Association of Anxiety-Related Traits with a Polymorphism in the Serotonin Transporter Gene Regulatory Region
29 Nov 1996-Science (American Association for the Advancement of Science)-Vol. 274, Iss: 5292, pp 1527-1531
TL;DR: The short variant of the polymorphism reduces the transcriptional efficiency of the 5-HTT gene promoter, resulting in decreased 5HTT expression and 5HT uptake in lymphoblasts as discussed by the authors, which is the site of action of widely used uptake-inhibiting antidepressant and antianxiety drugs.
Abstract: Transporter-facilitated uptake of serotonin (5-hydroxytryptamine or 5-HT) has been implicated in anxiety in humans and animal models and is the site of action of widely used uptake-inhibiting antidepressant and antianxiety drugs. Human 5-HT transporter (5-HTT) gene transcription is modulated by a common polymorphism in its upstream regulatory region. The short variant of the polymorphism reduces the transcriptional efficiency of the 5-HTT gene promoter, resulting in decreased 5-HTT expression and 5-HT uptake in lymphoblasts. Association studies in two independent samples totaling 505 individuals revealed that the 5-HTT polymorphism accounts for 3 to 4 percent of total variation and 7 to 9 percent of inherited variance in anxiety-related personality traits in individuals as well as sibships.
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01 Jan 1999
TL;DR: The Big Five taxonomy as discussed by the authors is a taxonomy of personality dimensions derived from analyses of the natural language terms people use to describe themselves 3 and others, and it has been used for personality assessment.
Abstract: 2 Taxonomy is always a contentious issue because the world does not come to us in neat little packages (S. Personality has been conceptualized from a variety of theoretical perspectives, and at various levels of Each of these levels has made unique contributions to our understanding of individual differences in behavior and experience. However, the number of personality traits, and scales designed to measure them, escalated without an end in sight (Goldberg, 1971). Researchers, as well as practitioners in the field of personality assessment, were faced with a bewildering array of personality scales from which to choose, with little guidance and no overall rationale at hand. What made matters worse was that scales with the same name often measure concepts that are not the same, and scales with different names often measure concepts that are quite similar. Although diversity and scientific pluralism are useful, the systematic accumulation of findings and the communication among researchers became difficult amidst the Babel of concepts and scales. Many personality researchers had hoped that they might devise the structure that would transform the Babel into a community speaking a common language. However, such an integration was not to be achieved by any one researcher or by any one theoretical perspective. As Allport once put it, " each assessor has his own pet units and uses a pet battery of diagnostic devices " (1958, p. 258). What personality psychology needed was a descriptive model, or taxonomy, of its subject matter. One of the central goals of scientific taxonomies is the definition of overarching domains within which large numbers of specific instances can be understood in a simplified way. Thus, in personality psychology, a taxonomy would permit researchers to study specified domains of personality characteristics, rather than examining separately the thousands of particular attributes that make human beings individual and unique. Moreover, a generally accepted taxonomy would greatly facilitate the accumulation and communication of empirical findings by offering a standard vocabulary, or nomenclature. After decades of research, the field is approaching consensus on a general taxonomy of personality traits, the " Big Five " personality dimensions. These dimensions do not represent a particular theoretical perspective but were derived from analyses of the natural-language terms people use to describe themselves 3 and others. Rather than replacing all previous systems, the Big Five taxonomy serves an integrative function because it can represent the various and diverse systems of personality …
7,787 citations
Cites background from "Association of Anxiety-Related Trai..."
...Research in diverse areas like behavior genetics (Plomin & Caspi, this volume), molecular genetics (Lesch et al., 1996), personality stability and change (Costa & McCrae, 1994; Helson & Stewart, 1994), and accura y and bias in interpersonal perception (Kenny, 1994; Robins & John, 1997; see also…...
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TL;DR: Evidence of a gene-by-environment interaction is provided, in which an individual's response to environmental insults is moderated by his or her genetic makeup.
