Research Program of Molecular Neurology, Biomedicum Helsinki, Helsinki, Finland.
Biol Psychiatry. 2010 Sep 1;68(5):474-83. doi: 10.1016/j.biopsych.2010.05.039.
The G protein-coupled receptor neuropeptide S receptor 1 (NPSR1) and its ligand neuropeptide S (NPS) form a signaling system mainly implicated in susceptibility to asthma and inflammatory disorders in humans and regulation of anxiety and arousal in rodents. We addressed here the role of NPS and NPSR1 as susceptibility genes for human anxiety disorders.
We performed comprehensive association analysis of genetic variants in NPS and NPSR1 in three independent study samples. We first studied a population-based sample (Health 2000, Finland) of 321 anxiety disorder patients and 1317 control subjects and subsequently a Spanish clinical panic disorder sample consisting of 188 cases and 315 control subjects. In addition, we examined a birth cohort of 2020 children (Barn Allergi Miljö Stockholm Epidemiologi [BAMSE], Sweden). We then tested whether alleles of the most significantly associated single nucleotide polymorphisms alter DNA-protein complex formation in electrophoretic mobility shift assays. Finally, we compared acute stress responses on the gene expression level in wild-type and Npsr1(-/-) mice.
We confirmed previously observed epidemiological association between anxiety and asthma in two population-based cohorts. Single nucleotide polymorphisms within NPS and NPSR1 associated with panic disorder diagnosis in the Finnish and Spanish samples and with parent-reported anxiety/depression in the BAMSE sample. Moreover, some of the implicated single nucleotide polymorphisms potentially affect transcription factor binding. Expression of neurotrophin-3, a neurotrophic factor connected to stress and panic reaction, was significantly downregulated in brain regions of stressed Npsr1(-/-) mice, whereas interleukin-1 beta, an active stress-related immunotransmitter, was upregulated.
Our results suggest that NPS-NPSR1 signaling is likely involved in anxiety.
G 蛋白偶联受体神经肽 S 受体 1（NPSR1）及其配体神经肽 S（NPS）形成了一个信号系统，主要与人类哮喘和炎症性疾病的易感性以及啮齿动物的焦虑和觉醒调节有关。在这里，我们研究了 NPS 和 NPSR1 作为人类焦虑障碍易感性基因的作用。
我们对 NPS 和 NPSR1 的遗传变异进行了全面的关联分析，共纳入了三个独立的研究样本。我们首先研究了一个基于人群的样本（芬兰的健康 2000 研究），包括 321 名焦虑症患者和 1317 名对照者，随后研究了一个由 188 例病例和 315 例对照者组成的西班牙临床惊恐障碍样本。此外，我们还检查了 2020 名儿童的出生队列（瑞典的 Barn Allergi Miljö Stockholm Epidemiologi [BAMSE]）。然后，我们测试了最显著相关的单核苷酸多态性的等位基因是否改变电泳迁移率变动分析中的 DNA-蛋白质复合物形成。最后，我们比较了野生型和 Npsr1(-/-) 小鼠在基因表达水平上的急性应激反应。
我们在两个基于人群的队列中证实了先前观察到的焦虑症与哮喘之间的流行病学关联。NPS 和 NPSR1 内的单核苷酸多态性与芬兰和西班牙样本中的惊恐障碍诊断相关，与 BAMSE 样本中的父母报告的焦虑/抑郁相关。此外，一些涉及的单核苷酸多态性可能影响转录因子结合。在应激 Npsr1(-/-) 小鼠的大脑区域中，神经生长因子-3（一种与应激和惊恐反应有关的神经营养因子）的表达显著下调，而白细胞介素-1β（一种活跃的应激相关免疫递质）的表达上调。
我们的研究结果表明，NPS-NPSR1 信号可能参与了焦虑的发生。
