Original article Association study of arcuate nucleus neuropeptide Y neuron receptor gene variation and serum NPY levels in clozapine treated patients with schizophrenia J.-P. Klemettila ¨ a, *, O. Kampman b,c , A. Solismaa b,c , L.-P. Lyytika ¨ inen d , N. Seppa ¨la ¨ a , M. Viikki b,e , M. Ha ¨ma ¨la ¨ inen f , E. Moilanen f , N. Mononen d , T. Lehtima ¨ki d , E. Leinonen a,b a Tampere University Hospital, Department of Psychiatry, Pitka ¨niemi Hospital, 33380 Pitka ¨niemi, Finland b University of Tampere, School of Medicine, 33014 Tampere, Finland c Seina ¨joki Hospital District, Department of Psychiatry, 60220 Seina ¨joki, Finland d Department of Clinical Chemistry, Fimlab Laboratories and University of Tampere, School of Medicine, 33014 Tampere, Finland e Tampere Mental Health Centre, Hallituskatu 8B, 33200 Tampere, Finland f The Immunopharmacology Research Group, University of Tampere, School of Medicine and Tampere University Hospital, 33014 Tampere, Finland 1. Introduction Weight gain is a common side effect of second-generation antipsychotics, and leads to metabolic consequences and comor- bidity, social stigmatization and nonadherence [1]. The mechanism of antipsychotic-induced weight gain (AIWG) is mostly unclear. Serotonin 5-HT2C- and histamine H1-blocking activity of antipsy- chotic agents has been associated with increased risk of metabolic side effects. Findings from twin and sibling studies and genetic association studies, especially concerning serotonin receptor HTR2C and leptin genes, suggest that genetic factors have a key role in susceptibility to drug-induced weight gain [2]. However, although individual weight gain varies widely, there are no tools available so far in clinical practice to predict the personalized risk of weight gain associated with antipsychotic treatment [3]. Neuropeptide Y (NPY) is a potent orexigenic peptide, with an important role as a central regulator of energy homeostasis and appetite in hypothalamus [4]. Arcuate nucleus (ARC) NPY neurons are the main source of hypothalamic NPY [5]. NPY neurons are activated by signals indicating reduced energy availability [4]. NPY synthesis and release in ARC NPY neurons is regulated by several European Psychiatry 40 (2017) 13–19 A R T I C L E I N F O Article history: Received 20 March 2016 Received in revised form 14 July 2016 Accepted 16 July 2016 Available online Keywords: Schizophrenia Genetics NPY receptor Weight gain Polymorphism Resistin A B S T R A C T Background: Antipsychotic-induced weight gain (AIWG) leads to metabolic consequences and comorbidity, social stigmatization and nonadherence in patients with schizophrenia. Neuropeptide Y (NPY) has an important role in appetite and body weight regulation. Associations between AIWG and serum NPY levels, and genetic polymorphisms (SNPs) associated with its serum levels have been little studied in these patients. Subjects and methods: Associations between serum NPY concentration and other metabolic and inflammatory markers, and 215 SNPs in 21 genes (NPY gene, NPY receptor genes and genes encoding arcuate nucleus NPY neuron receptors) were studied in 180 patients with schizophrenia on clozapine treatment. Results: The serum levels of NPY correlated with levels of resistin (r = 0.31, P < 0.001) and age (r = 0.22, P = 0.003). In the general linear univariate model the best-fitting model with explanatory factors age, serum resistin level, serum insulin level, BMI and gender explained 18.0% (P < 0.001) of the variance of serum NPY. Genetic risk score (GRS NPY ) analysis found twelve significant (P < 0.05) serum NPY concentration related SNPs among a7 nicotinic acetylcholine receptor gene CHRNA7, insulin receptor gene INSR, leptin receptor gene LEPR, glucocorticoid receptor (GR) gene NR3C1, and NPY gene. However, after permutation test of gene score the predictive value of GRS NPY remained non-significant (P = 0.078). Conclusions: Serum NPY level does not seem to be a feasible biomarker of AIWG. Serum NPY level alterations are not significantly associated with the candidate gene polymorphisms studied. ß 2016 Elsevier Masson SAS. All rights reserved. * Corresponding author. Tel.: +358 50 5928308. E-mail address: jari-pekka.klemettila@pshp.fi (J.-P. Klemettila ¨). Contents lists available at ScienceDirect European Psychiatry jo u rn al h om epag e: h ttp ://ww w.eu ro p s y- jo ur n al.co m http://dx.doi.org/10.1016/j.eurpsy.2016.07.004 0924-9338/ß 2016 Elsevier Masson SAS. All rights reserved.