Molecular Genetic Studies of Disturbed Serotonin Function

Goldman, D.

Abstract

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 who have several behavioral disorders and by measuring the serotonin metabolite 5HIAA in cerebrospinal fluid. Probands and family members receive detailed neurologic and psychiatric assessment and familial transmission and comorbidity is concurrently assessed. Subjects with aberrant serotonin function and their families will be the focus for genetic linkage analyses using dispersed probes and direct studies (for example, sequencing) of candidate genes such as tryptophan hydroxylase (TPH). We are also studying animal behavioral genetic models in which serotonin function may be perturbed. A TPH polymorphism was found to be associated with low CSF 5HIAA and suicidality in impulsive alcoholic Finns. Coding sequence polymorphisms of 5HTIA, 5HTIDalpha and 5HTIDbeta were identified by SSCP analysis. In mice, TPH was identified as a quantitative trait locus (QTL) for sleep time following ethanol injection.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• Type: Intramural Research (Z01)
• Project #: 1Z01AA000290-04
• Application #: 3745247
• Support Year: 4
• Fiscal Year: 1994

Institution

• Name: National Institute on Alcohol Abuse and Alcoholism
• Country: United States

Publications

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

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

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

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