Advertisement
Browse Subject Areas
?

Click through the PLOS taxonomy to find articles in your field.

For more information about PLOS Subject Areas, click here.

  • Loading metrics

Affect-Modulated Startle: Interactive Influence of Catechol-O-Methyltransferase Val158Met Genotype and Childhood Trauma

  • Benedikt Klauke,

    Affiliations Department of Psychiatry and Psychotherapy, University of Muenster, Muenster, Germany, Christoph Dornier Clinic of Psychotherapy, Muenster, Germany

  • Bernward Winter,

    Affiliation Department of Psychiatry and Psychotherapy, University of Muenster, Muenster, Germany

  • Agnes Gajewska,

    Affiliation Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany

  • Peter Zwanzger,

    Affiliation Department of Psychiatry and Psychotherapy, University of Muenster, Muenster, Germany

  • Andreas Reif,

    Affiliation Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany

  • Martin J. Herrmann,

    Affiliation Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany

  • Andrea Dlugos,

    Affiliation Department of Psychiatry and Psychotherapy, University of Muenster, Muenster, Germany

  • Bodo Warrings,

    Affiliation Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany

  • Christian Jacob,

    Affiliation Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany

  • Andreas Mühlberger,

    Affiliation Department of Psychology, University of Wuerzburg, Wuerzburg, Germany

  • Volker Arolt,

    Affiliation Department of Psychiatry and Psychotherapy, University of Muenster, Muenster, Germany

  • Paul Pauli,

    Affiliation Department of Psychology, University of Wuerzburg, Wuerzburg, Germany

  • Jürgen Deckert,

    Affiliation Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany

  • Katharina Domschke

    Domschke_K@klinik.uni-wuerzburg.de

    Affiliations Department of Psychiatry and Psychotherapy, University of Muenster, Muenster, Germany, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany

Affect-Modulated Startle: Interactive Influence of Catechol-O-Methyltransferase Val158Met Genotype and Childhood Trauma

  • Benedikt Klauke, 
  • Bernward Winter, 
  • Agnes Gajewska, 
  • Peter Zwanzger, 
  • Andreas Reif, 
  • Martin J. Herrmann, 
  • Andrea Dlugos, 
  • Bodo Warrings, 
  • Christian Jacob, 
  • Andreas Mühlberger
PLOS
x

Abstract

The etiology of emotion-related disorders such as anxiety or affective disorders is considered to be complex with an interaction of biological and environmental factors. Particular evidence has accumulated for alterations in the dopaminergic and noradrenergic system – partly conferred by catechol-O-methyltransferase (COMT) gene variation – for the adenosinergic system as well as for early life trauma to constitute risk factors for those conditions. Applying a multi-level approach, in a sample of 95 healthy adults, we investigated effects of the functional COMT Val158Met polymorphism, caffeine as an adenosine A2A receptor antagonist (300 mg in a placebo-controlled intervention design) and childhood maltreatment (CTQ) as well as their interaction on the affect-modulated startle response as a neurobiologically founded defensive reflex potentially related to fear- and distress-related disorders. COMT val/val genotype significantly increased startle magnitude in response to unpleasant stimuli, while met/met homozygotes showed a blunted startle response to aversive pictures. Furthermore, significant gene-environment interaction of COMT Val158Met genotype with CTQ was discerned with more maltreatment being associated with higher startle potentiation in val/val subjects but not in met carriers. No main effect of or interaction effects with caffeine were observed. Results indicate a main as well as a GxE effect of the COMT Val158Met variant and childhood maltreatment on the affect-modulated startle reflex, supporting a complex pathogenetic model of the affect-modulated startle reflex as a basic neurobiological defensive reflex potentially related to anxiety and affective disorders.

Introduction

The etiology of anxiety and affective disorders is considered to be complex with an interaction of biological factors and environmental influences: Family and twin studies propose a genetic contribution to the pathogenesis of these disorders with an estimated heritability of 30 to 60% [1][3]. The remaining part of the variance has been attributed to environmental factors [3], [4].

Particular evidence is accumulating for the catechol-O-methyltransferase (COMT) as a promising candidate gene in the pathogenesis of anxiety and affective disorders: COMT catalyzes the inactivation of monoaminergic neurotransmitters, particularly dopamine and norepinephrine, by an extraneural transfer of a methyl group to catechol compounds. Significantly elevated erythrocyte COMT activity has been reported in patients with anxiety states [5] and COMT inhibitors are effectively used in the treatment of anxiety symptoms in Parkinson's disease [6]. A single nucleotide polymorphism (472G/A) in the COMT gene, located on chromosome 22q11.2 [7], causes an amino acid change from valine to methionine at position 158 (Val158Met), with the val allele (472G) conferring an at least 40% higher COMT activity [8], [9]. This more active val allele has been reported to be associated with panic disorder [10][13], phobic anxiety [14], neuroticism [15], harm avoidance [16] and generalized anxiety [17]. However, there are also reports indicating no influence of COMT Val158Met on anxiety disorders or related phenotypes [18][23] or demonstrating association of the less active met allele with anxiety-related phenotypes [24][32]. Association studies of the COMT Val158Met polymorphism with respect to affective disorders, in particular depression, are similarly inconclusive [33][35].

Three aspects might have to be taken into consideration in order to reconcile these inconsistent molecular genetic findings and to elucidate the genetic underpinnings of anxiety/affective disorders in a more comprehensive way: 1) intermediate phenotypes, 2) interaction of several relevant neurotransmitter systems and 3) interaction of genetic and environmental factors.

  1. Specification to unravel the influence of genetic factors on complex traits or diseases can be reached by investigation of so-called endophenotypes on an intermediate level between genetic factors and categorical disease phenotypes [36]. The acoustic startle response and particularly the affect-modulated acoustic startle response are neurobiologically founded behavioral measures of emotional reactivity reflecting a defensive motivational state [37][46]. Accordingly, there is evidence for exaggerated startle potentiation in response to negative emotional stimuli in anxiety disorders [39][41], [46][48] and fear- or anxiety/distress-related states [37], [49]. Twin studies provide evidence for a genetic influence on different components of the startle reflex (heritability: ∼30–70%; [50][54]), with several studies having investigated the possible role of COMT gene variation: Montag et al. [55] found greater startle responses for met homozygotes in the unpleasant condition of an acoustic affect-modulated startle paradigm, while Pauli et al. [56] using the same paradigm failed to discern any influence of COMT gene variation on startle modulation. Armbruster et al. [57] discerned a significant COMT Val158Met genotype effect on average startle magnitudes across conditions with met/met carriers showing the highest and val/val homozygotes showing the lowest startle response, while no influence of COMT genotype on the emotional modulation of the startle reflex was detected. Lonsdorf et al. [31] and Klumpers et al. [58] did not discern any effect of COMT Val158Met on fear-potentiated startle during acquisition of fear conditioning or during instructed fear, respectively.
  2. The dopamine/norepinephrine system, as crucially driven by the COMT Val158Met polymorphism, ought not to be considered in an isolated way with respect to the modulation of anxiety or related phenotypes, but rather in interaction with other relevant neurotransmitter systems. Animal and human studies have e.g. suggested a tight functional link between the dopamine and the adenosine system on a cellular as well as a neurotransmitter level [59][61]. Caffeine, which is an antagonist at the adenosine A2A receptor and acts as a potent anxiogenic and arousal-increasing substance [62], [63], has been reported to increase acoustic startle reflex amplitude and confer a delayed habituation of acoustic startle blink amplitude [64][66]. In addition, we have previously observed a significant interactive effect of adenosine A2A receptor gene variation, caffeine intervention and emotional stimuli on startle magnitudes [67]. The COMT Val158Met polymorphism as a potent genetic modulator of dopaminergic signaling on the one hand and caffeine administration on the other hand might thus serve as valid biological measures to investigate the interactive influence of the dopaminergic and the adenosinergic system on the affect-modulated startle response.
  3. Given the complex-genetic nature of anxiety disorders entailing an interactive pathogenetic effect of genetic and environmental factors, neglect of environmental factors might have introduced a major bias to previous genetic studies. There is converging evidence for a crucial role of abuse [68][70] and loss/separation experiences [71], [72] on the pathogenesis of anxiety disorders [73], with childhood and adolescence being considered as particularly sensitive periods [74]. In mice, prolonged pre-pubertal stress enhanced the acoustic startle reflex [75]. Consistently, early environmental stressors such as perceived childhood physical and sexual abuse experiences have been shown to increase baseline startle reactivity in humans [76; but 77]. With respect to the interactive influence of COMT gene variation and life events in anxiety, only few gene-environment interaction (GxE) studies are available: Kolassa et al. [78] reported a GxE interaction of the Val158Met polymorphism and traumatic events in the etiology of posttraumatic stress disorder, with val allele carriers showing a trauma quantity dependent disease risk, while met homozygotes exhibited a high risk for PTSD independently of the severity of traumatic load. In contrast, no interaction effect was found between Val158Met and early adversity or stressor experiences on anxiety in young children [23] or anxiety-related traits [19], respectively.

Given these multi-level factors possibly modulating the influence of COMT gene variation on anxiety and affective disorders or related phenotypes, in the present study applying an integrative approach using the same study design as in Domschke et al. [67] we set out to elucidate the main as well as interactional effects of COMT gene variation, caffeine and childhood maltreatment on the affect-modulated startle response as a neurobiological measure of emotional and motivational processes potentially related to fear- and anxiety/distress-related states.

Results

Descriptive Data

Five of 95 examined participants showed too many zero startle responses (<5 µV; 2.5 standard deviations above mean value) and were therefore excluded from further analyses. For all affect-modulated startle responses, no outliers (>2.5 SD) were detected. For the mean intertrial interval (ITI) startle response, one subject was additionally excluded because of an extreme score (>2.5 SD), so that this analysis step was run with 89 participants only.

For age and CTQ, no differences were observed between sex (male vs. female probands), challenge conditions (caffeine vs. placebo) or COMT Val158Met genotype groups (data not shown). Descriptive statistics of age, CTQ and startle (ITI startle, startle after unpleasant and pleasant picture (International Affective Picture System; IAPS) presentation, startle magnitude potentiation after unpleasant picture presentation compared to neutral pictures [Diffunpl-neutr]) for the 90 probands are given in table 1.

thumbnail
Table 1. Descriptive characteristics of probands by sex, challenge condition and COMT Val158Met genotype.

https://doi.org/10.1371/journal.pone.0039709.t001

In the present sample, CTQ sum scores ranged between a minimum of 26 and a maximum of 52 (mean = 33.23, SD = 5.60).

Gene-Environment Correlation (rGE)

No significant gene-environment correlation between COMT Val158Met genotypes and CTQ was observed (rGE = −0.01, p = 0.92). Thus, confounding effects of a correlation between genetic and environmental predictors could be excluded.

Influence of COMT Val158Met on baseline startle reflex

No influence of COMT Val158Met genotype on mean ITI startle response was observed (F(2,87) = 0.24, p = 0.79).

Influence of COMT Val158Met, sex and challenge condition on affect-modulated startle

Because of the large variance of caffeine saliva concentrations especially in the placebo group (range: 0–132 mg/l), all subjects with a concentration differing more than one and a half interquartile ranges from the respective median in the placebo or verum group were excluded for analyses including challenge condition as an additional between-subjects factor. For this reason, five subjects in the placebo group had to be excluded, leaving 85 subjects for analyses including challenge condition (see table 1).

According to Mauchlýs test, sphericity assumption was violated (χ2(2) = 19.23, p<0.001), so that Huynh-Feld correction was used (ε = 0.95). In the presently analyzed sample of N = 85 probands, ANOVA revealed a significant effect of picture valence on startle magnitude (F(2,146) = 26.97, p<0.001), representing a linear trend (F(1,73) = 47.06, p<0.001) with increasing startle magnitudes from pleasant to unpleasant pictures.

Furthermore, significant interactions between COMT Val158Met genotype and picture valence (F(4,146) = 3.99, p = 0.005) and between sex and picture valences (F(2,146) = 4.43, p = 0.015) were observed. No significant interaction between challenge condition and picture valence (F(2,146) = 0.17, p = 0.83) and no significant 3- or 4-way-interactions between picture category and the between-subjects factors (COMT Val158Met genotype, sex, challenge condition) were observed, respectively (data not shown).

Post-hoc t-tests revealed a significantly increased startle response to unpleasant pictures in comparison to neutral pictures in val homozygotes (t(12) = 3.98, p = 0.002), but not in met homozygotes (t(29) = 0.98, p = 0.34). Vice versa, a significantly decreased startle response to pleasant pictures compared to neutral pictures was observed in met homozygotes (t(29) = 5.28, p<0.001), but not in homozygotes for the val allele (t(12) = 0.24, p = 0.82). For carriers of the val/met genotype, no differences, neither in response to unpleasant compared to neutral pictures (t(41) = 1.37, p = 0.18) nor in response to neutral compared to pleasant pictures (t(41) = 1.47, p = 0.16) were observed (see figure 1).

thumbnail
Figure 1. Mean startle magnitude modulated by picture category and COMT Val158Met genotype.

