Role of the Serotonin Transporter Promoter Polymorphism in Anxiety-Related Traits

Mazzanti, Chiara Maria; Lappalainen, Jaakko; Long, Jeffrey C.; Bengel, Dietmar; Naukkarinen, Hannu; Eggert, Monica; Virkkunen, Matti; Linnoila, Markku; Goldman, David

doi:10.1001/archpsyc.55.10.936

Cited by 239 publications

(147 citation statements)

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“…An association exists between 5-HTTLPR genotype and some personality factors, given that carriers of the s-allele are more likely to demonstrate anxiety-related personality traits, including neuroticism and harm avoidance, than l/l genotypes. 42,[296][297][298] It is unclear whether personality can directly cause SV. For example, it is also possible that certain personality traits simply co-occur with SV or depression, or that they represent the state of SV.…”

Section: Biopsychological Interactionsmentioning

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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Section: Biopsychological Interactionsmentioning

confidence: 99%

Serotonergic vulnerability and depression: assumptions, experimental evidence and implications

et al. 2006

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“…Thus, the original finding of higher neuroticism and harm avoidance in adult individuals with the short variant of the 5HTTLPR has been replicated and extended to younger individuals 3 and to other anxietyrelated dimensions of personality, [4][5][6] but has also failed replication. [7][8][9][10][11][12][13] Similarly, studies examining possible association between allelic variation in the promoter region of the serotonin transporter gene and risk for unipolar and bipolar depression have produced inconsistent findings (reviewed in Furlong et al 14 ). Among the potential sources for differences among these findings is the possibility that environmental variables may play an important role in the functional expression of the genotype.…”

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confidence: 99%

Early experience and serotonin transporter gene variation interact to influence primate CNS function

et al. 2002

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Nonhuman primates offer unique opportunities to study the effects of genes, environments, and their interaction, on physiology and complex behavior. We examined genotype and early environment contributions to CNS function in a large sample of rhesus monkeys. In humans, length variation of the serotonin (5-HT) transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) that results in allelic variation in 5-HTT expression is associated with decreased serotonergic function and 5-HT-mediated psychopathology. We report that an analogous variation of the gene's regulatory region in monkeys interacts with early experience to affect central 5-HT functioning. Monkeys with deleterious early rearing experiences were differentiated by genotype in cerebrospinal fluid concentrations of the 5-HT metabolite, 5-hydroxyindoleacetic acid, while monkeys reared normally were not. These findings demonstrate an environment-dependent effect of the rh5-HTTLPR genotype on CNS 5-HT function and suggest nonhuman primates may provide an important avenue for investigating gene/environment interactions using candidate genes for physiological and behavioral traits.

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“…30,31 More definitive studies investigating the association between neuroticism, anxiety, depression and the 5-HTTLPR await larger samples and family-based designs. An example of the latter is the observation of significant positive linkage between the 5-HTTLPR and harm avoidance subscales in a large sample of Finnish sib-pairs, 32 which provides converging evidence that the 5-HTTLPR may influence personality traits related to neuroticism. It is to be hoped that studies such as these will advance our understanding not only of possible genetic influences on personality, but will also be useful in refining conceptions of the relevant personality traits themselves, the disorders associated with them, and possible approaches to the treatment of those disorders.…”

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confidence: 99%

“…Linkage and association strategies are likely to become increasingly complementary approaches to studying complex diseases and behavioral dimensions. 32,34 Findings using newer methods in development that combine the categorical and dimensional approaches, or other techniques that account for the susceptibility enhancing (and reducing) influences of multiple genes, are needed. Nevertheless, the relatively high density of intriguing 5-HTT association findings over a short time is grounds for cautious optimism, together with the expectation of a long and often frustrating road ahead.…”

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confidence: 99%

Serotonin transporter candidate gene studies in affective disorders and personality: promises and potential pitfalls

1998

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While affective and anxiety disorders are substantially heritable, their inheritances are complex and multifactorial. 1 It is therefore unsurprising that such etiologically heterogeneous illnesses have not easily succumbed to genetic methodologies that are further challenged by an imperfect classification system. 2 Nevertheless, investigators continue to behave as if the problems are not insoluble. Association studies of candidate genes have lately held particular appeal, at least partly since this approach connects well with the familiar view that these disorders arise from alterations in particular brain neurochemical systems.The evidence implicating brain serotonin (5-HT) neurotransmission in anxiety and affective disorders is extensive and compelling. 3,4 In the attempt to investigate whether alterations in function of brain 5-HT systems are etiologically associated with these illnesses, attention has focused on polymorphisms in genes encoding components of the serotonergic system. These genes are seen as potential candidates influencing susceptibility, course, or symptoms. Researchers are investigating variants of genes for the 5-HT synthesis pathway, the 5-HT transporter (5-HTT), and several of the numerous 5-HT receptors. Potentially important sequence variations may occur in the coding region of a gene, in gene promoters (which could affect transcription efficiency), and in intronic regions, which, while non-coding, might affect gene expression or distribution of the gene product. Some variants of serotonin system genes are common, consistent with a role in complex, polygenic disorders with relatively high population incidences.The most common research strategy used in association studies, because it is often logistically easiest, is the population-based approach. Such studies compare the frequencies of polymorphic alleles in a group of individuals with a particular psychiatric diagnosis with those in a reference population. The use of this method is now widespread. Although this strategy has important limitations (see below), initial findings have been intriguing enough to spur further research by diverse groups of investigators.A number of reports have described associations between affective disorders and polymorphisms in or near the 5-HTT gene. The 5-HTT is a major modulator

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Role of the Serotonin Transporter Promoter Polymorphism in Anxiety-Related Traits

Abstract: In the present study we replicated the relationship of SLC6A4C to anxiety by sibpair linkage analysis but found no evidence of association, raising the question of whether SLC6A4C locus is itself affecting anxiety or is linked to another still unknown functional variant.

Cited by 239 publications

References 17 publications

Serotonergic vulnerability and depression: assumptions, experimental evidence and implications

Serotonergic vulnerability and depression: assumptions, experimental evidence and implications

Early experience and serotonin transporter gene variation interact to influence primate CNS function

Serotonin transporter candidate gene studies in affective disorders and personality: promises and potential pitfalls

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Role of the Serotonin Transporter Promoter Polymorphism in Anxiety-Related Traits

Abstract: In the present study we replicated the relationship of SLC6A4*C to anxiety by sibpair linkage analysis but found no evidence of association, raising the question of whether SLC6A4*C locus is itself affecting anxiety or is linked to another still unknown functional variant.

Cited by 239 publications

References 17 publications

Serotonergic vulnerability and depression: assumptions, experimental evidence and implications

Serotonergic vulnerability and depression: assumptions, experimental evidence and implications

Early experience and serotonin transporter gene variation interact to influence primate CNS function

Serotonin transporter candidate gene studies in affective disorders and personality: promises and potential pitfalls

Contact Info

Product

Resources

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Abstract: In the present study we replicated the relationship of SLC6A4C to anxiety by sibpair linkage analysis but found no evidence of association, raising the question of whether SLC6A4C locus is itself affecting anxiety or is linked to another still unknown functional variant.