A Single Nucleotide Polymorphism of the Neuropeptide B/W Receptor-1 Gene Influences the Evaluation of Facial Expressions Noriya Watanabe 1,2,3 , Mari Wada 1 , Yoko Irukayama-Tomobe 1,4 , Yousuke Ogata 1,2 , Natsuko Tsujino 5 , Mika Suzuki 5 , Naoki Furutani 5 , Takeshi Sakurai 5,6 *, Miyuki Yamamoto 1 * 1 Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan, 2 Japan Society for the Promotion of Science, Tokyo, Japan, 3 Graduate School of Engineering, Tamagawa University, Machida, Tokyo, Japan, 4 University of Tsukuba Center for Behavioral Molecular Genetics (FIRST Program), Tokyo, Japan, 5 Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan, 6 Exploratory Research for Advanced Technology Yanagisawa Orphan Receptor Project, Japan Science and Technology Agency, Tokyo, Japan Abstract Neuropeptide B/W receptor-1 (NPBWR1) is expressed in discrete brain regions in rodents and humans, with particularly strong expression in the limbic system, including the central nucleus of the amygdala. Recently, Nagata-Kuroiwa et al. reported that Npbwr1 2/2 mice showed changes in social behavior, suggesting that NPBWR1 plays important roles in the emotional responses of social interactions. The human NPBWR1 gene has a single nucleotide polymorphism at nucleotide 404 (404A.T; SNP rs33977775). This polymorphism results in an amino acid change, Y135F. The results of an in vitro experiment demonstrated that this change alters receptor function. We investigated the effect of this variation on emotional responses to stimuli of showing human faces with four categories of emotional expressions (anger, fear, happiness, and neutral). Subjects’ emotional levels on seeing these faces were rated on scales of hedonic valence, emotional arousal, and dominance (V-A-D). A significant genotype difference was observed in valence evaluation; the 404AT group perceived facial expressions more pleasantly than did the 404AA group, regardless of the category of facial expression. Statistical analysis of each combination of [V-A-D and facial expression] also showed that the 404AT group tended to feel less submissive to an angry face than did the 404AA group. Thus, a single nucleotide polymorphism of NPBWR1 seems to affect human behavior in a social context. Citation: Watanabe N, Wada M, Irukayama-Tomobe Y, Ogata Y, Tsujino N, et al. (2012) A Single Nucleotide Polymorphism of the Neuropeptide B/W Receptor-1 Gene Influences the Evaluation of Facial Expressions. PLoS ONE 7(4): e35390. doi:10.1371/journal.pone.0035390 Editor: Gregg Roman, University of Houston, United States of America Received November 8, 2011; Accepted March 15, 2012; Published April 24, 2012 Copyright: ß 2012 Watanabe et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study was supported by the 21st Center of Excellence program of the University of Tsukuba, and a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan. NW and YO were supported by Grant-in-Aid for Japan Society for the Promotion of Science Fellows. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: yamamoto444@gmail.com (MY); tsakurai@med.kanazawa-u.ac.jp (TS) Introduction Recent advances in molecular biology and brain-function imaging technology have enabled us to study genetic influences on emotional responses both behaviorally and physiologically. Nucleotide polymorphisms in monoamine transmitter-related molecules have been extensively studied in relation to emotion and reward systems. For example, in the serotonergic system, genetic variations in the regulatory region of 5-HT transporters (5- HTT) seem to influence the ‘‘harm avoidance’’ trait [1,2] as assessed by the Tri-dimensional Personality Questionnaire [3] and susceptibility to depression [4] as assessed by NEO personality tests [5]. This variability also causes differences in amygdala activity as shown by functional magnetic resonance imaging (fMRI) when observing emotional visual stimuli [6]. A single nucleotide polymorphism (SNP) in the regulatory region of the 5- HT receptor type 3 gene changes both amygdala activity in response to the stimuli of human faces, and personality trait as assessed by TCI [7,8]. In the dopaminergic system, Krugel et al. [9] reported that a catechol-O-methyltransferase SNP (V158M) affected learning rate during a reward-based learning paradigm. In their study, the Val/ Val group showed a higher learning rate than the Met/Met group, and higher activity in the ventral striatum which was correlated to prediction error. NPBWR1 (GPR7) is a G-protein-coupled receptor whose ligands were recently identified as neuropeptide W (NPW) and neuropeptide B (NPB) [10,11,12,13] (also see rev. [14]). NPBWR1 is highly conserved between humans and rodents, and its mRNA is localized in discrete brain regions including the hypothalamus, hippocampus, ventral tegmental area (VTA), and central nucleus of the amygdala (CeA) in rodents [11,13,14] and in humans [12]. The distribution of NPBWR1 suggested that it may have a role in the regulation of emotion-related responses that affect autonomic functions. The amygdala is well known to play a crucial role in emotional and social behaviors [15] (also see rev. [16,17,18]), while the hypothalamus plays an important role in emotion, especially aggression (see rev. [19]), as well as in controlling the autonomic nervous system. The distribution of NPBWR1 in the VTA may also suggest its involvement in the reward system (see rev. [20]). PLoS ONE | www.plosone.org 1 April 2012 | Volume 7 | Issue 4 | e35390