*** significant at significance level of p≤.005.

https://doi.org/10.1371/journal.pone.0039709.g001

Post-hoc t-tests stratified for sex revealed a significantly increased startle response in response to unpleasant pictures in comparison to neutral pictures in female subjects (t(39) = 4.22, p<0.001), but not in male participants (t(44) = −0.02, p = 0.98). A significantly increased startle response to neutral pictures compared to pleasant pictures was observed in male subjects (t(44) = 4.68, p<0.001), but not in female participants (t(39) = 1.18, p = 0.25).

Using untransformed raw startle data, the results remained stable, showing a significant effect of picture valence on startle magnitude, a significant interaction between COMT Val158Met genotype and picture valence and, a significant interaction between sex and picture valence (data not shown).

Influence of COMT Val158Met and CTQ on baseline startle reflex

Investigating influences of CTQ on mean ITI startle response for each COMT Val158Met genotype separately, no associations were observed, neither for subjects carrying the COMT val/val genotype (β = −0.40, t = −1.59, p = 0.14), nor for val/met (β = −0.05, t = −0.29, p = 0.77) or met/met genotype carriers (β = −0.15, t = −0.83, p = 0.41).

Influence of COMT Val158Met and CTQ on affect-modulated startle reflex

After presentation of unpleasant pictures, only for val homozygotes a significant influence of CTQ on startle response was observed: val/val carriers showed an increased startle when at the same time scoring high on the CTQ (β = 0.52, t = 2.18, p<0.05). No influence of CTQ on the startle reflex after unpleasant picture presentation was observed in val/met (β = −0.24, t = −1.55, p = 0.13) carriers or met homozygotes (β = 0.05, t = 0.30, p = 0.77).

After neutral picture presentation, startle responses for none of the COMT Val158Met genotype groups were influenced by CTQ (val/val: β = −0.15, t = −0.56, p = 0.59; val/met: β = 0.24, t = 1.54, p = 0.13; met/met: β = 0.12, t = 0.69, p = 0.50).

After pleasant picture presentation, a marginally significant decrease of the startle response was observed for val homozygotes dependent on an increase in CTQ scores (β = −0.51, t = −2.16, p = 0.05), while no associations were observed for val/met (β = 0.15, t = 0.97, p = 0.34) or met/met genotype carriers (β = −0.21, t = −1.17, p = 0.25), respectively.

The interaction of COMT Val158Met genotypes and CTQ scores after presentation of unpleasant and pleasant pictures, respectively, is shown in figure 2.

thumbnail
Figure 2. Linear regression analysis of CTQ sum score influence on startle magnitude potentiation after unpleasant and pleasant IAPS pictures stratified by COMT Val158Met genotype.

https://doi.org/10.1371/journal.pone.0039709.g002

Hierarchical Multiple Regression

Based on the above mentioned results, influences of COMT Val158Met genotype, sex and CTQ as well as their interactive influence on startle magnitude potentiation after unpleasant IAPS picture presentation compared to neutral pictures (Diffunpl-neutr) were tested. Additionally, based on the observed results (see figure 2), COMT Val158Met genotypes were grouped reflecting a recessive model for the val allele (COMT val/val vs. met allele carriers).

In step 1, significant main effects of sex and COMT Val158Met genotype were observed, while CTQ alone did not affect startle magnitude potentiation. In step 2, in addition to the main effects of sex and COMT Val158Met genotypes, a significant interaction between COMT Val158Met genotypes and CTQ on startle magnitude potentiation (Diffunpl-neutr) was discerned. The addition of a GxE interaction term in step 2 accounted for a significant increment in explained variance. The inclusion of interactions with sex in step 3, did not significantly increase the explained variance. No significant interaction terms with sex were observed (see table 2).

thumbnail
Table 2. Results of hierarchical multiple regression analysis regarding affect-modulated startle magnitude (contrast unpleasant/neutral IAPS pictures; Diffunpl-neutr).

https://doi.org/10.1371/journal.pone.0039709.t002

Post-hoc t-tests of the main effects revealed a significantly increased startle magnitude potentiation in female subjects compared to males (t(88) = 3.18, p = 0.002) and in val homozygotes compared to met allele carriers (t(88) = 2.95, p = 0.004).

Neither main nor interactive effects of COMT Val158Met genotype, sex and CTQ were observed on startle magnitude differences after neutral IAPS picture presentation compared to pleasant pictures (Diffneutr-pl) (data not shown). Accordingly, neither the GxE interaction term in step 2 (ΔR2 = 0.000, ΔF(1,85) = 0.03, p = 0.87) nor interactions with sex in step 3 (ΔR2 = 0.014, ΔF(3,82) = 0.40, p = 0.76) significantly increased the explained variance.

Discussion

In the present study, we observed a significant influence of COMT Val158Met genotype as well as an interactive effect of COMT Val158Met genotype and childhood maltreatment (CTQ) on the affect-modulated startle response: 1) Subjects homozygous for the more active val allele showed significant startle potentiation in response to unpleasant pictures, while met allele homozygotes displayed a blunted startle response to unpleasant stimuli and a significantly decreased startle response to pleasant stimuli. 2) Subjects homozygous for the val allele and at the same time scoring high on the CTQ showed increased potentiation of the startle magnitude after unpleasant picture presentation and a significantly decreased startle response to pleasant stimuli. 3) No influence of caffeine on affect-modulated startle responses dependent on the COMT Val158Met polymorphism could be discerned.

Ad 1) We discerned significant startle potentiation in response to unpleasant stimuli in homozygous carriers of the more active COMT val allele. This pattern corresponds to the expected modulation of the startle response by aversive stimuli constituting an inherently defensive response [38], [44] reported in both healthy probands [44], [45] as well as in anxiety and anxiety disorders [39][41], [46][48]. Val allele carriers did not show significant modulation in response to pleasant pictures, potentially due to a relatively decreased response to neutral stimuli (see figure 1). This lack of startle modulation by positive pictures, however, is not uncommon and not as reliably replicated as the startle potentation in response to aversive stimuli [37].

Some support for a modulatory influence of the val allele on startle potentiation by aversive stimuli as presently observed might be derived from studies reporting COMT val/val genotype to decrease prepulse inhibition (PPI) of the startle reflex [79], [80]. Also, using the COMT inhibitor tolcapone, Giakoumaki et al. [81] observed lowered prepulse inhibition in the placebo condition and increased prepulse inhibition in the tolcapone condition in val homozygotes. Diminished PPI has been observed in aversive contexts when using pictures as both prestimuli and affective prompts [82] and along with increased fear-potentiated startle in patients with anxiety disorders [43], [83][85]. However, there is experimental evidence for valence modulation and prepulse inhibition to constitute completely independent startle modulatory phenomena [86], thus rendering hypotheses regarding the relation between the genetic modulation of affect-modulated startle on the one hand and prepulse inhibition one the other hand highly speculative.

The neurobiological circuit underlying the defensive response of increased startle response to aversive stimuli has been postulated to critically involve input from the amygdala [38], [87]. The COMT val allele has previously been shown to be associated with increased amygdala activation during processing of aversive stimuli such as fearful faces in healthy probands as well as in patients with panic disorder [88][91]. Thus, increased excitability of the amygdala in val allele carriers might constitute one of the neurobiological underpinnings of the presently observed startle potentiation in response to aversive stimuli. It has to be noted, though, that the impact of COMT gene variation on amygdala response to aversive stimuli is highly controversial with several contradictory reports of association [92][94]. Research findings on the role of the dopaminergic and noradrenergic system, crucially driven by COMT activity, in mediating emotional processing is also not unequivocal: reports of increased norepinephrine availability to reverse the negative bias in information processing characterizing mood and anxiety disorders and to reduce amygdala response to fearful faces [95], [96] support the present finding of the more active COMT val allele – conferring decreased norepinephrine availability – to increase the defensive startle reaction to aversive emotional stimuli. Conversely, with respect to the dopaminergic system most evidence rather points to an increase in dopaminergic signalling to enhance limbic response to unpleasant stimuli [97], [98].

Homozygosity for the less active COMT met allele, conferring increased dopamine and norepinephrine availability, was presently associated with a blunted affective startle response to unpleasant stimuli and a significantly decreased startle response to pleasant stimuli in contrast to neutral pictures. This pattern corresponds to a study by Forbes et al. [99] showing greater startle during the neutral condition than during the pleasant condition, but no increase in startle during the unpleasant condition in patients with unipolar depression. Also, several other studies provide evidence for a diminished fear potentiated startle in depression-related states [100][102] and in patients with anxiety disorders and comorbid depression [103][105].

It has been suggested that affect-modulated startle response patterns might aid in a more differentiated understanding of the neurobiological underpinnings of anxiety disorders and depression, with enhanced fear-potentiated startle prevailing in patients with anxiety disorders and diminished affect modulation of the startle in patients with depression [49]. Thus, COMT gene variation might constitute one of the neurobiological mechanisms of this differentiation with the more active val allele potentially increasing defense reflexes and thereby conferring a higher risk for anxiety-related traits or disorders, respectively, while the less active met allele seems to be rather associated with defensive responding deficits and thereby traits or disorders on a depressive continuum. It has to be noted, though, that categorical association studies of COMT gene variation in both anxiety disorders [10][15], [24], [25], [28][30], [106] and depression [33][35] yielded inconclusive results with respect to the direction of allelic association. Also, in the present study dimensional measures of anxiety or depressive traits were not taken into consideration, which therefore does not allow for inferences on the relation of the present results to psychopathology. However, future studies investigating genetic effects on the affect-modulated startle response as an intermediate phenotype reflecting emotional reactivity in combination with assessment of psychometric correlates of emotion-related mental disorders might aid in a more neurobiologically informed understanding of the fear-anxiety-distress spectrum.

The present results are in contrast to a study by Montag et al. [55], who reported increased startle reflexes for met homozygotes in the unpleasant condition of an acoustic affect-modulated startle paradigm, and Pauli et al. [56] and Armbruster et al. [57], who failed to discern any influence of COMT gene variation on the emotional modulation of the startle reflex in healthy probands. These studies differ from the present one in several aspects: Montag et al. [55] investigated a sample of female probands only, who were controlled for their hormonal status, while in the present study both sexes were included and menstrual cycle phase was not ascertained. This might have accounted for differing startle responses across studies [107], particularly, as an estrogenic response element in the COMT gene promoter region might render COMT expression particularly dependent on estrogen levels [108]. Also, in the study by Montag et al. [55] probands were pre-stratified not only for the COMT Val158Met polymorphism, but also for the DRD2/ANKK1 Taq IA SNP, which could have fundamentally influenced their results in an epistatic way. The two studies failing to discern an effect of COMT gene variation on affect-modulated startle response investigated probands at an older age (m: 35.16±10.29 years, f: 35.00±10.18 years, [56]; 61.13±2.57 years, [57]) than the study by Montag et al. [55] (22.11±3.29 years) and the present one (26.42±6.11 years), which might have influenced the respective results, as an age-related decrease in emotional recognition and processing has been observed ([109], but: [110]).

Ad 2) Besides several possible explanations for diverging association results of COMT Val158Met with startle response and anxiety-/depression-related phenotypes as detailed above, the present study might contribute to further delineating the functional effect of COMT gene variation on vulnerability towards fear/anxiety/distress-related states by complementing molecular genetic information with environmental data. We identified significant gene-environment interaction of COMT Val158Met genotype with CTQ, with more maltreatment being associated with higher startle potentiation in val/val subjects but not in met carriers. This finding could reflect a possibly val allele driven inclination of traumatized individuals to experience excessive negative emotions, which would be in line with Kolassa et al. [78] reporting val allele carriers to display a trauma quantity dependent disease risk for posttraumatic stress disorder. Additionally, we observed more childhood trauma to predispose homozygous val allele carriers to an accentuated startle inhibition in response to pleasant pictures. This might point to a capacity of val allele carriers to nevertheless experience positive emotions as calming and safety-indicating. It has been suggested that after traumatic experiences positive emotions could buffer against depression by “correcting”, “restoring” or “undoing” the effects of negative emotions (e.g., [111], [112]). Based on this hypothesis, the COMT val allele in interaction with traumatic experiences could predispose to an increased risk of exaggerated negative emotional processing potentially predisposing to anxiety disorders such as PTSD (cf. [78]), while at the same time conferring resilience against depression by restoring autonomic quiescence following positive emotional stimuli (see [113]). However, as in the present study only healthy probands were investigated and no measures of coping strategies or other relevant psychometric measures were ascertained, future studies will have to probe his hypothesis.

