Journal
BIOLOGICAL PSYCHIATRY
Volume 68, Issue 5, Pages 474-483Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2010.05.039
Keywords
Anxiety disorders; asthma; genetic association; lexicon; neuropeptide S; SNP
Categories
Funding
- Academy of Finland
- Sigrid Juselius Foundation
- Yrjo Jahnsson Foundation
- Yrjo and Tuulikki Ilvonen Foundation
- Biocentrum Helsinki Foundation
- L'Oreal Finland
- United Nations Educational, Cultural, and Scientific Organization
- University of Helsinki
- Ny-lands Nation vid Helsingfors universitet
- H. Lundbeck A/S
- Finnish Foundation for Psychiatric Research
- The Helsinki Biomedical Graduate School
- Fondo de Investigaciones Sanitarias de la Seguridad Social [P1052565, PI040632, PI0406, CIBER-CB06/02/005819]
- Spanish Ministry of Education and Science [SAF2005-01005, SAF2007-60827, GEN2003-20651-C06-03]
- The Instituto Carlos III [GO3/184]
- The Fundacio la Marato-TV3 [014331]
- Department of Universities, Research and Information Society [2005SGR00008, 2005SGR 00322]
- Genoma Espana
- Swedish Research Council
- Stockholm County Council
- The Swedish Asthma and Allergy Association
- The Swedish Foundation for Health Care Science and Allergy Research
- The Swedish Heart and Lung Foundation
- Chronic Inflammation - Diagnosis and Therapy/Verket for innovationssystem, Sweden
- Centre for Allergy Research, Karolinska lnstitutet
- The Bernard Osher Initiative for Research on Severe Asthma at Karolinska Institutet
- The Swedish Society for Medical Research
- Professor Nanna Svartz Fund
- The Ruth and Richard Julin Foundation
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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 Miljo 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 immuno-transmitter, was upregulated. Conclusions: Our results suggest that NPS-NPSR1 signaling is likely involved in anxiety.
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