title: Assessment of the neuropeptide S system in anxiety disorders.
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 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.
  
  
  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.
authors: Research Program of Molecular Neurology, Biomedicum Helsinki, Helsinki, Finland.
authors: Jonas
authors: J
authors: Donner
authors: Rita
authors: R
authors: Haapakoski
authors: Sini
authors: S
authors: Ezer
authors: Erik
authors: E
authors: Melén
authors: Sami
authors: S
authors: Pirkola
authors: Mònica
authors: M
authors: Gratacòs
authors: Marco
authors: M
authors: Zucchelli
authors: Francesca
authors: F
authors: Anedda
authors: Lovisa E
authors: LE
authors: Johansson
authors: Cilla
authors: C
authors: Söderhäll
authors: Christina
authors: C
authors: Orsmark-Pietras
authors: Jaana
authors: J
authors: Suvisaari
authors: Rocío
authors: R
authors: Martín-Santos
authors: Marta
authors: M
authors: Torrens
authors: Kaisa
authors: K
authors: Silander
authors: Joseph D
authors: JD
authors: Terwilliger
authors: Magnus
authors: M
authors: Wickman
authors: Göran
authors: G
authors: Pershagen
authors: Jouko
authors: J
authors: Lönnqvist
authors: Leena
authors: L
authors: Peltonen
authors: Xavier
authors: X
authors: Estivill
authors: Mauro
authors: M
authors: D'Amato
authors: Juha
authors: J
authors: Kere
authors: Harri
authors: H
authors: Alenius
authors: Iiris
authors: I
authors: Hovatta
mesh_terms: D000328:Adult; D000818:Animals; D001008:Anxiety Disorders / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics* / Q000523:psychology; D001249:Asthma / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics* / Q000523:psychology; D002648:Child; D015331:Cohort Studies; D015897:Comorbidity; D015870:Gene Expression / Q000502:physiology; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D008875:Middle Aged; D009414:Nerve Growth Factors / Q000032:analysis / Q000502:physiology; D009479:Neuropeptides / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology
chemical_list: C484532:NPSR1 protein, human; C515062:NPSR1 protein, mouse; D009414:Nerve Growth Factors; D009479:Neuropeptides; D043562:Receptors, G-Protein-Coupled; C506531:neuropeptide S, human; C539972:neuropeptide S, mouse