The association between genetic variability in the NPS/NPSR1 system and chronic stress responses: A gene-environment-(quasi-) experiment

The neuropeptide S (NPS) and its receptor (NPSR1) have been implicated in stress regulation and stress-related disorders. The present study aimed at investigating the association between overall genetic variability in the NPS/NPSR1 system and psychological and cortisol stress regulation in everyday life. Our study was conceptualized as a gene-environment-(quasi-) experiment, a design that facilitates the detection of true GxE interactions. As environmental variable, we used the preparation for the first state examination for law students. In the prospective and longitudinal LawSTRESS project, students were examined at six sampling points over a 13-months period. While students who prepared for the exam and experienced long-lasting and significant stress, formed the stress group, law students experiencing usual study-related workload were assigned to the control group. As phenotypes we assessed changes over time in the cortisol awakening response (CAR; n = 176), perceived stress levels (n = 401), and anxiety symptoms (n = 397). The CAR was assessed at each sampling point immediately upon awakening and 30 as well as 45 min later. Perceived stress levels in daily life were measured by repeated ambulatory assessments and anxiety symptoms were repeatedly assessed with the anxiety subscale of the Hospital Anxiety and Depression Scale. With gene-set analyses we examined the joint association of 936 NPS/NPSR1 single nucleotide polymorphisms with the phenotypes to overcome well known limitations of candidate gene studies. As previously reported, we found a blunted CAR during the exam as well as significant increases in perceived stress levels and anxiety symptoms until the exam in the stress group, compared to the control group. The gene-set analysis did not confirm associations between genetic variability in the NPS/NPSR1 system and changes in perceived stress levels and anxiety symptoms. Regarding the CAR, we found a significant GxE interaction for the area under the curve with respect to the ground (p = .050) and a trend towards a significant effect for the area under the curve with respect to the increase (p = .054). When the analysis was restricted to the SG, associations for both CAR parameters were significant (ps < .050). This finding suggests that the association between genetic variability in the NPS/NPSR1 system and the CAR becomes visible under the environmental condition 'chronic stress exposure'. We conclude that the present study complements findings from animal models and that it provides novel evidence for a modulatory influence of the NPS/NPSR1 system on cortisol regulation in humans.