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  • Growing evidence has shown that ANS


    Growing evidence has shown that ANS dysregulation, indexed by heart rate variability (HRV), plays a critical role in the pathogenesis of anxiety (Minassian et al., 2014, 2015). Indeed, we have previously reported that patients with GAD are associated with reduced resting parasympathetical (vagal) control (Chang et al., 2013). Furthermore, young people who are at risk for anxiety disorders show decreased vagal regulation than a control group in resting conditions (Balle et al., 2013). Moreover, studies have demonstrated that low parasympathetically mediated HRV predicts greater risk for the future develpoment of general anxiety symptoms (Greaves-Lord et al., 2010; Kogan et al., 2012). As resting HRV is highly heritable, with estimated heritability ranging from 32% to 71% (Wang et al., 2005), lower vagal control at rest has been considered an important anxiety endophenotype (Crisan et al., 2009; Thayer and Lane, 2009), a heritable, primarily state-independent biomarker that is associated with related illness (e.g., GAD). Because endophenotypes are more directly related to relevant gene action than to the endpoint disorder (i.e., GAD), an endophenotype-based pathway approach may therefore aid gene-finding strategies (Gatt et al., 2008; Gottesman and Gould, 2003). Importantly, researchers have recently proposed that endophenotype can be manifested only at certain ages when taking into considertion of the importance of developmental and/or epigenetic factors (Flint and Munafo, 2007; Hasler et al., 2006). In addition, experimental evidence has demonstarted that the neurotransmitter dopamine attenuates prefrontal cortical suppression to the amygdala (Rosenkranz and Grace, 2001), one of the major components of the central autonomic network (Benarroch, 1993). Recently, research has further shown that prefrontal byl719 functional conneticity with the amagdala is associated with vagus-mediated HRV (Sakaki et al., 2016). Moreover, prejunctional beta-2 adrenoceptor-mediated reduction in cardiac norepinephrine spillover has also been reported to be related to reflex vagal HR responses (Kubo et al., 2005). Thus, taken all together, given that COMT is responsible for catecholamine metabolism (Clark and Noudoost, 2014), it seems reasonable to assume byl719 that GAD may be conferred by the COMT Val158Met polymorphism through effects on decreasing resting parasympathetic control, and that such effects are determined in an age-dependent way. To our knowledge, however, no previous study has investigated the potentially age-specific association of the COMT rs4680 polymorphism with vagus-mediated HRV to provide a neurophysiological insight into the complex role of COMT variation in GAD. ANS functions can also be affected by several factors, including perceived stress level, gender, smoking status, habitual physical exercise, use of medication, and morbidities of physical diseases and/or mental disorders (Chang et al., 2017; Cohen et al., 1999). Therefore, using a highly-controlled manner can minimize the effects of these confounding variables to precisely reveal the possible age-dependent pathways of the COMT Val158Met polymorphism, resting vagal control and GAD. Using a large cohort of Han Chinese adults and based on a genotype-endophenotype-phenotype pathway model, the current study, adjusting for the relevant confounding factors, aimed to test whether functional COMT Val158Met polymorphism has an age-specific correlation with decreased parasympathetically mediated HRV, and if so, whether it is further associated with increased risk of GAD. The hypothetical model is shown in Fig. 1.
    Materials and methods
    Discussion The current study was conducted to evaluate the potential age-specific pathways among COMT Val158Met variant, resting vagal control and GAD. After adjusting for all the confounders, our main results revealed that Met allele carriers exhibited lower HF-HRV values than Val-allele homozygous carriers in the younger age groups. However, opposite effects were found in the older age groups. Furthermore, in the pathway model, we demonstrated that the interaction of age and COMT variant was associated with lower HF-HRV, which in turn was related to increased risk for GAD. The findings here are the first to show that functional COMT polymorphism (rs4680) is associated with the risk of GAD via altered resting parasympathetic control in an age-dependent manner.