Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, No. 325, Sec. 2, Cheng-Kung Road, Nei-Hu District, Taipei 114, Taiwan.
Department of Family and Community Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
J Affect Disord. 2020 Jun 1;270:124-130. doi: 10.1016/j.jad.2020.03.059. Epub 2020 Apr 8.
Norepinephrine transporter (NET), which regulates synaptic norepinephrine for noradrenergic signaling, is involved in the pathogenesis of anxiety, while expression of the NET gene differs at different ages. Here, we examine whether genetic variants in the NET gene are associated, in an age-specific manner, with increased risk of generalized anxiety disorder (GAD), one of the most disabling anxiety disorders.
Three common single-nucleotide polymorphisms (SNPs) in the promoter (rs168924: A/G; rs2242446: T/C) and 5'-untranslated region (5'-UTR) (rs2397771: G/C) of the NET gene were genotyped in 2,317 Han-Chinese participants (791 GAD patients and 1,526 controls; age: 20-65). Potential confounding factors, such as gender, stress levels and psychiatric comorbidities, were included as covariates.
An interaction between age and NET genotypes and haplotypes was found for the risk of GAD. In the younger participants, rs168924 minor allele G homozygotes had the lowest incidence of GAD; however, older subjects displayed an inverse pattern, with homozygous G/G carriers presenting the highest prevalence of GAD. Additionally, younger individuals carrying 2 copies of the GGT haplotype composed of rs2397771-rs168924-rs2242446 had the lowest rate of GAD. However, those with 2 copies of the same haplotype exhibited the highest risk of GAD in the older groups.
Only 3 common SNPs in the promoter and 5'-UTR of the NET gene were analyzed.
Our findings are the first to demonstrate that potentially functional SNPs in the NET promoter and 5'-UTR are associated with an increased risk of GAD, and that such associations are determined in an age-specific way.
去甲肾上腺素转运体（NET）调节去甲肾上腺素能信号的突触去甲肾上腺素，参与焦虑症的发病机制，而 NET 基因的表达在不同年龄有所不同。在这里，我们研究 NET 基因中的遗传变异是否以年龄特异性的方式与广泛性焦虑症（GAD）的风险增加相关，GAD 是最具致残性的焦虑症之一。
在 2317 名汉族参与者（791 名 GAD 患者和 1526 名对照；年龄：20-65 岁）中，对 NET 基因启动子（rs168924：A/G；rs2242446：T/C）和 5'-非翻译区（5'-UTR）（rs2397771：G/C）中的 3 个常见单核苷酸多态性（SNP）进行了基因分型。将性别、压力水平和精神共病等潜在混杂因素作为协变量纳入。
发现 NET 基因型和单倍型与 GAD 风险之间存在年龄交互作用。在年轻参与者中，rs168924 次要等位基因 G 纯合子的 GAD 发生率最低；然而，老年患者呈现相反的模式，G/G 纯合子携带者的 GAD 患病率最高。此外，携带由 rs2397771-rs168924-rs2242446 组成的 GGT 单倍型的年轻个体 GAD 发生率最低。然而，在老年组中，携带相同单倍型的个体具有最高的 GAD 风险。
仅分析了 NET 基因启动子和 5'-UTR 中的 3 个常见 SNP。
我们的研究结果首次表明，NET 启动子和 5'-UTR 中潜在功能 SNP 与 GAD 的风险增加相关，并且这种关联以年龄特异性的方式确定。