The present results are in contrast to a previous study by Jovanovic et al. [76], who failed to discern an influence of early environmental stressors on the degree of fear-potentiated startle. As this study, however, did not include genetic information potentially mediating the impact on early life stress on the affect-modulated startle response, studies are not fully comparable. Gene-environment interaction studies on the effect of COMT gene variation on stress-related disorders are quite controversial: No interactional impact of COMT Val158Met and life events could be discerned on anxiety and depression in 7–8 years old children [23] or on extraversion and neuroticism among adults, respectively [114]. The COMT met/met genotype has, however, been shown to interact with maternity stressors in postpartum depression [115] and with stressors within the year preceding the onset of the first mood disorder episode in depressive adults [116]. Furthermore, carriers of both the 5-HTTLPR S and COMT met alleles exhibited the greatest depressive response to chronic stress in a three-way G x G x E interaction [117]. A possible explanation for this flip-flop phenomenon, i.e., opposite direction of allelic association across studies (cf. [118]), might be that different life events at different ages might differentially interact with dopaminergic tone in shaping the risk for different psychopathological states: As it has been shown that early life stress comparable to the presently investigated childhood traumata leads to decreases in the levels of norepinephrine and dopamine in the frontal cortex and metabolites of dopamine and serotonin in the amygdala (cf. [119]), carriers of the more active COMT val allele entailing a lowered noradrenaline and dopamine tonus might be particularly susceptible to the development of mental disorders related to childhood trauma. Additionally, linkage disequilibrium with other relevant polymorphisms, gene-gene interactions or epigenetic modifications following early environmental stress (see [120]) have to be taken into consideration when interpreting the present finding. Still, the present pilot data might foster future gene-environment interaction studies in fear-, anxiety- or distress-related disorders contributing to further disentangling their complex genetic nature (e.g., [121][123]).

Ad 3) No statistically significant influence of challenge condition (placebo/caffeine) on affect-modulated startle responses dependent on the COMT Val158Met polymorphism and/or childhood trauma could be discerned. Also, genotype distribution of the adenosine 2A receptor (ADORA2A) 1976T>C (rs5751876, formerly 1083T>C, Tyr/Tyr) variant, a silent polymorphism in exon 2 of the ADORA2A gene, which has previously found to be associated with panic disorder and anxiety-related traits [124][128], did not differ across COMT Val158Met genotype groups. The present results thus do not support a COMT driven interaction between the adenosinergic and the dopaminergic system in the mediation of stress and affect-modulated startle response. However, this interaction might not primarily be conferred by COMT, but rather by dopamine D2 receptor (DRD2) gene variation, as DRD2 receptors in the amygdala have been suggested to play a role in setting up adaptive responses to cope with aversive environmental stimuli [129] and to functionally interact with adenosine receptors on a cellular level [130].

In addition to the caveats mentioned above, the following limitations of our study have to be considered when interpreting the present results: First of all, the present sample size particularly regarding the val/val genotype group was limited. Despite there was sufficient power (>0.90) to explain 23% of startle magnitude variance with four predictors in step 2 with a type I error rate of 0.05 according to a post-hoc power calculation for multiple regression using G*Power calculation software available online (University of Duesseldorf, Germany; http://www.psycho.uni-duesseldorf.de/abteilungen/aap/gpower3/), we cannot exclude false positive or false negative results, respectively. Particularly, with respect to challenge condition or sex subgroups, sample sizes are very small and might not allow for sufficient power, although a separate analysis conducted in the placebo group only revealed the same effects as in the total sample and therefore might be taken as some confirmation of our overall results. However, the present results have to be considered pilot data, which warrant replication in larger independent samples. Furthermore, with a mean age of 26.5 years our final sample is relatively young, so that a potentially confounding neglect of genetic predisposition for mental disorders manifesting at a later age cannot be excluded. Also, the average sum score of the CTQ in the presently investigated sample is low, indicating a small quantity of childhood maltreatment experiences and thus potentially super-normality of the present sample. Childhood maltreatment was assessed retrospectively, entailing impaired accuracy and reliability of answers due to recall bias or false answers (cf. [131]). Moreover, the CTQ is designed as a multi-factorial questionnaire [132], [133], so that subdimensions of maltreatment (e.g., emotional abuse, sexual abuse, etc.) might even more specifically interact with genetic factors in the etiology of anxiety. Future studies will therefore require more complex models of mediating and moderating factors between genes and the investigated phenotype, particularly given that personality and behavioral characteristics such as neuroticism or cognitive appraisal might moderate the GxE influence on the pathogenesis of anxiety and related intermediate phenotypes (cf. [73]).

In summary, the present results indicate a main as well as a GxE effect of the COMT Val158Met variant and childhood maltreatment on the affect-modulated startle reflex, supporting a complex pathogenetic model of the affect-modulated startle reflex as a basic neurobiological defensive reflex potentially related to anxiety and affective disorders. Future, preferably longitudinal studies investigating genetic and environmental effects on the affect-modulated startle response reflecting emotional reactivity might aid in a more neurobiologically informed understanding of the fear-anxiety-distress spectrum.

Methods

Samples and Procedures

A sample of unrelated healthy participants (N = 95; male = 46, female = 49; mean age: 26.42 years, SD = 6.11) was consecutively recruited at the Departments of Psychiatry, Universities of Muenster and Wuerzburg, Germany, in the context of a collaborative research study. Inclusion criteria were European descent (self-report up to 3rd generation), right-handedness and fluency in German. Exclusion criteria were manifest mental axis I disorder (M.I.N.I.: [134]), pregnancy or breast feeding, severe medical conditions, use of illegal drugs (assessed by a urine drug screening), alcohol consumption of more than 140 g per week, daily smoking of more than 20 cigarettes a day, caffeine or lactose intolerance, high caffeine consumption (more than 3 cups of coffee per day), less than a high school education, and age under 18 and over 50 years. A blood sample (20 ml EDTA blood) was taken for genetic analysis. Participants were asked to refrain from caffeine or tea consumption for one week prior to the investigation and not to smoke, consume alcohol (assessed by a breath test) or take any medication for at least 24 h prior to the investigation. To exclude any neurological or other somatic disorders participants underwent a brief physical and neurological examination in a screening session one week before the startle-experiment, where additionally heart activity (electrocardiogram) and basic blood parameters were checked. The protocol was approved by the ethics committees of the Universities of Muenster and Wuerzburg, Germany, and written informed consent was obtained from all subjects during the screening session. The study has been conducted according to the principles expressed in the Declaration of Helsinki.

Genotyping

All participants were genotyped for the COMT Val158Met polymorphism according to published protocols [10], [88]. Genotypes were determined by investigators blinded for outcome measures (startle reflex). Hardy-Weinberg criteria, assessed with the online available program DeFinetti (Wienker and Strom, accessed February 2011), were fulfilled for COMT Val158Met genotype distribution in the present sample (val/val: 17%, val/met: 47%, met/met: 36%; p = 0.792). The present sample constitutes a subsample (due to missing data for the environmental variable or COMT genotype) of participants included in a larger study [67], which was originally stratified for adenosine A2A receptor (ADORA2A) gene variation. As we have previously observed a significant interactive effect of ADORA2A 1976T>C genotype, caffeine intervention and picture category in the extended sample [67], ADORA2A 1976T>C genotypes were retrieved for also for the present sample (see [67]). Furthermore, as there is accumulating evidence for variation in the serotonin transporter gene (5-HTTLPR) to influence fear-potentiated startle response [92] and to interact with stressful life events to influence startle response or anxiety sensitivity [122], [135], we additionally genotyped our sample for this variant according to published protocols with minor modifications (see [136], [137]). Hardy-Weinberg criteria were fulfilled for both ADORA2A 1976T>C and 5-HTTLPR genotype distribution (both p>0.05).

Affect-modulated startle paradigm

After screening negative for drugs and pregnancy, all electrodes were fixed and checked for impedances below 5 kΩ. At first, eight startle stimuli (random intervals of one second till twelve seconds; 50 ms of 95 dB white noise with an instantaneous rise-time presented via Bose® Around-Ear Headphones) were presented, to get participants accustomed to the startle procedure and to minimize outlier startle responses during the critical trials. The experiment consisted of three blocks à 24 pictures and three minute breaks between the blocks. Each block contained eight unpleasant, eight neutral, and eight pleasant environmental cues, derived from a total of 72 pictures from the International Affective Picture System (IAPS: [138]); 24 of each valence, respectively). Pictures were randomized with the constraint that not two of the same valence (unpleasant, neutral or pleasant) were presented successively. IAPS pictures were presented for 8 seconds each with an intertrial interval (ITI) between 16.5 and 25.5 seconds (mean = 21 seconds). Startle probes were administered 2.5, 4.0, or 5.5 seconds after picture onset during picture presentation as well as 10 or 12 seconds after picture offset during the ITI. 75% of all trials contained startle probes during picture presentation (evenly distributed across each picture category), 12.5% of all trials contained startle probes during the ITI and 12.5% of the trials did not contain any startle probe. Two electrodes were placed under the left eye [65] to measure the electromyogram (EMG) activity of the orbicularis oculi muscle. The reference electrode was placed on the forehead, the ground electrode was placed on the processus mastoideus. BrainVision Analyzer 2 (Brain Products GmbH, Gilching, Germany) was used as analyzing software, to rectify, filter (Low Cutoff 28 Hz, High Cutoff 500 Hz, Notch 50 Hz), and smooth the signals offline (using a time constant of 50 ms). The difference between the highest peak 21 to 200 ms after and the average across 50 ms before startle probe presentation was taken as startle magnitude.

Caffeine intervention

The above mentioned startle paradigm was embedded in a double-blind, placebo-controlled caffeine challenge study-design (as described in detail in Domschke et al., 2012 [67]). Briefly, caffeine intervention was performed by oral administration of 300 mg caffeine citrate (equivalent to 150 mg freebase caffeine; cf. [61], [139], [140]). Participants were given a placebo or caffeine capsule 60 minutes before starting the startle paradigm. Caffeine levels were determined by saliva test.

Assessment of Childhood Trauma

All participants completed the German version of the Childhood Trauma Questionnaire [132], [133], comprising 28 items with a total sum score between a minimum of 25 and a maximum of 128 designed to retrospectively assess negative childhood experiences [133], [141], [142]. After instruction by the investigators, participants completed the CTQ on a computer in the laboratory and had the opportunity to ask questions concerning the questionnaire during the test session. The internal consistency of the German version of the CTQ sum score was found to be excellent (Cronbach´s α = 0.94; [143]). Also, the retest-reliability (r = 0.74–0.94) was found to be high [144]. The construct validity was comparable to the original English version [143]. A distinct convergence with other assessments of childhood maltreatment was observed [144]. For the German version of the CTQ, mean scores are only reported for different mental disorders and range between 40.1 in patients with anxiety disorders up to 63 in patients with borderline personality disorder [143].

Statistical Analysis

To control for influences of potentially extreme scores, all analyzed startle data were checked for outliers (>2.5 SD; cf. [145]). To prevent statistical inference errors from non-normality of data and to reduce influences of potential outliers, CTQ score was logarithmized using the natural log with base e (cf. [146]).

To exclude a possibly confounding influence of ADORA2A 1976T>C and 5-HTTLPR genotype distribution (see above), we evaluated frequencies of these genotypes in COMT Val158Met genotype groups by χ2 tests: ADORA2A 1976T>C and 5-HTTLPR genotype distributions did not differ between COMT genotype groups (ADORA2A: χ2 = 6.75, p = 0.15; 5-HTTPLR: χ2 = 1.14, p = 0.89), sex (ADORA2A: χ2 = 0.59, p = 0.74; 5-HTTPLR: χ2 = 1.38, p = 0.50) or challenge conditions (ADORA2A: χ2 = 1.49, p = 0.48; 5-HTTPLR: χ2 = 0.43, p = 0.81).

Possible differences regarding age and CTQ between sex (male vs. female participants), challenge condition (caffeine vs. placebo) and COMT Val158Met genotype groups were analyzed by means of T tests.

For genetic analyses, in a first step COMT Val158Met genotypes were coded as 0, 1 and 2 for the number of val alleles. Sex was coded as 0.5 for females and −0.5 for males, challenge condition as 0.5 for caffeine and −0.5 for placebo (cf. [147]). To exclude possible objectionable confounding effects, gene-environment correlations (rGE) were analyzed using bivariate correlation analysis.

