title: Sex-specific association between functional neuropeptide S receptor gene (NPSR1) variants and cortisol and central stress responses.
abstract: The brain neuropeptide S (NPS) system has recently generated substantial interest and may be of major relevance for central stress regulation. The NPS receptor (NPSR1) is highly expressed in the limbic system, exogenous NPS exerts pronounced anxiolytic and fear-attenuating effects in rodents and extensive close crosstalk between the NPS system and the hypothalamic-pituitary-adrenal (HPA) axis has been demonstrated. In humans, associations between NPSR1 variants and anxiety and panic disorder, as well as amygdala responsiveness to fear- relevant faces and prefrontal cortex activity in a fear conditioning paradigm have been reported. Moreover, a NPSR1 sequence variant was found to be associated with cortisol stress responses in males.
  
  Here, we performed a haplotype-based analysis covering three functional NPSR1 single nucleotide polymorphisms in the promoter (rs2530547), in exon 3 (rs324981) and exon 6 (rs727162) in 277 healthy subjects who were exposed to the Trier Social Stress Test (TSST). A significant sex-specific association with salivary cortisol responses to acute psychosocial stress was detected for the common TTC haplotype 2 (frequency of about 20%). In an additional study using an imaging genetics approach, 65 healthy subjects were exposed to a stress paradigm for scanner environments (“ScanSTRESS”). We found a significant and, again, sex-specific interaction between rs324981 (whose minor T-allele is harbored by haplotype 2) and the neural stress response in a cluster close to the parahippocampal gyrus (whole brain corrected). Moreover, as in the TSST sample, NPSR1 variation was associated with salivary cortisol responses (on a trend level) in a sex-specific way.
  
  In summary, our preliminary findings in two independent cohorts exposed to different stress paradigms suggest that the NPS system significantly influences acute stress responses and that sequence variation in NPSR1 may contribute to sex differences in stress regulation.
authors.affiliation: Central Institute of Mental Health, University of Heidelberg/Medical Faculty Mannheim, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Streit
authors.affiliation: Central Institute of Mental Health, University of Heidelberg/Medical Faculty Mannheim, Germany.
authors.forename: Ceren
authors.initials: C
authors.lastname: Akdeniz
authors.affiliation: Central Institute of Mental Health, University of Heidelberg/Medical Faculty Mannheim, Germany.
authors.forename: Leila
authors.initials: L
authors.lastname: Haddad
authors.affiliation: Genetic Psychology, Faculty of Psychology, Ruhr- University Bochum, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Kumsta
authors.affiliation: Institute of Medical Psychology, Charité - University Medicine Berlin, Germany; Department of Pediatrics, University of California, Irvine, United States.
authors.forename: Sonja
authors.initials: S
authors.lastname: Entringer
authors.affiliation: Central Institute of Mental Health, University of Heidelberg/Medical Faculty Mannheim, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Frank
authors.affiliation: Department of Psychology and Social Behavior, University of California, Irvine, United States.
authors.forename: Ilona S
authors.initials: IS
authors.lastname: Yim
authors.affiliation: Institute of Experimental Psychology, University of Regensburg, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Zänkert
authors.affiliation: Central Institute of Mental Health, University of Heidelberg/Medical Faculty Mannheim, Germany.
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Witt
authors.affiliation: Central Institute of Mental Health, University of Heidelberg/Medical Faculty Mannheim, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kirsch
authors.affiliation: Central Institute of Mental Health, University of Heidelberg/Medical Faculty Mannheim, Germany.
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.affiliation: Central Institute of Mental Health, University of Heidelberg/Medical Faculty Mannheim, Germany; Institute of Experimental Psychology, University of Regensburg, Germany. Electronic address: stefan.wuest@ur.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wüst
mesh_terms: D000293:Adolescent; D000328:Adult; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D012463:Saliva / Q000737:chemistry; D012737:Sex Factors; D013315:Stress, Psychological / Q000235:genetics* / Q000378:metabolism*; D055815:Young Adult
chemical_list: C484532:NPSR1 protein, human; D043562:Receptors, G-Protein-Coupled; D006854:Hydrocortisone