Abstract: In a prospective-longitudinal study of a representative birth cohort, we tested why stressful experiences lead to depression in some people but not in others. A functional polymorphism in the promoter region of the serotonin transporter (5-HT T) gene was found to moderate the influence of stressful life events on depression. Individuals with one or two copies of the short allele of the 5-HT T promoter polymorphism exhibited more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events than individuals homozygous for the long allele. This epidemiological study thus provides evidence of a gene-by-environment interaction, in which an individual's response to environmental insults is moderated by his or her genetic makeup.
7,210 citations
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TL;DR: Genetically driven variation in the response of brain regions underlying human emotional behavior is demonstrated and differential excitability of the amygdala to emotional stimuli may contribute to the increased fear and anxiety typically associated with the short SLC6A4 allele.
Abstract: A functional polymorphism in the promoter region of the human serotonin transporter gene (SLC6A4) has been associated with several dimensions of neuroticism and psychopathology, especially anxiety traits, but the predictive value of this genotype against these complex behaviors has been inconsistent. Serotonin [5- hydroxytryptamine, (5-HT)] function influences normal fear as well as pathological anxiety, behaviors critically dependent on the amygdala in animal models and in clinical studies. We now report that individuals with one or two copies of the short allele of the serotonin transporter (5-HTT) promoter polymorphism, which has been associated with reduced 5-HTT expression and function and increased fear and anxiety-related behaviors, exhibit greater amygdala neuronal activity, as assessed by BOLD functional magnetic resonance imaging, in response to fearful stimuli compared with individuals homozygous for the long allele. These results demonstrate genetically driven variation in the response of brain regions underlying human emotional behavior and suggest that differential excitability of the amygdala to emotional stimuli may contribute to the increased fear and anxiety typically associated with the short SLC6A4 allele.
2,248 citations
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14 Nov 2016
2,100 citations
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TL;DR: Morphometrical analyses showed reduced gray matter volume in short-allele carriers in limbic regions critical for processing of negative emotion, particularly perigenual cingulate and amygdala, and relative uncoupling of this circuit.
Abstract: Carriers of the short allele of a functional 5¢ promoter polymorphism of the serotonin transporter gene have increased anxietyrelated temperamental traits, increased amygdala reactivity and elevated risk of depression. Here, we used multimodal neuroimaging in a large sample of healthy human subjects to elucidate neural mechanisms underlying this complex genetic association. Morphometrical analyses showed reduced gray matter volume in short-allele carriers in limbic regions critical for processing of negative emotion, particularly perigenual cingulate and amygdala. Functional analysis of those regions during perceptual processing of fearful stimuli demonstrated tight coupling as a feedback circuit implicated in the extinction of negative affect. Short-allele carriers showed relative uncoupling of this circuit. Furthermore, the magnitude of coupling inversely predicted almost 30% of variation in temperamental anxiety. These genotype-related alterations in anatomy and function of an amygdalacingulate feedback circuit critical for emotion regulation implicate a developmental, systems-level mechanism underlying normal emotional reactivity and genetic susceptibility for depression. Depression is among the four leading causes of disability and disease burden throughout the world and is associated with serious medical conditions and mortality across the lifespan 1,2 . The importance of serotonergic neurotransmission for the pathogenesis of depression is suggested clinically by the efficacy of serotonin re-uptake inhibitors (SSRIs), the first-line treatment of depression and most related anxiety disorders 1 and by induction of depression by tryptophan depletion in susceptible individuals 2 . Post-mortem and in vivo studies of the serotonin transporter (5-HTT) and receptors support a role for this neurotransmitter system in depression and anxiety disorders 1 . Further
1,928 citations
Cites background from "Association of Anxiety-Related Trai..."
...A variable number of tandem repeats in the 5′ promoter region (5-HTTLPR) of the human serotonin transporter gene ( SLC6A4 ) has been shown both in vitro and in vivo to influence transcriptional activity and subsequent availability of the 5-HT...
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References
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TL;DR: It is proposed that these drugs reduce anxiety by impairing the functioning of a widespread neural system including the septo-hippocampal system (SHS), the Papez circuit, the prefrontal cortex, and ascending monoaminergic and cholinergic pathways which innervate these forebrain structures.