Startle data were checked for zero responses and artifacts in each participant. Startle reactions with no detectable responses (fewer than 5 µV) were scored as zero. Artifacts were defined as spontaneous eye blinks during baseline or within 20 ms after startle probe onset and were scored as missing values. Participants with too many zero responses (more than 2.5 standard deviations above mean zero responses) or less than three acceptable startle responses in any picture category were excluded from data analysis. All startle responses were T-transformed within individual subjects in order to assure comparability of the data and to reduce interindividual variability (as described by [65];[56]). Despite the large variance in the untransformed raw data (startle (in µV) after presentation of unpleasant (M = 40.30, SD = 30.80), neutral (M = 37.18, SD = 28.27) and pleasant (M = 35.08, SD = 27.08) pictures) compared to the T-transformed data (see table 1), the basic ANOVA analysis was also conducted for raw data.

Influence of COMT Val158Met genotype on baseline startle response (ITI startle) was investigated using one-way ANOVA.

The affect-modulated startle responses were analyzed by ANOVA for repeated measures with picture category (unpleasant, neutral, and pleasant) as within-subjects factor and COMT genotype, sex and challenge condition (caffeine vs. placebo) as between-subjects factors. Pairwise comparisons of picture valence were assessed by means of post-hoc T-tests.

Influence of CTQ on ITI startle response and on response after presentation of pleasant, neutral and unpleasant pictures, respectively, was examined for the three COMT Val158Met genotypes separately by linear regression analyses.

For further genetic analyses based on the observed results yielded by the above mentioned statistics, COMT val/met and met/met genotypes were grouped together (0.5 = val/val vs −0.5 = val/met and −0.5 = met/met), reflecting a recessive model when assuming val to be the risk allele.

Also, the potentiations of the startle magnitude (T-transformed) after unpleasant IAPS picture presentation compared to neutral pictures (Diffunpl-neutr) and after neutral pictures compared to pleasant pictures (Diffneutr-pl) were calculated and used as dependent variables in the subsequent regression analyses. Based on the observed influences of sex, COMT Val158Met genotype and the interactive effects between COMT Val158Met genotype and CTQ (GxE), these effects on the potentiation of the startle magnitude were estimated by hierarchical multiple regression in a three-step procedure: The first included sex, grouped COMT Val158Met genotypes (see above) and logarithmized CTQ sum, in order to evaluate main effects on startle response. In a second step, a two-way interaction term for COMT Val158Met genotype and CTQ was added. Step 3 contained the two-way interaction of sex with COMT Val158Met genotype and CTQ sum and a three-way interaction with all three predictors (COMT Val158Met genotype, CTQ, sex). This order of variable entry enabled us to first investigate only main effects on startle magnitude potentiation. In a second step, we analyzed the increase in explained variance by inclusion of GxE. Thirdly, we tested for interactions with sex. Increase in explained variance (ΔR2) in successive regression steps was tested by means of F-test. For each regression step, Gaussian distribution of residual variances was confirmed by a post-hoc Kolmogorov-Smirnov test.

For all tests, a p-value <0.05 was considered statistically significant. All analyses were run with SPSS Version 18.0.

Acknowledgments

We acknowledge the valuable critical comments and statistical support by Fred Rist, Ph.D.

Author Contributions

Conceived and designed the experiments: KD JD PP. Performed the experiments: BK B. Winter AG. Analyzed the data: BK B. Winter AG AM. Contributed reagents/materials/analysis tools: PP AM PZ MJH VA B. Warrings CJ AR AD. Wrote the paper: BK KD JD.

