Assessment of the neuropeptide S system in anxiety disorders.
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.
Donner
Jonas
J
Research Program of Molecular Neurology, Biomedicum Helsinki, Helsinki, Finland.
Haapakoski
Rita
R
Ezer
Sini
S
Melén
Erik
E
Pirkola
Sami
S
Gratacòs
Mònica
M
Zucchelli
Marco
M
Anedda
Francesca
F
Johansson
Lovisa E
LE
Söderhäll
Cilla
C
Orsmark-Pietras
Christina
C
Suvisaari
Jaana
J
Martín-Santos
Rocío
R
Torrens
Marta
M
Silander
Kaisa
K
Terwilliger
Joseph D
JD
Wickman
Magnus
M
Pershagen
Göran
G
Lönnqvist
Jouko
J
Peltonen
Leena
L
Estivill
Xavier
X
D'Amato
Mauro
M
Kere
Juha
J
Alenius
Harri
H
Hovatta
Iiris
I
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
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