Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
Department of Family and Community Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
Psychoneuroendocrinology. 2019 Aug;106:57-64. doi: 10.1016/j.psyneuen.2019.03.020. Epub 2019 Mar 30.
The functional ValMet 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 ValMet 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 ValMet polymorphism is associated with risk of GAD via reduced resting parasympathetic nervous control, an age-specific risk pathway.
儿茶酚-O-甲基转移酶（COMT）基因的功能性 ValMet 多态性（rs4680）与广泛性焦虑障碍（GAD）有关；然而，潜在的神经机制仍未被研究。最近的证据表明，较低的静息副交感（迷走）控制是焦虑的一种内表型预测因子，而 COMT rs4680 的作用在不同年龄有所不同。因此，我们研究了 COMT ValMet 变体是否可以通过降低年龄特异性的静息副交感神经控制来增加 GAD 的风险。在 1655 名汉族成年人（1142 名健康对照和 513 名 GAD 患者；年龄：20-65 岁）中，对 COMT rs4680 多态性进行了基因分型。心率变异性（HRV）的高频功率（HF）用于测量静息状态下的副交感神经调节。非遗传因素，如性别、吸烟状况、用药情况和合并症情况，被视为协变量。在调整相关协变量后，静息 HRV 的 HF 存在年龄 x COMT 基因型的交互作用。在年轻成年人中，Met 等位基因携带者的 HF 指数显著降低；然而，老年人则表现出相反的模式，Val/Val 纯合子的 HF 值降低。此外，HF-HRV 的降低与 GAD 风险的增加有关。最后，通路分析表明，COMT 通过降低静息 HF-HRV 对 GAD 的风险存在显著的间接影响，且这种影响具有年龄依赖性。我们的研究结果首次表明，COMT ValMet 多态性通过降低静息副交感神经控制与 GAD 风险相关，这是一种具有年龄特异性的风险途径。
