No association between a TPH2 promoter polymorphism and mood disorders or monoamine turnover

Mann, J. John; Currier, Dianne; Murphy, Lauren; Huang, Yan-You; Galfalvy, Hanga; Brent, David A.; Greenhill, Laurence L.; Oquendo, María A.

doi:10.1016/j.jad.2007.05.031

Cited by 41 publications

(16 citation statements)

References 23 publications

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“…Furthermore, we could not demonstrate any association between haplotype variants of the TPH2 gene and BSI depression, BSI anxiety, BFI neuroticism, or IVE impulsiveness scores. This is in agreement with recent studies which failed to find any association between the TPH2 gene and depression/suicidal behavior (Mann et al, 2008;Must et al, 2007;Zill et al, 2007b;De Luca et al, 2006;Lopez et al, 2007b), but in contrast to earlier findings reporting such an involvement (Zill et al, 2004a, b;Zhou et al, 2005;Van Den Bogaert et al, 2006;Haghighi et al, 2008;Lopez et al, 2007a;Ke et al, 2006). Therefore, the interpretation we favor is that the variations in the TPH2 gene might be linked to an endophenotype influencing risktaking behavior that could be an additive or in some cases a vulnerability factor, for psychiatric disorders, for example, affective disorders or disturbed mood in impulse control or substance misuse disorders.…”

Section: Discussionsupporting

confidence: 94%

Risk-Taking Behavior in a Gambling Task Associated with Variations in the Tryptophan Hydroxylase 2 Gene: Relevance to Psychiatric Disorders

Juhász

Downey

Hinvest

et al. 2009

Neuropsychopharmacol

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Decision making, choosing the best option from the possible outcomes, is impaired in many psychiatric conditions including affective disorders. We tested the hypothesis that variations in serotonergic genes (TPH2, TPH1, SLC6A4, HTR1A), which influence serotonin availability, affect choice behavior in a probabilistic gambling task. A population cohort (N ¼ 1035) completed a paper-and-pencil gambling task, filled out personality and symptom questionnaires and gave consent for the use of their DNA in a genetic association study. A subgroup of subjects (N ¼ 69) also completed a computer version of the task. The gambling task was designed to estimate an individual's tendency to take a risk when choosing between a smaller but more certain 'win' and a larger, less probable one. We genotyped seven haplotype tagging SNPs in the TPH2 gene, and previously reported functional polymorphisms from the other genes (rs1800532, 5HTTLPR, and rs6295). Carriers of the more prevalent TPH2 haplotype, which was previously associated with less active enzyme variant, showed reduced risk taking on both tasks compared with subjects not carrying the common haplotype. The effect of TPH2 haplotypes on risk-taking was independent of current depression and anxiety symptoms, neuroticism and impulsiveness scores. We did not find an association between functional polymorphisms in the TPH1, SLC6A4, HTR1A genes and risk-taking behavior. In conclusion, our study demonstrates the role of the TPH2 gene and the serotonin system in risk taking and suggests that TPH2 gene may contribute to the expression of psychiatric phenotypes through altered decision making.

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Section: Discussionsupporting

confidence: 94%

Risk-Taking Behavior in a Gambling Task Associated with Variations in the Tryptophan Hydroxylase 2 Gene: Relevance to Psychiatric Disorders

Juhász

Downey

Hinvest

et al. 2009

Neuropsychopharmacol

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“…Although earlier studies reported significant associations between several TPH2 SNPs and both depression and suicidal behavior (Haghighi et al, 2008;Ke et al, 2006;Lopez de Lara et al, 2007;Van Den Bogaert et al, 2006;Zhou et al, 2005;Zill et al, 2004a, b) more recent studies failed to confirm these findings (De Luca et al, 2006;Mann et al, 2008;Zill et al, 2007). Among functionally characterized TPH2 polymorphisms only a few (including G1463A) result in a clear reduction in enzymatic activity, whereas other polymorphisms have only a minor effect on TPH2 activity (McKinney et al, 2009).…”

Section: Human Tph2 Polymorphismsmentioning

confidence: 99%

“…Since the discovery of the tryptophan hydroxylase 2 (TPH2) isoenzyme (Walther et al, 2003)Fthe rate-limiting enzyme of 5-HT synthesis in the brainFTPH2 polymorphisms in humans have been associated with anxiety traits, depressive disorders, and suicidality (Gutknecht et al, 2007;Reuter et al, 2007;Van Den Bogaert et al, 2006;Zhang et al, 2005;Zill et al, 2004a, b) yet these results have not been supported by other studies (De Luca et al, 2006;Garriock et al, 2005;Juhasz et al, 2010;Mann et al, 2008;Middeldorp et al, 2010). These discrepancies might be partially attributed to the fact that different SNPs in the TPH2 gene were analyzed.…”

