Genetic architecture of the human tryptophan hydroxylase 2 Gene: existence of neural isoforms and relevance for major depression

Haghighi, Fatemah; Bach-Mizrachi, Helene; Huang, Yan-You; Arango, Victoria; Shi, Shundi; Dwork, Andrew J.; Rosoklija, Gorazd; Sheng, Huitao; Morozova, Irina; Ju, Jingyue; Russo, James J.; Mann, J. John

doi:10.1038/sj.mp.4002127

Cited by 79 publications

(56 citation statements)

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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: Discussioncontrasting

confidence: 56%

“…However, we could not exclude that these genes modulate other aspects of decision making that were not measured by our task, such as punishment-or feedback-related processing, as previous studies reported (Jollant et al, 2007;Must et al, 2007;Blair et al, 2008;Homberg et al, 2008). Accumulating evidence suggest that the more common allele/haplotype variants in the TPH2 gene are associated with lower cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations (Zhou et al, 2005) and with decreased TPH2 mRNA expression Haghighi et al, 2008;Lim et al, 2007). Thus, a considerable proportion of the population, who carry the wild-type (most ancient) variation of the TPH2 gene, express TPH2 at low level that results in decreased serotonin availability at the raphe nucleus and its projections, and also show risk aversion on the basis of our results.…”

Section: Discussionmentioning

confidence: 95%

“…Variations in the TPH2 gene have been repeatedly implicated in major depression disorder (MDD), and in suicidal behavior in MDD patients (Zill et al, 2004a, b;Zhang et al, 2005;Zhou et al, 2005;Lopez et al, 2007a;Haghighi et al, 2008). To cover this gene, we used haplotype tagging SNPs (htSNPs) similar to the previous studies.…”

Section: Introductionmentioning

confidence: 99%

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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: Discussioncontrasting

confidence: 56%

Section: Discussionmentioning

confidence: 95%

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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: 53%

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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“…Maternal psychopathology appears therefore to be related to actual child psychopathology by means of genetic transmission, social learning processes, lack of maternal sensitivity, insecure attachment patterns, or inadequate or inconsistent parenting behaviour [31,44,49,52,65]. Higher maternal ratings may therefore also reflect a truly higher level of mental health symptoms in their children.…”

Section: Introductionmentioning

confidence: 99%

The influence of maternal psychopathology on ratings of child psychiatric symptoms: an SEM analysis on cross-informant agreement

Müller

Achtergarde

Fürniss

2011

Eur Child Adolesc Psychiatry

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The distorting influence of maternal depression on the ratings of child behaviour is known as the depression-distortion hypothesis. This study investigated the depression-distortion hypothesis in a clinical sample of child psychiatric preschool children and extended the depression-distortion-hypothesis to maternal psychopathology-distortion-hypothesis in general. Subjects were 124 children, who were referred for treatment in a Child Psychiatric Family Day Hospital for preschool children, and their parents. Children were rated on the CBCL/1.5-5 and the C-TRF/1.5-5 by their mothers, kindergarten teachers and therapists.

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Genetic architecture of the human tryptophan hydroxylase 2 Gene: existence of neural isoforms and relevance for major depression

Cited by 79 publications

References 36 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

The influence of maternal psychopathology on ratings of child psychiatric symptoms: an SEM analysis on cross-informant agreement

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