Genetic Association of Objective Sleep Phenotypes with a Functional Polymorphism in the Neuropeptide S Receptor Gene

Abstract

BackgroundThe neuropeptide S receptor (NPSR1) and its ligand neuropeptide S (NPS) have received increased attention in the last few years, as both establish a previously unknown system of neuromodulation. Animal research studies have suggested that NPS may be involved in arousal/wakefulness and may also have a crucial role in sleep regulation. The single nucleotide polymorphism (SNP) rs324981 in NPSR1 has begun to shed light on a function of the NPS-system in human sleep regulation. Due to an amino acid exchange, the T-allele leads to an increased sensitivity of the NPSR1. In the only genome-wide association study to date on circadian sleep parameters in humans, an association was found between rs324981 and regular bedtime. However, the sleep parameters in this study were only measured by self-rating. Therefore, our study aimed to replicate these findings using an objective measure of sleep.MethodsThe study included n = 393 white subjects (62–79 years) who participated in an actigraphic assessment for determining sleep duration, rest duration, sleep onset, rest onset and sleep onset latency. Genotyping of the SNP rs324981 was performed using the TaqMan OpenArray System.ResultsThe genotype at rs324981 was not significantly associated with rest onset (bedtime) or sleep onset (p = .146 and p = .199, respectively). However, the SNP showed a significant effect on sleep- and rest duration (p = .007 and p = .003, respectively). Subjects that were homozygous for the minor T-allele had a significantly decreased sleep- and rest duration compared to A-allele carriers.ConclusionThe results of this study indicate that the sleep pattern in humans is influenced by the NPS-system. However, the previously reported association between bedtime and rs324981 could not be confirmed. The current finding of decreased sleep duration in T/T allele carriers is in accordance with studies in rodents reporting similar results after NPS application.

Nocturnal asthma is affected by genetic interactions between RORA and NPSR1

“…These studies followed the hypothesis that mutations in ADRB2 increase airway constriction in asthmatics and reduce the response to treatment, thus increasing symptoms and severity, possibly even pronounced at night. Our study now shows a mechanism specific for nocturnal symptoms by deciphering molecular associations within genes of the circadian rhythm: as both genes under investigation have been independently associated with asthma susceptibility and seem to play a role in defining the circadian rhythm, the observed associations are biologically plausible.…”

“…The NPS/NPSR1 system as well as RORA have been shown to play a role in circadian rhythm: NPSR knockout mice exhibited lower activity levels under light‐dark conditions, NPS injections lead to an increased wakefulness and nonsynonymous NPSR1 rs324981 was recently associated with a delay of bedtime and sleep duration . RORA gene expression varies throughout the day and Rora ‐deficient mice showed a decreased activity and could not adjust to light‐dark cycles .…”

“…Interestingly, two candidate genes for asthma, Neuropeptide S Receptor 1 ( NPSR1 ; chromosome 7p14.3) and Retinoid Acid Receptor‐Related Orphan Receptor Alpha ( RORA ; chromosome 15q22.2), have recently been suggested to play a role in controlling circadian rhythm . NPSR1 , a G protein‐coupled receptor, has been associated with asthma susceptibility in numerous studies, while also having been related to the circadian rhythm in mice and humans . RORA , a nuclear hormone receptor, was associated with asthma and its mRNA expression varies during human lung development and during murine lung inflammation .…”

Endogenous neuropeptide S tone influences sleep–wake rhythm in rats

“…Subjects with the homozygote T/T genotype had significantly shorter duration of both sleep and rest compared to the A-allele carriers [26]. This study suggests that endogenous NPS could be involved in sleep-wake regulation.…”

Neuropeptide S (NPS) variants modify the signaling and risk effects of NPS Receptor 1 (NPSR1) variants in asthma

“…A GWAS on circadian sleep parameters found an association between rs324981 and regular bedtime [24] and another study showed that the same SNP was associated with sleep and rest duration [25]. In cell models, the change of Asn(107) to Ile(107) results in 10-fold increase in NPS-mediated intracellular signaling [26] and changes in genome-wide transcriptional profiles [27].…”