References

  1. 1. Hettema JM, Neale MC, Kendler KS (2001) A review and meta-analysis of the genetic epidemiology of anxiety disorders. Am J Psychiatry 158: 1568–1578.JM HettemaMC NealeKS Kendler2001A review and meta-analysis of the genetic epidemiology of anxiety disorders.Am J Psychiatry15815681578
  2. 2. Kendler KS, Karkowski LM, Prescott CA (1999) Fears and phobias: reliability and heritability. Psychol Med 29: 539–553.KS KendlerLM KarkowskiCA Prescott1999Fears and phobias: reliability and heritability.Psychol Med29539553
  3. 3. Sullivan PF, Neale MC, Kendler KS (2000) Genetic epidemiology of major depression. review and meta-analysis. Am J Psychiatry 157: 1552–1562.PF SullivanMC NealeKS Kendler2000Genetic epidemiology of major depression. review and meta-analysis.Am J Psychiatry15715521562
  4. 4. Hettema JM, Prescott CA, Myers JM, Neale MC, Kendler KS (2005) The structure of genetic and environmental risk factors for anxiety disorders in men and women. Arch Gen Psychiatry 62: 182–189.JM HettemaCA PrescottJM MyersMC NealeKS Kendler2005The structure of genetic and environmental risk factors for anxiety disorders in men and women.Arch Gen Psychiatry62182189
  5. 5. Shulman R, Griffiths J, Diewold P (1978) Catechol-O-methyl transferase activity in patients with depressive illness and anxiety states. Br J Psychiatry 132: 133–138.R. ShulmanJ. GriffithsP. Diewold1978Catechol-O-methyl transferase activity in patients with depressive illness and anxiety states.Br J Psychiatry132133138
  6. 6. Richard IH, Schiffer RB, Kurlan R (1996) Anxiety and Parkinson's disease. J Neuropsychiatry Clin Neurosci 8: 383–392.IH RichardRB SchifferR. Kurlan1996Anxiety and Parkinson's disease.J Neuropsychiatry Clin Neurosci8383392
  7. 7. Winqvist R, Lundstrom K, Salminen M, Laatikainen M, Ulmanen I (1991) Mapping of human catechol-Omethyltransferase gene to 22q11.2 and detection of a frequent RFLP with BglI. Cytogenet Cell Genet 59: 253–257.R. WinqvistK. LundstromM. SalminenM. LaatikainenI. Ulmanen1991Mapping of human catechol-Omethyltransferase gene to 22q11.2 and detection of a frequent RFLP with BglI.Cytogenet Cell Genet59253257
  8. 8. Chen J, Lipska BK, Halim N, Ma QD, Matsumoto M, et al. (2004) Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet 75: 807–821.J. ChenBK LipskaN. HalimQD MaM. Matsumoto2004Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain.Am J Hum Genet75807821
  9. 9. Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, et al. (1996) Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 6: 243–250.HM LachmanDF PapolosT. SaitoYM YuCL Szumlanski1996Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders.Pharmacogenetics6243250
  10. 10. Domschke K, Freitag CM, Kuhlenbaumer G, Schirmacher A, Sand P, et al. (2004) Association of the functional V158M catechol-O-methyl-transferase polymorphism with panic disorder in women. Int J Neuropsychopharmacol 7: 183–188.K. DomschkeCM FreitagG. KuhlenbaumerA. SchirmacherP. Sand2004Association of the functional V158M catechol-O-methyl-transferase polymorphism with panic disorder in women.Int J Neuropsychopharmacol7183188
  11. 11. Hamilton SP, Slager SL, Heiman GA, Deng Z, Haghighi F, et al. (2002) Evidence for a susceptibility locus for panic disorder near the catechol-O-methyltransferase gene on chromosome 22. Biol Psychiatry 51: 591–601.SP HamiltonSL SlagerGA HeimanZ. DengF. Haghighi2002Evidence for a susceptibility locus for panic disorder near the catechol-O-methyltransferase gene on chromosome 22.Biol Psychiatry51591601
  12. 12. Lonsdorf TB, Ruck C, Bergstrom J, Andersson G, Ohman A, et al. (2010) The COMTval158met polymorphism is associated with symptom relief during exposure-based cognitive-behavioral treatment in panic disorder. BMC Psychiatry 10: 99.TB LonsdorfC. RuckJ. BergstromG. AnderssonA. Ohman2010The COMTval158met polymorphism is associated with symptom relief during exposure-based cognitive-behavioral treatment in panic disorder.BMC Psychiatry1099
  13. 13. Rothe C, Koszycki D, Bradwejn J, King N, Deluca V, et al. (2006) Association of the Val158Met catechol O-methyltransferase genetic polymorphism with panic disorder. Neuropsychopharmacology 31: 2237–2242.C. RotheD. KoszyckiJ. BradwejnN. KingV. Deluca2006Association of the Val158Met catechol O-methyltransferase genetic polymorphism with panic disorder.Neuropsychopharmacology3122372242
  14. 14. McGrath M, Kawachi I, Ascherio A, Colditz GA, Hunter DJ, et al. (2004) Association between catechol-O-methyltransferase and phobic anxiety. Am J Psychiatry 161: 1703–1705.M. McGrathI. KawachiA. AscherioGA ColditzDJ Hunter2004Association between catechol-O-methyltransferase and phobic anxiety.Am J Psychiatry16117031705
  15. 15. Hettema JM, An SS, Bukszar J, van den Oord EJ, Neale MC, et al. (2008) Catechol-O-methyltransferase contributes to genetic susceptibility shared among anxiety spectrum phenotypes. Biol Psychiatry 64: 302–310.JM HettemaSS AnJ. BukszarEJ van den OordMC Neale2008Catechol-O-methyltransferase contributes to genetic susceptibility shared among anxiety spectrum phenotypes.Biol Psychiatry64302310
  16. 16. Kim SJ, Kim YS, Kim SY, Lee HS, Kim CH (2006) An association study of catechol-O-methyltransferase and monoamine oxidase A polymorphisms and personality traits in Koreans. Neuroscience Letters 401: 154–158.SJ KimYS KimSY KimHS LeeCH Kim2006An association study of catechol-O-methyltransferase and monoamine oxidase A polymorphisms and personality traits in Koreans.Neuroscience Letters401154158
  17. 17. Olsson CA, Byrnes GB, Anney RJ, Collins V, Hemphill SA, et al. (2007) COMT Val(158)Met and 5HTTLPR functional loci interact to predict persistence of anxiety across adolescence: results from the Victorian Adolescent Health Cohort Study. Brain Behav 6: 647–652.CA OlssonGB ByrnesRJ AnneyV. CollinsSA Hemphill2007COMT Val(158)Met and 5HTTLPR functional loci interact to predict persistence of anxiety across adolescence: results from the Victorian Adolescent Health Cohort Study.Brain Behav6647652
  18. 18. Baekken PM, Skorpen F, Stordal E, Zwart JA, Hagen K (2008) Depression and anxiety in relation to catechol-O-methyltransferase Val158Met genotype in the general population: the Nord-Trondelag Health Study (HUNT). BMC Psychiatry 8: 48.PM BaekkenF. SkorpenE. StordalJA ZwartK. Hagen2008Depression and anxiety in relation to catechol-O-methyltransferase Val158Met genotype in the general population: the Nord-Trondelag Health Study (HUNT).BMC Psychiatry848
  19. 19. Henderson AS, Korten AE, Jorm AF, Jacomb PA, Christensen H, et al. (2000) COMT and DRD3 polymorphisms, environmental exposures, and personality traits related to common mental disorders. Am J Med Genet C Semin Med Genet 96: 102–107.AS HendersonAE KortenAF JormPA JacombH. Christensen2000COMT and DRD3 polymorphisms, environmental exposures, and personality traits related to common mental disorders.Am J Med Genet C Semin Med Genet96102107
  20. 20. Ohara K, Nagai M, Suzuki Y, Ochiai M, Ohara K (1998a) No association between anxiety disorders and catechol-O-methyltransferase polymorphism. Psychiatry Res 80: 145–148.K. OharaM. NagaiY. SuzukiM. OchiaiK. Ohara1998aNo association between anxiety disorders and catechol-O-methyltransferase polymorphism.Psychiatry Res80145148
  21. 21. Samochowiec J, Hajduk A, Samochowiec A, Horodnicki J, Stepien G, et al. (2004) Association studies of MAO-A, COMT, and 5-HTT genes polymorphisms in patients with anxiety disorders of the phobic spectrum. Psychiatry Res 128: 21–26.J. SamochowiecA. HajdukA. SamochowiecJ. HorodnickiG. Stepien2004Association studies of MAO-A, COMT, and 5-HTT genes polymorphisms in patients with anxiety disorders of the phobic spectrum.Psychiatry Res1282126
  22. 22. Wray NR, James MR, Dumenil T, Handoko HY, Lind PA, et al. (2008) Association study of candidate variants of COMT with neuroticism, anxiety and depression. Am J Med Genet B Neuropsychiatr Genet 147B: 1314–1318.NR WrayMR JamesT. DumenilHY HandokoPA Lind2008Association study of candidate variants of COMT with neuroticism, anxiety and depression.Am J Med Genet B Neuropsychiatr Genet147B13141318
  23. 23. Evans J, Xu K, Heron J, Enoch MA, Araya R, et al. (2009) Emotional symptoms in children: The effect of maternal depression, life events, and COMT genotype. Am J Med Genet B Neuropsychiatr Genet 150B: 209–218.J. EvansK. XuJ. HeronMA EnochR. Araya2009Emotional symptoms in children: The effect of maternal depression, life events, and COMT genotype.Am J Med Genet B Neuropsychiatr Genet150B209218
  24. 24. Woo JM, Yoon KS, Yu BH (2002) Catechol O-methyltransferase genetic polymorphism in panic disorder. Am J Psychiatry 159: 1785–1787.JM WooKS YoonBH Yu2002Catechol O-methyltransferase genetic polymorphism in panic disorder.Am J Psychiatry15917851787
  25. 25. Woo JM, Yoon KS, Choi YH, Oh KS, Lee YS, et al. (2004) The association between panic disorder and the L/L genotype of catechol-O-methyltransferase. J Psychiatr Res 38: 365–370.JM WooKS YoonYH ChoiKS OhYS Lee2004The association between panic disorder and the L/L genotype of catechol-O-methyltransferase.J Psychiatr Res38365370
  26. 26. Kang EH, Song YJ, Kim KJ, Shim HB, Park JE, et al. (2010) Sympathetic nervous function and the effect of the catechol-O-methyltransferase Val(158)Met polymorphism in patients with panic disorder. J Affect Disord 123: 337–340.EH KangYJ SongKJ KimHB ShimJE Park2010Sympathetic nervous function and the effect of the catechol-O-methyltransferase Val(158)Met polymorphism in patients with panic disorder.J Affect Disord123337340
  27. 27. Olsson CA, Anney RJ, Lotfi-Miri M, Byrnes GB, Williamson R, et al. (2005) Association between the COMT Val158Met polymorphism and propensity to anxiety in an Australian population-based longitudinal study of adolescent health. Psychiatr Genet 15: 109–115.CA OlssonRJ AnneyM. Lotfi-MiriGB ByrnesR. Williamson2005Association between the COMT Val158Met polymorphism and propensity to anxiety in an Australian population-based longitudinal study of adolescent health.Psychiatr Genet15109115
  28. 28. Eley TC, Tahir E, Angleitner A, Harriss K, McClay J, et al. (2003) Association analysis of MAOA and COMT with neuroticism assessed by peers. Am J Med Genet B Neuropsychiatr Genet 120B: 90–96.TC EleyE. TahirA. AngleitnerK. HarrissJ. McClay2003Association analysis of MAOA and COMT with neuroticism assessed by peers.Am J Med Genet B Neuropsychiatr Genet120B9096
  29. 29. Enoch MA, Xu K, Ferro E, Harris CR, Goldman D (2003) Genetic origins of anxiety in women: a role for a functional catechol-O-methyltransferase polymorphism. Psychiatr Genet 13: 33–41.MA EnochK. XuE. FerroCR HarrisD. Goldman2003Genetic origins of anxiety in women: a role for a functional catechol-O-methyltransferase polymorphism.Psychiatr Genet133341
  30. 30. Stein MB, Fallin MD, Schork NJ, Gelernter J (2005) COMT polymorphisms and anxiety-related personality traits. Neuropsychopharmacology 30: 2092–2102.MB SteinMD FallinNJ SchorkJ. Gelernter2005COMT polymorphisms and anxiety-related personality traits.Neuropsychopharmacology3020922102
  31. 31. Lonsdorf TB, Weike AI, Nikamo P, Schalling M, Hamm AO, et al. (2009) Genetic gating of human fear learning and extinction: possible implications for gene-environment interaction in anxiety disorder. Psychol Sci 20: 198–206.TB LonsdorfAI WeikeP. NikamoM. SchallingAO Hamm2009Genetic gating of human fear learning and extinction: possible implications for gene-environment interaction in anxiety disorder.Psychol Sci20198206
  32. 32. Enoch MA, White KV, Waheed J, Goldman D (2008) Neurophysiological and genetic distinctions between pure and comorbid anxiety disorders. Depress Anxiety 25: 383–392.MA EnochKV WhiteJ. WaheedD. Goldman2008Neurophysiological and genetic distinctions between pure and comorbid anxiety disorders.Depress Anxiety25383392
  33. 33. Massat I, Souery D, Del-Favero J, Nothen M, Blackwood D, et al. (2005) Association between COMT (Val158Met) functional polymorphism and early onset in patients with major depressive disorder in a European multicenter genetic association study. Mol Psychiatry 10: 598–605.I. MassatD. SoueryJ. Del-FaveroM. NothenD. Blackwood2005Association between COMT (Val158Met) functional polymorphism and early onset in patients with major depressive disorder in a European multicenter genetic association study.Mol Psychiatry10598605
  34. 34. Funke B, Malhotra AK, Finn CT, Plocik AM, Lake SL, et al. (2005) COMT genetic variation confers risk for psychotic and affective disorders: a case control study. Behav Brain Funct 1: 19.B. FunkeAK MalhotraCT FinnAM PlocikSL Lake2005COMT genetic variation confers risk for psychotic and affective disorders: a case control study.Behav Brain Funct119
  35. 35. Ohara K, Nagai M, Suzuki Y, Ohara K (1998b) Low activity allele of catechol-o-methyltransferase gene and Japanese unipolar depression. Neuroreport 9: 1305–1308.K. OharaM. NagaiY. SuzukiK. Ohara1998bLow activity allele of catechol-o-methyltransferase gene and Japanese unipolar depression.Neuroreport913051308
  36. 36. Meyer-Lindenberg A, Weinberger DR (2006) Intermediate phenotypes and genetic mechanisms of psychiatric disorders. Nat Rev Neurosci 7: 818–827.A. Meyer-LindenbergDR Weinberger2006Intermediate phenotypes and genetic mechanisms of psychiatric disorders.Nat Rev Neurosci7818827
  37. 37. Grillon C, Baas J (2003) A review of the modulation of the startle reflex by affective states and its application in psychiatry. Clin Neurophysiol 114: 1557–1579.C. GrillonJ. Baas2003A review of the modulation of the startle reflex by affective states and its application in psychiatry.Clin Neurophysiol11415571579
