Assessment of the neuropeptide S system in anxiety disorders

Jonas Donner, Rita Haapakoski, Sini Ezer, Erik Meln, Sami Pirkola, Mnica Gratacs, Marco Zucchelli, Francesca Anedda, Lovisa E. Johansson, Cilla Sderhll, Christina Orsmark-Pietras, Jaana Suvisaari, Roco Martn-Santos, Marta Torrens, Kaisa Silander, Joseph D. Terwilliger, Magnus Wickman, Gran Pershagen, Jouko Lnnqvist, Leena PeltonenXavier Estivill, Mauro D'Amato, Juha Kere, Harri Alenius, Iiris Hovatta

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Abstract

Background: 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. Methods: 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 Milj 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. Results: 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. Conclusions: Our results suggest that NPS-NPSR1 signaling is likely involved in anxiety.

Original languageEnglish
Pages (from-to)474-483
Number of pages10
JournalBiological Psychiatry
Volume68
Issue number5
DOIs
Publication statusPublished - 1 Sep 2010

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Keywords

  • Anxiety disorders
  • SNP
  • asthma
  • genetic association
  • lexicon
  • neuropeptide S

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Donner, J., Haapakoski, R., Ezer, S., Meln, E., Pirkola, S., Gratacs, M., Zucchelli, M., Anedda, F., Johansson, L. E., Sderhll, C., Orsmark-Pietras, C., Suvisaari, J., Martn-Santos, R., Torrens, M., Silander, K., Terwilliger, J. D., Wickman, M., Pershagen, G., Lnnqvist, J., ... Hovatta, I. (2010). Assessment of the neuropeptide S system in anxiety disorders. Biological Psychiatry, 68(5), 474-483. https://doi.org/10.1016/j.biopsych.2010.05.039