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  • As mentioned previously dopamine plays

    2020-11-24

    As mentioned previously, dopamine plays a crucial role in reducing prefrontal cortical suppression to the amygdala (Rosenkranz and Grace, 2001) and prefrontal cortex mediated amygdala supression has recently been associated with vagal regulation of HRV (Sakaki et al., 2016). In addition, evidence has shown that blockade of cardiac sympathetic prejunctional beta-2 adrenoceptors that facilitate norepinephrine release can augment reflex vagal control of HR (Kubo et al., 2005). Since COMT is important in determining the levels of catecholamine neurotransmitters (Clark and Noudoost, 2014), and since COMT rs4680 effects differ at different ages (Meyer et al., 2016; Smith and Boettiger, 2012); all of these, taken together, support our findings that COMT rs4680-driven functional variation may be related to different levels of vagal regulation in an age-dependent manner. Indeed, a previous study has shown that children carrying at least one Met allele of COMT represent reduced vagally-mediated HRV responsiveness to stress when compared to those with two Val any social pitfall (Mueller et al., 2012). Our result that the Met allele carriers presented lower resting HF-HRV values than Val-allele homozygotes in younger adult participants may complement the previous research and together indicate that young people with the Met COMT allele have decreased parasympathetic function. Moreover, the current study further revealed that older adults showed the opposite pattern, demonstrating Val/Val homozygotes as having a reduction in HF index of HRV. Our intriguing findings were in line with the recent growing evidence for age-dependent gene effects of COMT rs4680 on neural functions and related phenotypes, including brain resting state functional connectivity (Meyer et al., 2016), grey matter volume (Rowe et al., 2010), cortical language processing/language ability (Sugiura et al., 2017), and delay reward discounting (Smith and Boettiger, 2012). As mentioned in the Introduction, the functional Val158Met polymorphism of the COMT gene has been reported as a risk factor for GAD and related phenotypes (e.g., anticipatory worry), but with conflicting and confused results. In the current study, considering only the COMT rs4680, we did not find an effect of this polymorphism on GAD. However, since neurophysiological endophenotypical markers reflect more proximal effects of genes involved in the development of psychopathology (Gottesman and Gould, 2003), analyzing resting state vagal control, considering also the moderator role of age, may enhance power for genetic discovery to unveil the complex role of COMT functional variation in GAD. Indeed, our pathway analysis, in the whole sample, revealed that there was an age-specific correlation of COMT Val158Met variant with decreased resting parasympathetic control, which, in turn, was associated with increased risk for GAD. The indirect effects of COMT on GAD via resting HF index were significant in both the younger groups and the older groups, any social pitfall with an opposite pattern. In the largest recent genome-wide association study (including all ethnicities), Duncan et al. (2018) have reported no association between COMT rs4680 and anxiety-related phenotypes. As the age-dependent COMT effects run in the reverse direction, our findings are therefore in line with Duncan et al. (2018) and provide an age-dependent neurophysiological explanation for previous completely conflicting results on associations of COMT Val158Met polymorphism with GAD and related phenotypes. Furthermore, when we analyzed only the healthy subsample, the interaction effects of age and COMT on reducing HF-HRV were similar and remained significant, indicating that the interactions were independent of GAD diagnosis. Since decreased vagal tone at rest is associated with GAD, the findings in our healthy cohort suggest that reduced resting parasympathetic control may thus be an endophenotype relevant to GAD rather than the result of the development of the illness. This also provides support for the temporal order of the relationship between decreased resting vagal control and GAD in our pathway model. Notably, the Polyvagal theory, proposed by Porges (2007), has highlighted diminished resting vagal control as the key final common pathway leading to the adverse effects of stress, with the myelinated vagus circuit dampening sympathetically mediated stress responses and fostering calm behavioral states and emotional self-regulation. In line with Porges’ perspectives, our results may thus precisely reveal the resting parasympathetic pathway, altered by the age-specific effect of COMT gene, linking to GAD.