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. 2019 Aug:106:57-64.
doi: 10.1016/j.psyneuen.2019.03.020. Epub 2019 Mar 30.

Age-specific associations among functional COMT Val158Met polymorphism, resting parasympathetic nervous control and generalized anxiety disorder

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Age-specific associations among functional COMT Val158Met polymorphism, resting parasympathetic nervous control and generalized anxiety disorder

Hsin-An Chang et al. Psychoneuroendocrinology. 2019 Aug.

Abstract

The functional Val158Met polymorphism (rs4680) of the Catechol-O-Methyltransferase (COMT) gene has been implicated in generalized anxiety disorder (GAD); however, the underlying neural mechanisms remain unexamined. Recent evidence reveals that low resting parasympathetic (vagal) control is an endophenotypic predictor of anxiety, while the effect of COMT rs4680 differs at different ages. Thus, we examined whether the COMT Val158Met variant could increase the risk of GAD through decreased resting parasympathetic nervous control in an age-specific manner. COMT rs4680 polymorphism was genotyped in 1,655 Han Chinese adults (1,142 healthy subjects and 513 patients with GAD; age: 20-65). High-frequency power (HF) of heart rate variability (HRV) was used to measure resting state parasympathetic nervous regulation. Non-genetic factors, such as gender, smoking status, medication use and comorbidity conditions, were treated as covariates. After adjusting for relevant covariates, there was a significant age x COMT genotype interaction on resting HF of HRV. In younger adults, Met allele carriers had a significantly lower HF index; however, older adults exhibited the opposite pattern, with Val/Val homozygotes exhibiting decreased HF values. Moreover, reduced HF-HRV is associated with increased risk of GAD. Finally, pathway analysis revealed a significant indirect effect of COMT on the risk of GAD via reduced resting HF-HRV, in the aforementioned age-dependent manner. Our findings are the first to demonstrate that COMT Val158Met polymorphism is associated with risk of GAD via reduced resting parasympathetic nervous control, an age-specific risk pathway.

Keywords: Age-specific pathway; COMT gene; Generalized anxiety disorder (GAD); Heart rate variability (HRV); Resting parasympathetic (vagal) control; Val(158)Met (rs4680) polymorphism.

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