Association Between the Tryptophan Hydroxylase Gene and Manic-depressive Illness

Bellivier, Frank; Leboyer, Marion; Courtet, Philippe; Burési, Catherine; Beaufils, B.; Samolyk, D; Allilaire, Jean‐François; Feingold, Josué; Mallet, Jacques; Malafosse, Alain

doi:10.1001/archpsyc.55.1.33

Cited by 188 publications

(127 citation statements)

References 38 publications

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“…Recent molecular genetic studies have emerged providing evidence of polymorphisms in the TPH gene associated with several types of mood disorders (Nielsen et al, 1994;Mann et al, 1997;New et al, 1997;Bellivier et al, 1998). For example, Nielsen and colleagues (1994) examined TPH genotype in impulsive and nonimpulsive violent offenders with a history of suicide attempts and alcohol abuse or dependence.…”

Section: Discussionmentioning

confidence: 99%

“…A subsequent study showed that the rarer U allele of the TPH genotype was associated with individuals with major depression who had attempted suicide (Mann et al, 1997). However, other studies have reported no association of TPH genotype or allele frequency with suicidal behavior (Abbar et al, 1995;Bellivier et al, 1998;Furlong et al, 1998). Given the evidence that alterations in the serotonergic system occur in depressed patients and in individuals commiting suicide, it is interesting that alterations in TPH gene expression may contribute to the diminished serotonin neurotransmission in depression and suicidal behavior.…”

Section: Discussionmentioning

confidence: 99%

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Regional Distribution and Cellular Expression of Tryptophan Hydroxylase Messenger RNA in Postmortem Human Brainstem and Pineal Gland

Austin

O’Donnell

1999

Journal of Neurochemistry

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Abstract:The characterization and cellular localization of tryptophan hydroxylase mRNA in the human brainstem and pineal gland were investigated by using northern blot analysis and in situ hybridization histochemistry. Northern analysis of human pineal gland revealed the presence of two mRNA species that were absent in RNA isolated from human raphe. In situ hybridization experiments revealed very dense hybridization signal corresponding to tryptophan hydroxylase mRNA in cells throughout the pineal gland. In contrast, tryptophan hydroxylase mRNA was heterogeneously distributed in neurons in the dorsal and median raphe nuclei. Within the dorsal raphe, the ventrolateral and interfascicular subnuclei contained the greatest number of tryptophan hydroxylase mRNA-positive neurons. Also, the cellular concentration of tryptophan hydroxylase mRNA varied widely within the dorsal and median raphe. Comparison of the cellular concentration of tryptophan hydroxylase mRNA between the pineal gland and the raphe nuclei revealed an 11 -and 46-fold greater average grain density of tryptophan hydroxylase mRNA positive cells in the pineal gland compared with the dorsal and median raphe, respectively. These findings are the first to demonstrate the cellular localization of tryptophan hydroxylase mRNA in the human brain and pineal gland as well as heterogeneity in the cellular concentration within and between these tissues.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Regional Distribution and Cellular Expression of Tryptophan Hydroxylase Messenger RNA in Postmortem Human Brainstem and Pineal Gland

Austin

O’Donnell

1999

Journal of Neurochemistry

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“…61 TPH catalyzes the oxygenation of tryptophan to 5-hydroxytryptophan, which is then decarboxylated to form 5-HT. 62 Walther et al 63 discovered a new brain-specific TPH isoform, called TPH2. Biochemical studies in mice 64 and humans 65 suggest that a TPH2 polymorphism results in decreased 5-HT synthesis.…”

Section: -Ht Transportermentioning

confidence: 99%

Serotonergic vulnerability and depression: assumptions, experimental evidence and implications

