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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Intramural Research (Z01)
Project #
1Z01AA000290-10
Application #
6431380
Study Section
(LNG)
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2000
Total Cost
Indirect Cost
Name
Alcohol Abuse and Alcoholism
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Oquendo, Maria A; Hastings, Ramin S; Huang, Yung-Yu et al. (2007) Brain serotonin transporter binding in depressed patients with bipolar disorder using positron emission tomography. Arch Gen Psychiatry 64:201-8
Finger, Elizabeth C; Marsh, Abigail A; Buzas, Beata et al. (2007) The impact of tryptophan depletion and 5-HTTLPR genotype on passive avoidance and response reversal instrumental learning tasks. Neuropsychopharmacology 32:206-15
Parsey, Ramin V; Hastings, Ramin S; Oquendo, Maria A et al. (2006) Effect of a triallelic functional polymorphism of the serotonin-transporter-linked promoter region on expression of serotonin transporter in the human brain. Am J Psychiatry 163:48-51
Zalsman, Gil; Huang, Yung-Yu; Oquendo, Maria A et al. (2006) Association of a triallelic serotonin transporter gene promoter region (5-HTTLPR) polymorphism with stressful life events and severity of depression. Am J Psychiatry 163:1588-93
Hu, Xian-Zhang; Lipsky, Robert H; Zhu, Guanshan et al. (2006) Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. Am J Hum Genet 78:815-26
Neumeister, Alexander; Hu, Xian-Zhang; Luckenbaugh, David A et al. (2006) Differential effects of 5-HTTLPR genotypes on the behavioral and neural responses to tryptophan depletion in patients with major depression and controls. Arch Gen Psychiatry 63:978-86
Hasler, G; Pine, D S; Kleinbaum, D G et al. (2005) Depressive symptoms during childhood and adult obesity: the Zurich Cohort Study. Mol Psychiatry 10:842-50
Hu, Xianzhang; Oroszi, Gabor; Chun, Jeffrey et al. (2005) An expanded evaluation of the relationship of four alleles to the level of response to alcohol and the alcoholism risk. Alcohol Clin Exp Res 29:8-16
Zhou, Zhifeng; Peters, Eric J; Hamilton, Steven P et al. (2005) Response to Zhang et al. (2005): loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 45, 11-16. Neuron 48:702-3; author reply 705-6
Zhou, Zhifeng; Roy, Alec; Lipsky, Robert et al. (2005) Haplotype-based linkage of tryptophan hydroxylase 2 to suicide attempt, major depression, and cerebrospinal fluid 5-hydroxyindoleacetic acid in 4 populations. Arch Gen Psychiatry 62:1109-18

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