Section: Introductionmentioning

confidence: 99%

A Functional Tph2 C1473G Polymorphism Causes an Anxiety Phenotype via Compensatory Changes in the Serotonergic System

Berger

Weber

Perreau-Lenz

et al. 2012

Neuropsychopharmacol

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The association of single-nucleotide polymorphisms (SNPs) in the human tryptophan hydroxylase 2 (TPH2) gene with anxiety traits and depression has been inconclusive. Observed inconsistencies might result from the fact that TPH2 polymorphisms have been studied in a genetically heterogeneous human population. A defined genetic background, control over environmental factors, and the ability to analyze the molecular and neurochemical consequences of introduced genetic alterations constitute major advantages of investigating SNPs in inbred laboratory mouse strains. To investigate the behavioral and neurochemical consequences of a functional C1473G SNP in the mouse Tph2 gene, we generated congenic C57BL/6N mice homozygous for the Tph2 1473G allele. The Arg 447 substitution in the TPH2 enzyme resulted in a significant reduction of the brain serotonin (5-HT) in vivo synthesis rate. Despite decreased 5-HT synthesis, we could detect neither a reduction of brain region-specific 5-HT concentrations nor changes in baseline and stress-induced 5-HT release using a microdialysis approach. However, using a [ 35 S]GTP-g-S binding assay and 5-HT 1A receptor autoradiography, a functional desensitization of 5-HT 1A autoreceptors could be identified. Furthermore, behavioral analysis revealed a distinct anxiety phenotype in homozygous Tph2 1473G mice, which could be reversed with chronic escitalopram treatment. Alterations in depressive-like behavior could not be detected under baseline conditions or after chronic mild stress. These findings provide evidence for an involvement of functional Tph2 polymorphisms in anxiety-related behaviors, which are likely not caused directly by alterations in 5-HT content or release but are rather due to compensatory changes during development involving functional desensitization of 5-HT 1A autoreceptors.

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“…[104][105][106] There are almost no reports of functional consequences of TPH2 gene variation. One recent study in healthy volunteers found evidence of a frequent functional cis-acting polymorphism in the TPH2 gene that affected mRNA expression.…”

Section: Tph Genes and Suicidal Behaviormentioning

confidence: 99%

Stress, Genes and the Biology of Suicidal Behavior

Currier

Mann

2008

Psychiatric Clinics of North America

Self Cite

131

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Suicidal behavior is in part heritable. Studies seeking the responsible candidate genes have examined genes involved in neurotransmitter systems demonstrated to have altered function in suicide and attempted suicide. These neurotransmitter systems include the serotonergic, noradrenergic and dopaminergic systems and the HPA axis. With some exceptions, most notably the serotonin transporter promotor HTTLPR polymorphism, replication of candidate gene association studies findings has proven difficult. This chapter reviews what is known of specific gene effects and geneenvironment interactions that influence risk for suicidal behavior. Effects of childhood stress on development and how that influences adult responses to current stress will be shown to be relevant for mood disorders, aggressive/impulsive traits and suicidal behavior. KeywordsSuicide; Mood Disorders; Genetics; Stress; Serotonin; HPA axis Suicidal Behavior and GeneticsFamily, twin, and adoption studies provide evidence of the heritability of suicide and attempted suicide, in part independent of the familial transmission of major psychiatric disorders (see Brent & Mann for a review 1 ). From twin studies, based on case and register studies, estimates of heritability for suicide range between 21-50%, and 30-55% for a broader phenotype of suicidal behavior (attempts, thoughts, plans) based on general population studies. 2 Identifying the relevant genes and the neurobiological pathways through which they contribute to the etiology of suicidal behavior is important for designing and implementing preventative strategies. The first wave of genetic studies sought to identify genes involved in suicide and/ or attempted suicide by linkage studies or specific single nucleotide polymorphisms (SNPs) in association studies. Emerging approaches aim to investigate functional genomics using microarray technologies to profile expression of thousands of genes simultaneously (see Mirnics et al 3 for a review) or doing a genome wide array for hundreds of thousands of SNPs.Candidate genes for association studies have been generally selected based on evidence from neurobiological studies in suicide. Consequently, the serotonergic system has been most extensively investigated, with other target systems including the dopaminergic and

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No association between a TPH2 promoter polymorphism and mood disorders or monoamine turnover

Cited by 41 publications

References 23 publications

Risk-Taking Behavior in a Gambling Task Associated with Variations in the Tryptophan Hydroxylase 2 Gene: Relevance to Psychiatric Disorders

Risk-Taking Behavior in a Gambling Task Associated with Variations in the Tryptophan Hydroxylase 2 Gene: Relevance to Psychiatric Disorders

A Functional Tph2 C1473G Polymorphism Causes an Anxiety Phenotype via Compensatory Changes in the Serotonergic System

Stress, Genes and the Biology of Suicidal Behavior

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