  38. 38. Lang PJ, Bradley MM, Cuthbert BN (1990) Emotion, attention, and the startle reflex. Psychol Rev 97: 377–395.PJ LangMM BradleyBN Cuthbert1990Emotion, attention, and the startle reflex.Psychol Rev97377395
  39. 39. Butler RW, Braff DL, Rausch JL, Jenkins MA, Sprock J, et al. (1990) Physiological evidence of exaggerated startle response in a subgroup of Vietnam veterans with combat-related PTSD. Am J Psychiatry 147: 1308–1312.RW ButlerDL BraffJL RauschMA JenkinsJ. Sprock1990Physiological evidence of exaggerated startle response in a subgroup of Vietnam veterans with combat-related PTSD.Am J Psychiatry14713081312
  40. 40. Grillon C, Ameli R, Goddard A, Woods SW, Davis M (1994) Baseline and fear-potentiated startle in panic disorder patients. Biol Psychiatry 35: 431–439.C. GrillonR. AmeliA. GoddardSW WoodsM. Davis1994Baseline and fear-potentiated startle in panic disorder patients.Biol Psychiatry35431439
  41. 41. Grillon C, Morgan CA III, Davis M, Southwick SM (1998) Effects of experimental context and explicit threat cues on acoustic startle in Vietnam veterans with posttraumatic stress disorder. Biol Psychiatry 44: 1027–1036.C. GrillonCA Morgan IIIM. DavisSM Southwick1998Effects of experimental context and explicit threat cues on acoustic startle in Vietnam veterans with posttraumatic stress disorder.Biol Psychiatry4410271036
  42. 42. Hamm AO, Greenwald MK, Bradley MM, Cuthbert BN, Lang PJ (1991) The fear potentiated startle effect. Blink reflex modulation as a result of classical aversive conditioning. Integr Physiol Behav Sci 26: 119–126.AO HammMK GreenwaldMM BradleyBN CuthbertPJ Lang1991The fear potentiated startle effect. Blink reflex modulation as a result of classical aversive conditioning.Integr Physiol Behav Sci26119126
  43. 43. Hamm AO, Cuthbert BN, Globisch J, Vaitl D (1997) Fear and the startle reflex: blink modulation and autonomic response patterns in animal and mutilation fearful subjects. Psychophysiology 34: 97–107.AO HammBN CuthbertJ. GlobischD. Vaitl1997Fear and the startle reflex: blink modulation and autonomic response patterns in animal and mutilation fearful subjects.Psychophysiology3497107
  44. 44. Vrana SR, Spence EL, Lang PJ (1988) The startle probe response: a new measure of emotion? J Abnorm Psychol 97: 487–491.SR VranaEL SpencePJ Lang1988The startle probe response: a new measure of emotion?J Abnorm Psychol97487491
  45. 45. Filion DL, Dawson ME, Schell AM (1998) The psychological significance of human startle eyeblink modification: a review. Biol Psychol 47: 1–43.DL FilionME DawsonAM Schell1998The psychological significance of human startle eyeblink modification: a review.Biol Psychol47143
  46. 46. Grillon C (2002) Startle reactivity and anxiety disorders: aversive conditioning, context, and neurobiology. Biol Psychiatry 52: 958–975.C. Grillon2002Startle reactivity and anxiety disorders: aversive conditioning, context, and neurobiology.Biol Psychiatry52958975
  47. 47. Melzig CA, Weike AI, Hamm AO, Thayer JF (2009) Individual differences in fear-potentiated startle as a function of resting heart rate variability: implications for panic disorder. Int J Psychophysiol 71: 109–117.CA MelzigAI WeikeAO HammJF Thayer2009Individual differences in fear-potentiated startle as a function of resting heart rate variability: implications for panic disorder.Int J Psychophysiol71109117
  48. 48. Michalowski JM, Melzig CA, Weike AI, Stockburger J, Schupp HT, et al. (2009) Brain dynamics in spider-phobic individuals exposed to phobia-relevant and other emotional stimuli. Emotion. 9: 306–315.JM MichalowskiCA MelzigAI WeikeJ. StockburgerHT Schupp2009Brain dynamics in spider-phobic individuals exposed to phobia-relevant and other emotional stimuli. Emotion.9306315
  49. 49. Vaidyanathan U, Patrick CJ, Cuthbert BN (2009) Linking dimensional models of internalizing psychopathology to neurobiological systems: affect-modulated startle as an indicator of fear and distress disorders and affiliated traits. Psychol Bull 135: 909–942.U. VaidyanathanCJ PatrickBN Cuthbert2009Linking dimensional models of internalizing psychopathology to neurobiological systems: affect-modulated startle as an indicator of fear and distress disorders and affiliated traits.Psychol Bull135909942
  50. 50. Anokhin AP, Heath AC, Myers E, Ralano A, Wood S (2003) Genetic influences on prepulse inhibition of startle reflex in humans. Neurosci Lett 353: 45–48.AP AnokhinAC HeathE. MyersA. RalanoS. Wood2003Genetic influences on prepulse inhibition of startle reflex in humans.Neurosci Lett3534548
  51. 51. Anokhin AP, Golosheykin S, Heath AC (2007) Genetic and environmental influences on emotion-modulated startle reflex: a twin study. Psychophysiology 44: 106–112.AP AnokhinS. GolosheykinAC Heath2007Genetic and environmental influences on emotion-modulated startle reflex: a twin study.Psychophysiology44106112
  52. 52. Hasenkamp W, Epstein MP, Green A, Wilcox L, Boshoven W, et al. (2010) Heritability of acoustic startle magnitude, prepulse inhibition, and startle latency in schizophrenia and control families. Psychiatry Res 178: 236–243.W. HasenkampMP EpsteinA. GreenL. WilcoxW. Boshoven2010Heritability of acoustic startle magnitude, prepulse inhibition, and startle latency in schizophrenia and control families.Psychiatry Res178236243
  53. 53. Greenwood TA, Braff DL, Light GA, Cadenhead KS, Calkins ME, et al. (2007) Initial heritability analyses of endophenotypic measures for schizophrenia: the consortium on the genetics of schizophrenia. Arch Gen Psychiatry 64: 1242–1250.TA GreenwoodDL BraffGA LightKS CadenheadME Calkins2007Initial heritability analyses of endophenotypic measures for schizophrenia: the consortium on the genetics of schizophrenia.Arch Gen Psychiatry6412421250
  54. 54. Carlson SR, Katsanis J, Iacono WG, McGue M (1997) Emotional modulation of the startle reflex in twins: preliminary findings. Biol Psychol 46: 235–246.SR CarlsonJ. KatsanisWG IaconoM. McGue1997Emotional modulation of the startle reflex in twins: preliminary findings.Biol Psychol46235246
  55. 55. Montag C, Buckholtz JW, Hartmann P, Merz M, Burk C, et al. (2008) COMT genetic variation affects fear processing: psychophysiological evidence. Behav Neurosci 122: 901–909.C. MontagJW BuckholtzP. HartmannM. MerzC. Burk2008COMT genetic variation affects fear processing: psychophysiological evidence.Behav Neurosci122901909
  56. 56. Pauli P, Conzelmann A, Mucha RF, Weyers P, Baehne CG, et al. (2010) Affect-modulated startle reflex and dopamine D4 receptor gene variation. Psychophysiology 47: 25–33.P. PauliA. ConzelmannRF MuchaP. WeyersCG Baehne2010Affect-modulated startle reflex and dopamine D4 receptor gene variation.Psychophysiology472533
  57. 57. Armbruster D, Mueller A, Strobel A, Lesch KP, Kirschbaum C, et al. (2011) Variation in genes involved in dopamine clearance influence the startle response in older adults. J Neural Transm 118: 1281–1292.D. ArmbrusterA. MuellerA. StrobelKP LeschC. Kirschbaum2011Variation in genes involved in dopamine clearance influence the startle response in older adults.J Neural Transm11812811292
  58. 58. Klumpers F, Heitland I, Oosting RS, Kenemans JL, Baas JM (2008) Genetic variation in serotonin transporter function affects human fear expression indexed by fear-potentiated startle. Biol Psychol. 89: 277–82.F. KlumpersI. HeitlandRS OostingJL KenemansJM Baas2008Genetic variation in serotonin transporter function affects human fear expression indexed by fear-potentiated startle. Biol Psychol.8927782
  59. 59. Powell KR, Koppelman LF, Holtzman SG (1999) Differential involvement of dopamine in mediating the discriminative stimulus effects of low and high doses of caffeine in rats. Behav Pharmacol 10: 707–716.KR PowellLF KoppelmanSG Holtzman1999Differential involvement of dopamine in mediating the discriminative stimulus effects of low and high doses of caffeine in rats.Behav Pharmacol10707716
  60. 60. Huang ZL, Qu WM, Eguchi N, Chen JF, Schwarzschild MA, et al. (2005) Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine. Nat Neurosci 8: 858–859.ZL HuangWM QuN. EguchiJF ChenMA Schwarzschild2005Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine.Nat Neurosci8858859
  61. 61. Childs E, Hohoff C, Deckert J, Xu K, Badner J, et al. (2008) Association between ADORA2A and DRD2 polymorphisms and caffeine-induced anxiety. Neuropsychopharmacology 33: 2791–2800.E. ChildsC. HohoffJ. DeckertK. XuJ. Badner2008Association between ADORA2A and DRD2 polymorphisms and caffeine-induced anxiety.Neuropsychopharmacology3327912800
  62. 62. Charney DS, Heninger GR, Jatlow PI (1985) Increased anxiogenic effects of caffeine in panic disorders. Arch Gen Psychiatry 42: 233–243.DS CharneyGR HeningerPI Jatlow1985Increased anxiogenic effects of caffeine in panic disorders.Arch Gen Psychiatry42233243
  63. 63. Yang A, Palmer AA, de Wit H (2010) Genetics of caffeine consumption and responses to caffeine. Psychopharmacology (Berl) 211: 245–257.A. YangAA PalmerH. de Wit2010Genetics of caffeine consumption and responses to caffeine.Psychopharmacology (Berl)211245257
  64. 64. Andrews SE, Blumenthal TD, Flaten MA (1998) Effects of caffeine and caffeine-associated stimuli on the human startle eyeblink reflex. Pharmacol Biochem Behav 59: 39–44.SE AndrewsTD BlumenthalMA Flaten1998Effects of caffeine and caffeine-associated stimuli on the human startle eyeblink reflex.Pharmacol Biochem Behav593944
  65. 65. Blumenthal TD, Cuthbert BN, Filion DL, Hackley S, Lipp OV, et al. (2005) Committee report: Guidelines for human startle eyeblink electromyographic studies. Psychophysiology 42: 1–15.TD BlumenthalBN CuthbertDL FilionS. HackleyOV Lipp2005Committee report: Guidelines for human startle eyeblink electromyographic studies.Psychophysiology42115
  66. 66. Schicatano EJ, Blumenthal TD (1995) The effects of different doses of caffeine on habituation of the human acoustic startle reflex. Pharmacol Biochem Behav 52: 231–236.EJ SchicatanoTD Blumenthal1995The effects of different doses of caffeine on habituation of the human acoustic startle reflex.Pharmacol Biochem Behav52231236
  67. 67. Domschke K, Gajewska A, Winter B, Mühlberger A, Reif A, et al. (2012) ADORA2A gene variation, caffeine and emotional perception – a multi-level interactional effect on startle reflex. Neuropsychopharmacology 37: 759–769.K. DomschkeA. GajewskaB. WinterA. MühlbergerA. Reif2012ADORA2A gene variation, caffeine and emotional perception – a multi-level interactional effect on startle reflex.Neuropsychopharmacology37759769
  68. 68. Bandelow B, Spath C, Tichauer GA, Broocks A, Hajak G, et al. (2002) Early traumatic life events, parental attitudes, family history, and birth risk factors in patients with panic disorder. Compr Psychiatry 43: 269–278.B. BandelowC. SpathGA TichauerA. BroocksG. Hajak2002Early traumatic life events, parental attitudes, family history, and birth risk factors in patients with panic disorder.Compr Psychiatry43269278
  69. 69. Brown GW, Harris TO (1993) Aetiology of anxiety and depressive disorders in an inner-city population. 1. Early adversity. Psychol Med 23: 143–154.GW BrownTO Harris1993Aetiology of anxiety and depressive disorders in an inner-city population. 1. Early adversity.Psychol Med23143154
  70. 70. Stein MB, Walker JR, Anderson G, Hazen AL, Ross CA, et al. (1996) Childhood physical and sexual abuse in patients with anxiety disorders and in a community sample. Am J Psychiatry 153: 275–277.MB SteinJR WalkerG. AndersonAL HazenCA Ross1996Childhood physical and sexual abuse in patients with anxiety disorders and in a community sample.Am J Psychiatry153275277
  71. 71. Bandelow B, Alvarez TG, Spath C, Broocks A, Hajak G, et al. (2001) Separation anxiety and actual separation experiences during childhood in patients with panic disorder. Can J Psychiatry 46: 948–952.B. BandelowTG AlvarezC. SpathA. BroocksG. Hajak2001Separation anxiety and actual separation experiences during childhood in patients with panic disorder.Can J Psychiatry46948952
  72. 72. Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ (1992) Childhood parental loss and adult psychopathology in women. A twin study perspective. Arch Gen Psychiatry 49: 109–116.KS KendlerMC NealeRC KesslerAC HeathLJ Eaves1992Childhood parental loss and adult psychopathology in women. A twin study perspective.Arch Gen Psychiatry49109116
  73. 73. Klauke B, Deckert J, Reif A, Pauli P, Domschke K (2010) Life events in panic disorder – an update on “candidate stressors” Depress Anxiety 27: 716–730.B. KlaukeJ. DeckertA. ReifP. PauliK. Domschke2010Life events in panic disorder – an update on “candidate stressors”Depress Anxiety27716730
  74. 74. Spatola CA, Scaini S, Pesenti-Gritti P, Medland SE, Moruzzi S, et al. (2011) Gene-environment interactions in panic disorder and CO sensitivity: Effects of events occurring early in life. Am J Med Genet B Neuropsychiatr Genet 156: 79–88.CA SpatolaS. ScainiP. Pesenti-GrittiSE MedlandS. Moruzzi2011Gene-environment interactions in panic disorder and CO sensitivity: Effects of events occurring early in life.Am J Med Genet B Neuropsychiatr Genet1567988
  75. 75. Maslova LN, Bulygina VV, Popova NK (2002) Immediate and long-lasting effects of chronic stress in the prepubertal age on the startle reflex. Physiol Behav 75: 217–225.LN MaslovaVV BulyginaNK Popova2002Immediate and long-lasting effects of chronic stress in the prepubertal age on the startle reflex.Physiol Behav75217225
