Aggression and anger-related traits associated with a polymorphism of the tryptophan hydroxylase gene

Manuck, Stephen B.; Flory, Janine D.; Ferrell, Robert E.; Dent, Karin M.; Mann, J. John; Muldoon, Matthew F.

doi:10.1016/s0006-3223(98)00375-8

Cited by 255 publications

(170 citation statements)

References 51 publications

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“…The study of sex differences in the causes of personality traits that increase the risk to CHD might be relevant and informative, as the risk to suffer coronary problems is larger in males than in females (Dolan et al, 1992). A lower heritability in females is consistent with previous studies on genetic markers where serotonin gene polymorphisms have been found to be related with anger on males, but not in females (Manuck et al, 1999). These results could imply different prevention and therapeutic programs for males and females, with the former more focused on biological genetic related sources of variance, and the former more directed to environmental factors e.g.…”

Section: Discussionsupporting

confidence: 80%

Genetic Analysis of Anger: Genetic Dominance or Competitive Sibling Interaction

Rebollo

Boomsma

2006

Behav Genet

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The knowledge of the causes and development of anger is still scarce. Previous studies on the sources of variance on Type A Behavior Pattern (TABP) related measures found variable heritability estimates ranging from 0.12 to 0.68, and large differences between MZ and DZ correlations. Some authors considered dominance genetic effects, competitive sibling interaction and sex differences as possible mechanisms to explain the results, but most studies lacked power. The present study uses a large sample of more than 2500 families, with longitudinal data from MZ and DZ pairs as well as their parents, to disentangle the sources of variance on anger. Model Fitting results showed that the sources of variance differ across sexes. For males 23% of the variance is due to additive genetic effects, and 26% to dominance genetic effects. For females 34% of the variance is due to additive genetic effects, and no dominance effects are found. There was no consistent evidence to confirm the presence of competitive sibling interaction as an alternative explanation for the low correlations in DZ males. The focus of research on the prediction of coronary heart disease (CHD) risk through psychological characteristics has recently changed from the multidimensional TABP to its emotional component: Anger. Understanding the sources of individual differences on anger can help to clarify the mechanisms that link it with CHD and its possible implications for treatment and prevention.

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Section: Discussionsupporting

confidence: 80%

Genetic Analysis of Anger: Genetic Dominance or Competitive Sibling Interaction

Rebollo

Boomsma

2006

Behav Genet

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“…8 Second, two recent studies have suggested that there is a correlation between low central serotonergic activity, and the 218A allele. Jö nsson et al 24 found that men with UU (218A/218A) and UL (218A/218C) genotypes have lower levels of CSF 5-HIAA, and more recently Manuck et al 25 reported that in men with a U allele, the peak prolactin response to fenfluramine was attenuated. As low central serotonergic activity is a known factor for susceptibility to violent suicide attempt, 10 these findings are consistent with our own.…”

Section: Commentmentioning

confidence: 99%

“…Our data support the notion that TPH is mainly associated with the combination of both a history of MDD and violent suicide attempt. The recently reported association between the TPH 218A allele and individual differences in aggressive disposition 25 suggests that the precise phenotype related to this TPH variant probably combines three dimensions: mood disorders, suicidal behavior (mainly violent) and aggressive disposition. Clinically, this is consistent with the 'stress-diathesis' model of suicidal behavior proposed by Mann et al 28 This model is also consistent with that proposed by Depue 29 who suggested that 'suicidal behavior and impulsive aggression may represent two different indicators of a central (behavioral and biochemical) trait, such as a low threshold of emotional facilitation'.…”

Section: Commentmentioning

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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“…2 In contrast, both TPH1 and TPH2 are expressed in the human brain 3 and genetic variation in both isoforms have been associated with alterations in mood and 5-HT function. 4,5 Furthermore, a relatively rare single nucleotide polymorphism in human TPH2 (hTPH2) associated with depression has been shown to alter TPH enzymatic efficiency in vitro. 6 However, the functional consequence of genetic variation in hTPH2 on the neural circuitry of mood and emotional behaviors is unknown.…”

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confidence: 99%

A regulatory variant of the human tryptophan hydroxylase-2 gene biases amygdala reactivity

et al. 2005

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Recent studies have indicated that a newly identified second isoform of the tryptophan hydroxylase gene (TPH2) is preferentially involved in the rate-limiting synthesis of neuronal serotonin. Genetic variation in the human TPH2 gene (hTPH2) has been associated with altered in vitro enzyme activity as well as increased risk for mood disorders. Here, we provide the first in vivo evidence that a relatively frequent regulatory variant (G(À844)T) of hTPH2 biases the reactivity of the amygdala, a neural structure critical in the generation and regulation of emotional behaviors. Keywords: TPH2; amygdala; serotonin; fMRI Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin (5-HT), a key modulator of mood and affect. Thus, the identification of genetic variation contributing to functional changes in TPH enzymatic activity is of great interest in determining the biological pathways underpinning individual differences in emotional behaviors and risk for psychiatric disorders, including depression, anxiety, and suicidality. Recent molecular and cellular studies have revealed the existence of a second TPH isoform, tryptophan hydroxylase-2 (TPH2), exclusively expressed in the murine brain. 1 Functional assays demonstrate that TPH2-and not the original isoform, referred to now as TPH1-is responsible for regulating TPH expression and 5-HT synthesis in the murine central nervous system. 2 In contrast, both TPH1 and TPH2 are expressed in the human brain 3 and genetic variation in both isoforms have been associated with alterations in mood and 5-HT function. 4,5 Furthermore, a relatively rare single nucleotide polymorphism in human TPH2 (hTPH2) associated with depression has been shown to alter TPH enzymatic efficiency in vitro. 6 However, the functional consequence of genetic variation in hTPH2 on the neural circuitry of mood and emotional behaviors is unknown.In the current study, we used functional magnetic resonance imaging (fMRI) to examine the effects of a single nucleotide polymorphism (G(À844)T) in the upstream regulatory region of hTPH2 on the reactivity of the amygdala, a central structure in the mediation of behavioral and physiologic arousal associated with emotional behaviors. Although the molecular and cellular effects of the G(À844)T polymorphism are unknown, we focused on this regulatory variant for several reasons. First, unlike other hTPH2 variants with demonstrated impact on enzymatic activity, 6 the G(À844)T has a relatively high minor allele frequency (T allele ¼ 38%) and thus, has the potential to contribute more broadly to brain function and risk for mood disorders. Second, this variant is located within 1 kb (844 bp upstream) of the transcription initiation site of hTPH2 and is likely a constituent of the proximal promoter of the gene. Regulatory variants in general often impact gene expression 7 and several specific promoter polymorphisms in other 5-HT subsystem genes have demonstrated effects on brain function and emotional behaviors. [8][9][10]

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Aggression and anger-related traits associated with a polymorphism of the tryptophan hydroxylase gene

Cited by 255 publications

References 51 publications

Genetic Analysis of Anger: Genetic Dominance or Competitive Sibling Interaction

Genetic Analysis of Anger: Genetic Dominance or Competitive Sibling Interaction

Suicide attempts and the tryptophan hydroxylase gene

A regulatory variant of the human tryptophan hydroxylase-2 gene biases amygdala reactivity

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