As mentioned in the Introduction the functional Val Met poly

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 Z-FA-FMK 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, 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 radiometric time 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. It is noteworthy that epidemiological studies have demonstrated that some GAD patients have experienced anxiety symptoms in childhood and young adulthood, whereas others have developed their disorder at a later age (especially persons ≥ 50 years of age) (Hoehn-Saric et al., 1993; Le Roux et al., 2005). Therefore, our results that COMT Val158Met polymorphism is associated with the risk of GAD via decreased resting vagal control in an age-specific way may help to explain, at least partly, the underlying neural and genetic mechanisms of a bimodal distribution for age of onset of GAD that peaked in early life and late adulthood (Hoehn-Saric et al., 1993; Le Roux et al., 2005). However, since the ages of our study subjects range only from 20 to 65 years, further studies in adolescents and those aged over 65 years are warranted.