Abstract: A model of the neuropsychology of anxiety is proposed. The model is based in the first instance upon an analysis of the behavioural effects of the antianxiety drugs (benzodiazepines, barbiturates, and alcohol) in animals. From such psychopharmacologi-cal experiments the concept of a “behavioural inhibition system” (BIS) has been developed. This system responds to novel stimuli or to those associated with punishment or nonreward by inhibiting ongoing behaviour and increasing arousal and attention to the environment. It is activity in the BIS that constitutes anxiety and that is reduced by antianxiety drugs. The effects of the antianxiety drugs in the brain also suggest hypotheses concerning the neural substrate of anxiety. Although the benzodiazepines and barbiturates facilitate the effects of γ-aminobutyrate, this is insufficient to explain their highly specific behavioural effects. Because of similarities between the behavioural effects of certain lesions and those of the antianxiety drugs, it is proposed that these drugs reduce anxiety by impairing the functioning of a widespread neural system including the septo-hippocampal system (SHS), the Papez circuit, the prefrontal cortex, and ascending monoaminergic and cholinergic pathways which innervate these forebrain structures. Analysis of the functions of this system (based on anatomical, physiological, and behavioural data) suggests that it acts as a comparator: it compares predicted to actual sensory events and activates the outputs of the BIS when there is a mismatch or when the predicted event is aversive. Suggestions are made as to the functions of particular pathways within this overall brain system. The resulting theory is applied to the symptoms and treatment of anxiety in man, its relations to depression, and the personality of individuals who are susceptible to anxiety or depression.
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TL;DR: In this article, a method for clinical description and classification of both normal and abnormal personality variants is proposed based on a general biosocial theory of personality, and three dimensions of personality are defined in terms of the basic stimulus-response characteristics of novelty seeking, harm avoidance and reward dependence.
Abstract: • A systematic method for clinical description and classification of both normal and abnormal personality variants is proposed based on a general biosocial theory of personality. Three dimensions of personality are defined in terms of the basic stimulus-response characteristics of novelty seeking, harm avoidance, and reward dependence. The possible underlying genetic and neuroanatomical bases of observed variation in these dimensions are reviewed and considered in relation to adaptive responses to environmental challenge. The functional interaction of these dimensions leads to integrated patterns of differential response to novelty, punishment, and reward. The possible tridimensional combinations of extreme (high or low) variants on these basic stimulusresponse characteristics correspond closely to traditional descriptions of personality disorders. This reconciles dimensional and categorical approaches to personality description. It also implies that the underlying structure of normal adaptive traits is the same as that of maladaptive personality traits, except for schizotypal and paranoid disorders.
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TL;DR: This article synthesizes the current state of the genetic dissection of complex traits--describing the methods, limitations, and recent applications to biological problems.
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15 Jan 1995TL;DR: Part 1 Preclinical section: critical analysis of methods transmitter systems - amino acids, amines, peptides, new transmitterscritical analysis of integrative concepts.
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TL;DR: Mood, emotion, cognition, and motor functions as well as circadian and neuroendocrine rhythms, including food intake, sleep, and reproductive activity, are modulated by the midbrain raphe serotonin (5‐HT) system and allele‐dependent differential 5‐HTT promoter activity may play a role in the expression and modulation of complex traits and behavior.
Abstract: Mood, emotion, cognition, and motor functions as well as circadian and neuroendocrine rhythms, including food intake, sleep, and reproductive activity, are modulated by the midbrain raphe serotonin (5-HT) system. By directing the magnitude and duration of postsynaptic responses, carrier-facilitated 5-HT transport into and release from the presynaptic neuron are essential for the fine tuning of serotonergic neurotransmission. Interest in the mechanism of environmental factor-, disease-, and therapy-induced modification of 5-HT transporter (5-HTT) function and its impact on early brain development, event-related synaptic plasticity, and neurodegeneration is widespread and intensifying. We have recently characterized the human and murine 5-HTT genes and performed functional analyses of their 5'-flanking regulatory regions. A tandemly repeated sequence associated with the transcriptional apparatus of the human 5-HTT gene displays a complex secondary structure, represses promoter activity in nonserotonergic neuronal cells, and contains positive regulatory components. We now report a novel polymorphism of this repetitive element and provide evidence for allele-dependent differential 5-HTT promoter activity. Allelic variation in 5-HTT-related functions may play a role in the expression and modulation of complex traits and behavior.
2,202 citations