et al. 2006

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In recent years, the term serotonergic vulnerability (SV) has been used in scientific literature, but so far it has not been explicitly defined. This review article attempts to elucidate the SV concept. SV can be defined as increased sensitivity to natural or experimental alterations of the serotonergic (5-HTergic) system. Several factors that may disrupt the 5-HTergic system and hence contribute to SV are discussed, including genetic factors, female gender, personality characteristics, several types of stress and drug use. It is explained that SV can be demonstrated by means of manipulations of the 5-HTergic system, such as 5-HT challenges or acute tryptophan depletion (ATD). Results of 5-HT challenge studies and ATD studies are discussed in terms of their implications for the concept of SV. A model is proposed in which a combination of various factors that may compromise 5-HT functioning in one person can result in depression or other 5-HT-related pathology. By manipulating 5-HT levels, in particular with ATD, vulnerable subjects may be identified before pathology initiates, providing the opportunity to take preventive action. Although it is not likely that this model applies to all cases of depression, or is able to identify all vulnerable subjects, the strength of the model is that it may enable identification of vulnerable subjects before the 5-HT related pathology occurs. Molecular Psychiatry ( Keywords: serotonin; mood disorders; stress; genetics; sex; tryptophan Involvement of serotonin in depressionMood disorders are one of the most prevalent forms of mental illness. 1 According to the DSM-IV, the lifetime risk for major depressive disorder is between 10 and 25% for women and between 5 and 12% for men. 2 Depression has been studied intensively during the last few decades, but the psychological and neurobiological determinants of depression have not yet been precisely defined. Although several factors are known to contribute to the etiology of depression, it is not clear how these factors cause depression, and why some subjects become depressed while others remain unaffected. In terms of biological factors in the etiology of depression, there are several hypotheses. These include neurotransmitter dysfunctions (serotonin, 5-HT; dopamine, DA; norepinephrine, NE); dysregulations in hypothalamic-pituitary-adrenal (HPA) axis activity; and immune system imbalance. The aim of this article is not to discuss all of these hypotheses in detail, but to evaluate the role that serotonin may play within these hypothesized mechanisms.It is widely accepted that diminished serotonergic (5-HTergic) function is involved in the onset and course of depression. 3,4 The 5-HTergic system is a large and complex system. Although nearly all cell bodies of 5-HTergic neurons are located in the raphe nuclei in the brain stem, the axons of these neurons innervate almost the entire brain. The actions of 5-HT are mediated by 16 types and subtypes of receptors. 5 As the 5-HTergic system is assumed to be a modulatory system, the exact func...

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“…4 However, subsequent studies have concluded that there is an association between suicidal behavior and TPH gene polymorphism. 5,6,8,12 These recent studies used two genetic markers located in intron 7 of this gene. The first polymorphism used (A779C) was originally identified by single strand conformational analysis 13 and the two alleles, TPH 779A and TPH 779C, were referred to as U and L, respectively.…”

Section: Introductionmentioning

confidence: 99%

Suicide attempts and the tryptophan hydroxylase gene

et al. 2001

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Tryptophan hydroxylase (TPH) is the rate-limiting enzyme of serotonin synthesis. In this casecontrol study, we investigated whether the TPH gene was a susceptibility factor for suicidal behavior. Seven polymorphisms spanning the entire gene were studied in a case-control study including 231 individuals who had attempted suicide and 281 controls. Significant associations were found between variants in introns 7, 8 and 9 ( 2 = 11.2, df = 1, P Ͻ 0.0008 for the allele distribution; these loci are in complete linkage disequilibrium) and in the 3Ј noncoding region ( 2 = 30.94, P = 0.0014) and suicide attempt. The association was strongest for subjects who had attempted suicide by violent means and who had a history of major depression. No significant association was observed between suicide attempts and polymorphisms in the promoter, intron 1 and intron 3. The results presented here, and those of previous studies, suggest that a genetic variant of the 3Ј part of the TPH gene may be a susceptibility factor for a phenotype combining suicidal behavior, mood disorder and impulsive aggression. Molecular Psychiatry (2001) 6, 268-273.

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Association Between the Tryptophan Hydroxylase Gene and Manic-depressive Illness

Abstract: This result suggests the involvement of the TPH gene in susceptibility to manic-depressive illness. This preliminary result requires confirmation in further groups of patients and controls.

Cited by 188 publications

References 38 publications

Regional Distribution and Cellular Expression of Tryptophan Hydroxylase Messenger RNA in Postmortem Human Brainstem and Pineal Gland

Regional Distribution and Cellular Expression of Tryptophan Hydroxylase Messenger RNA in Postmortem Human Brainstem and Pineal Gland

Serotonergic vulnerability and depression: assumptions, experimental evidence and implications

Suicide attempts and the tryptophan hydroxylase gene

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