Studies on individuals and animals with genetic defects in serotonin function can shed light on the role of this neurotransmitter in behavior and on the role of milder functional variants in serotonin genes in predisposing individuals to psychopathologies and to alcoholism. We are identifying probands for family studies by measuring the serotonin metabolite 5-HIAA in cerebrospinal fluid and by identifying individuals with amino acid substitutions in genes involved with serotonin function. Two 5-HT1A variants are rare amino acid substitutions (Gly22Ser and Val28Ile), one conservative and one nonconservative. The 5-HT2C variant is a common (allele frequency=0.18) nonconservative substitution (Cys23Ser). Two 5HT2A amino acid substitutions (Ala477Val and His452Tyr) have allele frequencies of 0.01 and 0.09. Rare serotonin transporter and 5-HT7 amino acid substitutions were also discovered. Three of these amino acid substitutions were shown to alter the functional properties of the corresponding receptor. 5HT1A Gly22Ser when expressed in CHO-K1 cells dramatically altered desensitization and down regulation of these receptors. 5HT2C Cys23Ser in oocytes and COS-7 cells decreased ligand binding. 5HT2A His452Tyr impaired signal transduction in platelets from subjects with the 452Tyr allele. For association and direct gene analysis, we have collected more than 40 cell lines from each of the following populations: anorexia nervosa (collaboratively with W. Kaye), obsessive compulsive disorder (D. Murphy), low CSF 5-HIAA with Type II alcoholism (M. Linnoila, M. Virkkunen, M. Eggert), and seasonal affective disorder (N. Rosenthal, N. Ozaki). The detected polymorphisms are converted to PCR RFLPs or allele-specific amplification markers for ease of analysis. Using the CEPH reference pedigrees and the polymorphisms at these genes, each gene is genetically mapped to its chromosomal location. For direct gene analysis, we mainly use single-strand conformational polymorphism analysis and direct sequencing. Association of a TPH polymorphism with suicidality in impulsive alcoholic Finns was replicated. Sib-pair linkage of 5HT1B to antisocial alcoholism was found in Finns (J. Lappalainen) and replicated in Southwestern American Indians. The serotonin transporter promoter variant 5-HTTLPR which was previously linked to neuroticism was linked to the two anxiety related subscales of the TPQ in a sib pair analysis (C. Mazzanti), partially replicating an earlier finding. In a series of publications, we have shown that the 5HT2A-1438 G>A promoter variant is linked to anxiety related conditions. These include OCD, seasonal affective disorder, anorexia nervosa and anxiety-related scales from the Tridimensional Personality Questionnaire.
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