  76. 76. Jovanovic T, Blanding NQ, Norrholm SD, Duncan E, Bradley B, et al. (2009) Childhood abuse is associated with increased startle reactivity in adulthood. Depress Anxiety 26: 1018–1026.T. JovanovicNQ BlandingSD NorrholmE. DuncanB. Bradley2009Childhood abuse is associated with increased startle reactivity in adulthood.Depress Anxiety2610181026
  77. 77. Medina AM, Mejia VY, Schell AM, Dawson ME, Margolin G (2001) Startle reactivity and PTSD symptoms in a community sample of women. Psychiatry Res 101: 157–169.AM MedinaVY MejiaAM SchellME DawsonG. Margolin2001Startle reactivity and PTSD symptoms in a community sample of women.Psychiatry Res101157169
  78. 78. Kolassa IT, Kolassa S, Ertl V, Papassotiropoulos A, de Quervain DJ (2010) The risk of posttraumatic stress disorder after trauma depends on traumatic load and the catechol-o-methyltransferase Val(158)Met polymorphism. Biol Psychiatry 67: 304–308.IT KolassaS. KolassaV. ErtlA. PapassotiropoulosDJ de Quervain2010The risk of posttraumatic stress disorder after trauma depends on traumatic load and the catechol-o-methyltransferase Val(158)Met polymorphism.Biol Psychiatry67304308
  79. 79. Quednow BB, Schmechtig A, Ettinger U, Petrovsky N, Collier DA, et al. (2009) Sensorimotor gating depends on polymorphisms of the serotonin-2A receptor and catechol-O-methyltransferase, but not on neuregulin-1 Arg38Gln genotype: a replication study. Biol Psychiatry 66: 614–620.BB QuednowA. SchmechtigU. EttingerN. PetrovskyDA Collier2009Sensorimotor gating depends on polymorphisms of the serotonin-2A receptor and catechol-O-methyltransferase, but not on neuregulin-1 Arg38Gln genotype: a replication study.Biol Psychiatry66614620
  80. 80. Roussos P, Giakoumaki SG, Rogdaki M, Pavlakis S, Frangou S, et al. (2008) Prepulse inhibition of the startle reflex depends on the catechol O-methyltransferase Val158Met gene polymorphism. Psychol Med 38: 1651–1658.P. RoussosSG GiakoumakiM. RogdakiS. PavlakisS. Frangou2008Prepulse inhibition of the startle reflex depends on the catechol O-methyltransferase Val158Met gene polymorphism.Psychol Med3816511658
  81. 81. Giakoumaki SG, Roussos P, Bitsios P (2008) Improvement of prepulse inhibition and executive function by the COMT inhibitor tolcapone depends on COMT Val158Met polymorphism. Neuropsychopharmacology 33: 3058–3068.SG GiakoumakiP. RoussosP. Bitsios2008Improvement of prepulse inhibition and executive function by the COMT inhibitor tolcapone depends on COMT Val158Met polymorphism.Neuropsychopharmacology3330583068
  82. 82. Bradley MM, Cuthbert BN, Lang PJ (1993) Pictures as prepulse: Attention and emotion in startle modification. Psychophysiology 30: 541–545.MM BradleyBN CuthbertPJ Lang1993Pictures as prepulse: Attention and emotion in startle modification.Psychophysiology30541545
  83. 83. Ludewig S, Geyer MA, Ramseier M, Vollenweider FX, Rechsteiner E, et al. (2005) Information-processing deficits and cognitive dysfunction in panic disorder. J Psychiatry Neurosci 30: 37–43.S. LudewigMA GeyerM. RamseierFX VollenweiderE. Rechsteiner2005Information-processing deficits and cognitive dysfunction in panic disorder.J Psychiatry Neurosci303743
  84. 84. Sabatinelli D, Bradley MM, Lang PJ (2001) Affective startle modulation in anticipation and perception. Psychophysiology 38: 719–722.D. SabatinelliMM BradleyPJ Lang2001Affective startle modulation in anticipation and perception.Psychophysiology38719722
  85. 85. Lang PJ, McTeague LM (2009) The anxiety disorder spectrum: fear imagery, physiological reactivity, and differential diagnosis. Anxiety Stress Coping 22: 5–25.PJ LangLM McTeague2009The anxiety disorder spectrum: fear imagery, physiological reactivity, and differential diagnosis.Anxiety Stress Coping22525
  86. 86. Hawk LW, Cook EW (2000) Independence of valence modulation and prepulse inhibition of startle. Psychophysiology 37: 5–12.LW HawkEW Cook2000Independence of valence modulation and prepulse inhibition of startle.Psychophysiology37512
  87. 87. Davis M, Walker DL, Lee Y (1997) Roles of the amygdala and bed nucleus of the stria terminalis in fear and anxiety measured with the acoustic startle reflex. Ann N Y Acad Sci 831: 305–331.M. DavisDL WalkerY. Lee1997Roles of the amygdala and bed nucleus of the stria terminalis in fear and anxiety measured with the acoustic startle reflex.Ann N Y Acad Sci831305331
  88. 88. Domschke K, Ohrmann P, Braun M, Suslow T, Bauer J, et al. (2008) Influence of the catechol-O-methyltransferase val158met genotype on amygdala and prefrontal cortex emotional processing in panic disorder. Psychiatry Res 163: 13–20.K. DomschkeP. OhrmannM. BraunT. SuslowJ. Bauer2008Influence of the catechol-O-methyltransferase val158met genotype on amygdala and prefrontal cortex emotional processing in panic disorder.Psychiatry Res1631320
  89. 89. Domschke K, Baune BT, Havlik L, Stuhrmann A, Suslow T, et al. Catechol-O-methyltransferase gene variation: Impact on amygdala response to aversive stimuli, NeuroImage, in press. Domschke K, Baune BT, Havlik L, Stuhrmann A, Suslow T, et al.Catechol-O-methyltransferase gene variation: Impact on amygdala response to aversive stimuli, NeuroImage, in press
  90. 90. Kempton MJ, Haldane M, Jogia J, Christodoulou T, Powell J, et al. (2009) The effects of gender and COMT Val158Met polymorphism on fearful facial affect recognition: a fMRI study. Int J Neuropsychopharmacol 12: 371–381.MJ KemptonM. HaldaneJ. JogiaT. ChristodoulouJ. Powell2009The effects of gender and COMT Val158Met polymorphism on fearful facial affect recognition: a fMRI study.Int J Neuropsychopharmacol12371381
  91. 91. Lelli-Chiesa G, Kempton MJ, Jogia J, Tatarelli R, Girardi P, et al. (2011) The impact of the Val158Met catechol-O-methyltransferase genotype on neural correlates of sad facial affect processing in patients with bipolar disorder and their relatives. Psychol Med 41: 779–788.G. Lelli-ChiesaMJ KemptonJ. JogiaR. TatarelliP. Girardi2011The impact of the Val158Met catechol-O-methyltransferase genotype on neural correlates of sad facial affect processing in patients with bipolar disorder and their relatives.Psychol Med41779788
  92. 92. Lonsdorf TB, Golkar A, Lindstöm KM, Fransson P, Schalling M, et al. (2011) 5-HTTLPR and COMTval158met genotype gate amygdala reactivity and habituation. Biol Psychol 87: 106–112.TB LonsdorfA. GolkarKM LindstömP. FranssonM. Schalling20115-HTTLPR and COMTval158met genotype gate amygdala reactivity and habituation.Biol Psychol87106112
  93. 93. Smolka MN, Schumann G, Wrase J, Grusser SM, Flor H, et al. (2005) Catechol-O-methyltransferase val158met genotype affects processing of emotional stimuli in the amygdala and prefrontal cortex. J Neurosci 25: 836–842.MN SmolkaG. SchumannJ. WraseSM GrusserH. Flor2005Catechol-O-methyltransferase val158met genotype affects processing of emotional stimuli in the amygdala and prefrontal cortex.J Neurosci25836842
  94. 94. Domschke K, Dannlowski U (2010) Imaging genetics of anxiety disorders. Neuroimage 53: 822–831.K. DomschkeU. Dannlowski2010Imaging genetics of anxiety disorders.Neuroimage53822831
  95. 95. Harmer CJ, Shelley NC, Cowen PJ, Goodwin GM (2004) Increased positive versus negative affective perception and memory in healthy volunteers following selective serotonin and norepinephrine reuptake inhibition. Am J Psychiatry 161: 1256–1263.CJ HarmerNC ShelleyPJ CowenGM Goodwin2004Increased positive versus negative affective perception and memory in healthy volunteers following selective serotonin and norepinephrine reuptake inhibition.Am J Psychiatry16112561263
  96. 96. Norbury R, Mackay CE, Cowen PJ, Goodwin GM, Harmer CJ (2007) Short-term antidepressant treatment and facial processing. Functional magnetic resonance imaging study. Br J Psychiatry 190: 531–532.R. NorburyCE MackayPJ CowenGM GoodwinCJ Harmer2007Short-term antidepressant treatment and facial processing. Functional magnetic resonance imaging study.Br J Psychiatry190531532
  97. 97. Hariri AR, Mattay VS, Tessitore A, Fera F, Smith WG, et al. (2002) Dextroamphetamine modulates the response of the human amygala. Neuropsychopharmacology 27: 1036–1040.AR HaririVS MattayA. TessitoreF. FeraWG Smith2002Dextroamphetamine modulates the response of the human amygala.Neuropsychopharmacology2710361040
  98. 98. Kroner S, Rosenkranz JA, Grace AA, Barrionuevo G (2005) Dopamine modulates excitability of basolatera amygdala neurons in vitro. J Neurophysiol 93: 1598–1610.S. KronerJA RosenkranzAA GraceG. Barrionuevo2005Dopamine modulates excitability of basolatera amygdala neurons in vitro.J Neurophysiol9315981610
  99. 99. Forbes EE, Miller A, Cohn JF, Fox NA, Kovacs M (2005) Affect-modulated startle in adults with childhood-onset depression: relations to bipolar course and number of lifetime depressive episodes. Psychiatry Res 134: 11–25.EE ForbesA. MillerJF CohnNA FoxM. Kovacs2005Affect-modulated startle in adults with childhood-onset depression: relations to bipolar course and number of lifetime depressive episodes.Psychiatry Res1341125
  100. 100. Allen NB, Trinder J, Brennan C (1999) Affective startle modulation in clinical depression: preliminary findings. Biol Psychiatry 46: 542–550.NB AllenJ. TrinderC. Brennan1999Affective startle modulation in clinical depression: preliminary findings.Biol Psychiatry46542550
  101. 101. Dichter GS, Tomarken AJ, Shelton RC, Sutton SK (2004) Early- and late-onset startle modulation in unipolar depression. Psychophysiology 41: 433–440.GS DichterAJ TomarkenRC SheltonSK Sutton2004Early- and late-onset startle modulation in unipolar depression.Psychophysiology41433440
  102. 102. Sloan DM, Sandt AR (2010) Depressed mood and emotional responding. Biol Psychol 84: 368–374.DM SloanAR Sandt2010Depressed mood and emotional responding.Biol Psychol84368374
  103. 103. McTeague LM, Lang PJ, Laplante MC, Cuthbert BN, Strauss CC, et al. (2009) Fearful imagery in social phobia: generalization, comorbidity, and physiological reactivity. Biol Psychiatry 65: 374–382.LM McTeaguePJ LangMC LaplanteBN CuthbertCC Strauss2009Fearful imagery in social phobia: generalization, comorbidity, and physiological reactivity.Biol Psychiatry65374382
  104. 104. Melzig CA, Weike AI, Zimmermann J, Hamm AO (2007) Startle reflex modulation and autonomic responding during anxious apprehension in panic disorder patients. Psychophysiology 44: 846–854.CA MelzigAI WeikeJ. ZimmermannAO Hamm2007Startle reflex modulation and autonomic responding during anxious apprehension in panic disorder patients.Psychophysiology44846854
  105. 105. Taylor-Clift A, Morris BH, Rottenberg J, Kovacs M (2011) Emotion-modulated startle in anxiety disorders is blunted by co-morbid depressive episodes. Psychol Med 41: 129–139.A. Taylor-CliftBH MorrisJ. RottenbergM. Kovacs2011Emotion-modulated startle in anxiety disorders is blunted by co-morbid depressive episodes.Psychol Med41129139
  106. 106. Domschke K, Deckert J, O'Donovan MC, Glatt SJ (2007) Meta-analysis of COMT val158met in panic disorder: ethnic heterogeneity and gender specificity. Am J Med Genet B Neuropsychiatr Genet 144B: 667–673.K. DomschkeJ. DeckertMC O'DonovanSJ Glatt2007Meta-analysis of COMT val158met in panic disorder: ethnic heterogeneity and gender specificity.Am J Med Genet B Neuropsychiatr Genet144B667673
  107. 107. Epperson CN, Pittman B, Czarkowski KA, Stiklus S, Krystal JH, et al. (2007) Luteal-Phase Accentuation of Acoustic Startle Response in Women with Premenstrual Dysphoric Disorder. Neuropsychopharmacology 32: 2190–2198.CN EppersonB. PittmanKA CzarkowskiS. StiklusJH Krystal2007Luteal-Phase Accentuation of Acoustic Startle Response in Women with Premenstrual Dysphoric Disorder.Neuropsychopharmacology3221902198
  108. 108. Xie T, Ho SL, Ramsden D (1999) Characterization and implications of estrogenic down-regulation of human catechol-O-methyltransferase gene transcription. Mol Pharmacol 56: 31–38.T. XieSL HoD. Ramsden1999Characterization and implications of estrogenic down-regulation of human catechol-O-methyltransferase gene transcription.Mol Pharmacol563138
  109. 109. Ruffman T, Henry JD, Livingstone V, Phillips LH (2008) A meta-analytic review of emotion recognition and aging: Implications for neuropsychological models of aging. Neurosci Biobehav Rev 32: 863–881.T. RuffmanJD HenryV. LivingstoneLH Phillips2008A meta-analytic review of emotion recognition and aging: Implications for neuropsychological models of aging.Neurosci Biobehav Rev32863881
  110. 110. Smith DP, Hillman CH, Duley AR (2005) Influences of age on emotional reactivity during picture processing. J Gerontol B Psychol Sci Soc Sci 60: 49–56.DP SmithCH HillmanAR Duley2005Influences of age on emotional reactivity during picture processing.J Gerontol B Psychol Sci Soc Sci604956
  111. 111. Fredrickson BL 1998. What good are positive emotions? Rev Gen Psychol 2: 300–319.Fredrickson BL 1998. What good are positive emotions?Rev Gen Psychol2300319
  112. 112. Fredrickson BL, Levenson RW (1998) Positive emotions speed recovery from the cardiovascular sequelae of negative emotions. Cogn Emot 12: 191–220.BL FredricksonRW Levenson1998Positive emotions speed recovery from the cardiovascular sequelae of negative emotions.Cogn Emot12191220
