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  • For the first time we provide evidence for COMT

    2019-07-11

    For the first time, we provide evidence for COMT Val158Met modulation of long-term fear extinction in humans, evident both in cortical (LPP) and autonomic (fear bradycardia) components of the conditioned fear response. We further found that the initial acquisition of fear is related to dispositional fearfulness and provide tentative evidence that the stability of extinction memories may be relevant for neuroticism/anxiety. The present findings are of potential relevance for the understanding of dispositional fearfulness and neuroticism/anxiety, as well as development and treatment of anxiety disorders.
    Acknowledgements This study was supported by a grant of the German Research Foundation to Erik M. Mueller [DFG MU3535/2-1]. Parts of the reported data were presented at the 2015 and 2016 meetings of the Society for Psychophysiological Research. None of the authors has financial interests or other potential conflicts of interest.
    Introduction Generalized anxiety disorder (GAD) is characterized by excessive, long-lasting worry associated with restlessness, fatigue, poor concentration, irritability, muscle tension, and insomnia. In addition, it is further characterized by a number of autonomic nervous system (ANS) symptoms, including hot flashes, palpitations, sweating, and shaking (Jetty et al., 2001; Tully et al., 2013). GAD is highly prevalent and debilitating, with a lifetime prevalence in the Pergolide mesylate estimated to range from 5.1%ā€“11.9% (Kessler et al., 2008; Wittchen et al., 1994). Twin and family studies have suggested that genetic factors are important in the etiology of GAD, estimating 32% of the variation in the risk of GAD being attributable to genetic variability (Hettema et al., 2001). As such, interest has been focused on the identification and verification of specific genes that contribute to the development of GAD. One of the most promising candidate genes for GAD is COMT (chromosome 22q11), encoding the eponymous enzyme Catechol-O-methyltransferase (COMT). COMT induces the transfer of a methyl group from S-adenosylmethionine to catalyze catecholamines (e.g., dopamine and norepinephrine), which are essential neurotransmitters in the prefrontal cortex (Clark and Noudoost, 2014), a known brain region involved in anxiety (Kim and Whalen, 2009). A common single nucleotide polymorphism (SNP) rs4680 (Gā€‰>ā€‰A) Pergolide mesylate in the COMT gene, resulting in a valine (Val) to methionine (Met) substitution at protein position 158 (Val158Met), alters COMT expression, with the Val allele presenting higher COMT activity than the Met allele (Lachman et al., 1996). Notably, the high-activity COMT Val allele has been linked with increased risk of anticipatory worry (the core feature of GAD), persisting generalized anxiety and GAD (Hettema et al., 2008; Mc Fie et al., 2017; Olsson et al., 2007). Conversely, research has also revealed that low-activity Met allele of COMT is associated with anticipatory worry, anxiety sensitivity and symptomatology related to anxiety (Baumann et al., 2013; Enoch et al., 2003; Olsson et al., 2005). However, the neurobiological reasons for these completely conflicting results are currently unclear. COMT enzyme activity and protein expression have been shown to increase with age across the human lifespan (Tunbridge et al., 2007). In addition, healthy individuals carrying the COMT Val/Val genotype have higher grey matter density in early adulthood, but this difference disappears as age increases (Rowe et al., 2010). Furthermore, Smith and Boettiger (2012) have reported that age modulates the COMT rs4680 effect on task performance of delay-discounting, a behavioral tendency to choose immediate over delayed rewards. Moreover, effects of COMT Val158Met genotypes have been shown to have opposite influences in adolescents and adults, with Val-allele homozygous adults exhibiting elevated, and adolescents presenting diminished, resting-state functional connectivity of brain regions including the prefrontal cortex, compared to Met-allele homozygotes (Meyer et al., 2016). Thus, age itself may play a role in moderating the effect of COMT Val158Met polymorphism on neural function and related behavioral phenotypes.