Psychiatry.