  113. 113. Fredrickson BL, Tugade MM, Waugh CE, Larkin GR (2003) What good are positive emotions in crises? A prospective study of resilience and emotions following the terrorist attacks on the United States on September 11th, 2001. J Pers Soc Psychol 84: 365–376.BL FredricksonMM TugadeCE WaughGR Larkin2003What good are positive emotions in crises? A prospective study of resilience and emotions following the terrorist attacks on the United States on September 11th, 2001.J Pers Soc Psychol84365376
  114. 114. Hoth KF, Paul RH, Williams LM, Dobson-Stone C, Todd E, et al. (2006) Associations between the COMT Val/Met polymorphism, early life stress, and personality among healthy adults. Neuropsychiatr Dis Treat 2: 219–225.KF HothRH PaulLM WilliamsC. Dobson-StoneE. Todd2006Associations between the COMT Val/Met polymorphism, early life stress, and personality among healthy adults.Neuropsychiatr Dis Treat2219225
  115. 115. Comasco E, Sylven SM, Papadopoulos FC, Sundstrom-Poromaa I, Oreland L, et al. (2011) Postpartum depression symptoms: a case-control study on monoaminergic functional polymorphisms and environmental stressors. Psychiatr Genet 21: 19–28.E. ComascoSM SylvenFC PapadopoulosI. Sundstrom-PoromaaL. Oreland2011Postpartum depression symptoms: a case-control study on monoaminergic functional polymorphisms and environmental stressors.Psychiatr Genet211928
  116. 116. Mandelli L, Serretti A, Marino E, Pirovano A, Calati R, et al. (2007) Interaction between serotonin transporter gene, catechol-O-methyltransferase gene and stressful life events in mood disorders. Int J Neuropsychopharmacol 10: 437–447.L. MandelliA. SerrettiE. MarinoA. PirovanoR. Calati2007Interaction between serotonin transporter gene, catechol-O-methyltransferase gene and stressful life events in mood disorders.Int J Neuropsychopharmacol10437447
  117. 117. Conway CC, Hammen C, Brennan PA, Lind PA, Najman JM (2010) Interaction of chronic stress with serotonin transporter and catechol-O-methyltransferase polymorphisms in predicting youth depression. Depress Anxiety 27: 737–745.CC ConwayC. HammenPA BrennanPA LindJM Najman2010Interaction of chronic stress with serotonin transporter and catechol-O-methyltransferase polymorphisms in predicting youth depression.Depress Anxiety27737745
  118. 118. Lin PI, Vance JM, Pericak-Vance MA, Martin ER (2007) No gene is an island: the flip-flop phenomenon. Am J Hum Genet 80: 531–538.PI LinJM VanceMA Pericak-VanceER Martin2007No gene is an island: the flip-flop phenomenon.Am J Hum Genet80531538
  119. 119. Niwa M, Matsumoto Y, Mouri A, Ozaki N, Nabeshima T (2010) Vulnerability in early life to changes in the rearing environment plays a crucial role in the aetiopathology of psychiatric disorders. Int J Neuropsychopharmacol 1–19. M. NiwaY. MatsumotoA. MouriN. OzakiT. Nabeshima2010Vulnerability in early life to changes in the rearing environment plays a crucial role in the aetiopathology of psychiatric disorders.Int J Neuropsychopharmacol 1–19
  120. 120. Abdolmaleky HM, Smith CL, Zhou JR, Thiagalingam S (2008) Epigenetic alterations of the dopaminergic system in major psychiatric disorders. Methods Mol Biol 448: 187–212.HM AbdolmalekyCL SmithJR ZhouS. Thiagalingam2008Epigenetic alterations of the dopaminergic system in major psychiatric disorders.Methods Mol Biol448187212
  121. 121. Grabe HJ, Spitzer C, Schwahn C, Marcinek A, Frahnow A, et al. (2009) Serotonin transporter gene (SLC6A4) promoter polymorphisms and the susceptibility to posttraumatic stress disorder in the general population. Am J Psychiatry 166: 926–933.HJ GrabeC. SpitzerC. SchwahnA. MarcinekA. Frahnow2009Serotonin transporter gene (SLC6A4) promoter polymorphisms and the susceptibility to posttraumatic stress disorder in the general population.Am J Psychiatry166926933
  122. 122. Klauke B, Deckert J, Reif A, Pauli P, Zwanzger P, et al. (2011) Serotonin transporter gene and childhood trauma – a GxE effect on anxiety sensitivity. Depress Anxiety 28: 1048–1057.B. KlaukeJ. DeckertA. ReifP. PauliP. Zwanzger2011Serotonin transporter gene and childhood trauma – a GxE effect on anxiety sensitivity.Depress Anxiety2810481057
  123. 123. Laucht M, Treutlein J, Blomeyer D, Buchmann AF, Schmid B, et al. (2009) Interaction between the 5-HTTLPR serotonin transporter polymorphism and environmental adversity for mood and anxiety psychopathology: evidence from a high-risk community sample of young adults. Int J Neuropsychopharmacol 12: 737–747.M. LauchtJ. TreutleinD. BlomeyerAF BuchmannB. Schmid2009Interaction between the 5-HTTLPR serotonin transporter polymorphism and environmental adversity for mood and anxiety psychopathology: evidence from a high-risk community sample of young adults.Int J Neuropsychopharmacol12737747
  124. 124. Deckert J, Nothen MM, Franke P, Delmo C, Fritze J, et al. (1998) Systematic mutation screening and association study of the A1 and A2a adenosine receptor genes in panic disorder suggest a contribution of the A2a gene to the development of disease. Mol Psychiatry 3: 81–85.J. DeckertMM NothenP. FrankeC. DelmoJ. Fritze1998Systematic mutation screening and association study of the A1 and A2a adenosine receptor genes in panic disorder suggest a contribution of the A2a gene to the development of disease.Mol Psychiatry38185
  125. 125. Hamilton SP, Slager SL, De Leon AB, Heiman GA, Klein DF, et al. (2004) Evidence for genetic linkage between a polymorphism in the adenosine 2A receptor and panic disorder. Neuropsychopharmacology 29: 558–565.SP HamiltonSL SlagerAB De LeonGA HeimanDF Klein2004Evidence for genetic linkage between a polymorphism in the adenosine 2A receptor and panic disorder.Neuropsychopharmacology29558565
  126. 126. Hohoff C, Domschke K, Schwarte K, Spellmeyer G, Vogele C, et al. (2009) Sympathetic activity relates to adenosine A(2A) receptor gene variation in blood-injury phobia. J Neural Transm 116: 659–662.C. HohoffK. DomschkeK. SchwarteG. SpellmeyerC. Vogele2009Sympathetic activity relates to adenosine A(2A) receptor gene variation in blood-injury phobia.J Neural Transm116659662
  127. 127. Hohoff C, Mullings EL, Heatherley SV, Freitag CM, Neumann LC, et al. (2010) Adenosine A(2A) receptor gene: evidence for association of risk variants with panic disorder and anxious personality. J Psychiatr Res 44: 930–937.C. HohoffEL MullingsSV HeatherleyCM FreitagLC Neumann2010Adenosine A(2A) receptor gene: evidence for association of risk variants with panic disorder and anxious personality.J Psychiatr Res44930937
  128. 128. Lam P, Hong CJ, Tsai SJ (2005) Association study of A2a adenosine receptor genetic polymorphism in panic disorder. Neurosci Lett 378: 98–101.P. LamCJ HongSJ Tsai2005Association study of A2a adenosine receptor genetic polymorphism in panic disorder.Neurosci Lett37898101
  129. 129. de la Mora MP, Gallegos-Cari A, Arizmendi-García Y, Marcellino D, Fuxe K (2010) Role of dopamine receptor mechanisms in the amygdaloid modulation of fear and anxiety: Structural and functional analysis. Prog Neurobiol 90: 198–216.MP de la MoraA. Gallegos-CariY. Arizmendi-GarcíaD. MarcellinoK. Fuxe2010Role of dopamine receptor mechanisms in the amygdaloid modulation of fear and anxiety: Structural and functional analysis.Prog Neurobiol90198216
  130. 130. Fuxe K, Ferre S, Genedani S, Franco R, Agnati LF (2007) Adenosine receptor-dopamine receptor interactions in the basal ganglia and their relevance for brain function. Physiol Behav 92: 210–217.K. FuxeS. FerreS. GenedaniR. FrancoLF Agnati2007Adenosine receptor-dopamine receptor interactions in the basal ganglia and their relevance for brain function.Physiol Behav92210217
  131. 131. Henry B, Moffitt TE, Caspi A, Langley J, Silva PA (1994) On the “Remembrance of Things Past”: A Longitudinal Evaluation of the Retrospective Method. Psychological Assessment 6: 92–101.B. HenryTE MoffittA. CaspiJ. LangleyPA Silva1994On the “Remembrance of Things Past”: A Longitudinal Evaluation of the Retrospective Method.Psychological Assessment692101
  132. 132. Bernstein DP, Fink L (1998) Childhood trauma questionnaire: A retrospective self-report manual. San Antonio: The Psychological Corporation. DP BernsteinL. Fink1998Childhood trauma questionnaire: A retrospective self-report manual.San Antonio: The Psychological Corporation
  133. 133. Gast U, Rodewald F, Benecke HH, Driessen M (2001) Deutsche Bearbeitung des Childhood Traum Questionnaire (unautorisiert). Medizinische Hochschule: Hannover. U. GastF. RodewaldHH BeneckeM. Driessen2001Deutsche Bearbeitung des Childhood Traum Questionnaire (unautorisiert).Medizinische Hochschule: Hannover
  134. 134. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, et al. (1998) The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 59: 22–33.DV SheehanY. LecrubierKH SheehanP. AmorimJ. Janavs1998The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10.J Clin Psychiatry592233
  135. 135. Armbruster D, Moser DA, Strobel A, Hensch T, Kirschbaum C, et al. (2009) Serotonin transporter gene variation and stressful life events impact processing of fear and anxiety. Int J Neuropsychopharmacol 12: 393–401.D. ArmbrusterDA MoserA. StrobelT. HenschC. Kirschbaum2009Serotonin transporter gene variation and stressful life events impact processing of fear and anxiety.Int J Neuropsychopharmacol12393401
  136. 136. Baffa A, Hohoff C, Baune BT, Müller-Tidow C, Tidow N, et al. (2010) Norepinephrine and serotonin transporter genes: Impact on treatment response in depression. Neuropsychobiology 62: 121–131.A. BaffaC. HohoffBT BauneC. Müller-TidowN. Tidow2010Norepinephrine and serotonin transporter genes: Impact on treatment response in depression.Neuropsychobiology62121131
  137. 137. Baune BT, Hohoff C, Roehrs T, Deckert J, Arolt V, et al. (2008) Serotonin receptor 1A -1019C/G variant: Impact on antidepressant pharmacoresponse in melancholic depression? Neurosci Lett 436: 111–115.BT BauneC. HohoffT. RoehrsJ. DeckertV. Arolt2008Serotonin receptor 1A -1019C/G variant: Impact on antidepressant pharmacoresponse in melancholic depression?Neurosci Lett436111115
  138. 138. Lang A, Bradley B, Cuthbert BN (2005) International affective picture system (IAPS): Affective ratings of pictures and instruction manual. University of Florida, Gainesville. A. LangB. BradleyBN Cuthbert2005International affective picture system (IAPS): Affective ratings of pictures and instruction manual.University of Florida, Gainesville
  139. 139. Alsene K, Deckert J, Sand P, de Wit H (2003) Association between A2a receptor gene polymorphisms and caffeine-induced anxiety. Neuropsychopharmacology 28: 1694–1702.K. AlseneJ. DeckertP. SandH. de Wit2003Association between A2a receptor gene polymorphisms and caffeine-induced anxiety.Neuropsychopharmacology2816941702
  140. 140. Rogers PJ, Hohoff C, Heatherley SV, Mullings EL, Maxfield PJ, et al. (2010) Association of the anxiogenic and alerting effects of caffeine with ADORA2A and ADORA1 polymorphisms and habitual level of caffeine consumption. Neuropsychopharmacology 35: 1973–1983.PJ RogersC. HohoffSV HeatherleyEL MullingsPJ Maxfield2010Association of the anxiogenic and alerting effects of caffeine with ADORA2A and ADORA1 polymorphisms and habitual level of caffeine consumption.Neuropsychopharmacology3519731983
  141. 141. Bernstein DP, Fink L, Handelsman L, Foote J, Lovejoy M, et al. (1994) Initial reliability a142. nd validity of a new retrospective measure of child abuse and neglect. Am J Psychiatry 151: 1132–1136.DP BernsteinL. FinkL. HandelsmanJ. FooteM. Lovejoy1994Initial reliability a142. nd validity of a new retrospective measure of child abuse and neglect.Am J Psychiatry15111321136
  142. 142. Scher CD, Stein MB, Asmundson GJ, McCreary DR, Forde DR (2001) The childhood trauma questionnaire in a community sample: psychometric properties and normative data. J Trauma Stress 14: 843–857.CD ScherMB SteinGJ AsmundsonDR McCrearyDR Forde2001The childhood trauma questionnaire in a community sample: psychometric properties and normative data.J Trauma Stress14843857
  143. 143. Wingenfeld K, Spitzer C, Mensebach C, Grabe HJ, Hill A, et al. (2010) The German version of the Childhood Trauma Questionnaire (CTQ): preliminary psychometric properties. Psychother Psychosom Med Psychol 60: 442–450.K. WingenfeldC. SpitzerC. MensebachHJ GrabeA. Hill2010The German version of the Childhood Trauma Questionnaire (CTQ): preliminary psychometric properties.Psychother Psychosom Med Psychol60442450
  144. 144. Bader K, Hänny C, Schäfer V, Neuckel A, Kuhl C (2009) Childhood Trauma Questionnaire – Psychometrische Eigenschaften einer deutschsprachigen Version. Z Psychosom Med Psychother 38: 223–230.K. BaderC. HännyV. SchäferA. NeuckelC. Kuhl2009Childhood Trauma Questionnaire – Psychometrische Eigenschaften einer deutschsprachigen Version.Z Psychosom Med Psychother38223230
  145. 145. Osborne JW, Overbay A (2004) The power of outliers (and why researchers should always check for them). Practical Assessment, Research & Evaluation 9. JW OsborneA. Overbay2004The power of outliers (and why researchers should always check for them).Practical Assessment, Research & Evaluation 9
  146. 146. Osborne JW (2002) Note on the use of data transformation. Practical Assessment, Research & Evaluation 8. JW Osborne2002Note on the use of data transformation.Practical Assessment, Research & Evaluation 8
  147. 147. Kraemer HC, Blasey CM (2004) Centring in regression analyses: a strategy to prevent errors in statistical inference. Int J Methods Psychiatr Res 13: 141–151.HC KraemerCM Blasey2004Centring in regression analyses: a strategy to prevent errors in statistical inference.Int J Methods Psychiatr Res13141151