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.
Highlights
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% [1,2,3]
For the mean intertrial interval (ITI) startle response, one subject was excluded because of an extreme score (.2.5 SD), so that this analysis step was run with 89 participants only
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
Summary
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% [1,2,3]. 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 [10,11,12,13], phobic anxiety [14], neuroticism [15], harm avoidance [16] and generalized anxiety [17]. Association studies of the COMT Val158Met polymorphism with respect to affective disorders, in particular depression, are inconclusive [33,34,35]
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