Association between a novel polymorphism in the promoter region of the neuropeptide Y gene and schizophrenia in humans

doi:10.1016/S0304-3940(03)00718-3

Neuroscience Letters

Volume 347, Issue 3, 28 August 2003, Pages 202-204

https://doi.org/10.1016/S0304-3940(03)00718-3 Get rights and content

Abstract

Hypoactivity of neuropeptide Y (NPY) is thought to be involved in the pathophysiology of schizophrenia, because post-mortem brain studies revealed a decrease of the NPY in schizophrenia, and antipsychotic treatments increase the NPY in animal brains and in cerebrospinal fluid of patients. We performed genetic analysis of the NPY gene in schizophrenia. Mutation screening of the gene detected nine single nucleotide polymorphisms, of which we typed a −485C>T variation from potential functional relevance. The −485T allele was overly represented in the disease group (P=0.0043). An in vitro promoter assay revealed that a C to T change at nt −485 significantly reduced transcriptional activity. These results suggest that the −485T allele in NPY may confer susceptibility to schizophrenia by decreasing the neuropeptide in brains.

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Acknowledgements

This work was partly funded by a Grant-in-Aid for Scientific Research (C) from the JSPS, Japan (No. 14570953).

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Cross talk about the role of Neuropeptide Y in CNS disorders and diseases
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A peptide composed of a 36 amino acid called Neuropeptide Y (NPY) is employed in a variety of physiological processes to manage and treat conditions affecting the endocrine, circulatory, respiratory, digestive, and neurological systems. NPY naturally binds to G-protein coupled receptors, activating the Y-receptors (Y1-Y5 and y6). The findings on numerous therapeutic applications of NPY for CNS disease are presented in this review by the authors. New targets for treating diseases will be revealed by medication combinations that target NPY and its receptors. This review is mainly focused on disorders such as anxiety, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Machado Joseph disease, multiple sclerosis, schizophrenia, depression, migraine, alcohol use disorder, and substance use disorder. The findings from the preclinical studies and clinical studies covered in this article may help create efficient therapeutic plans to treat neurological conditions on the one hand and psychiatric disorders on the other. They may also open the door to the creation of novel NPY receptor ligands as medications to treat these conditions.
Association study of arcuate nucleus neuropeptide Y neuron receptor gene variation and serum NPY levels in clozapine treated patients with schizophrenia
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The association with obesity susceptibility is inconclusive [28,29]. It moreover seems that NPY gene polymorphism rs16147 is not linked to schizophrenia susceptibility [30–33]. NPY polymorphism rs16139 has been found to be associated with alterations in the synthesis and secretion of NPY [34], higher serum levels of total and LDL cholesterol in obese subjects [35], coronary artery atherosclerosis [36], insulin resistance and risk for type II diabetes [37], plasma levels of inflammatory molecules and NPY in diabetes patients [38], and metabolic syndrome [39].
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.
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.
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 α7 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).
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.
Association study of two functional single nucleotide polymorphisms of neuropeptide y gene with multiple sclerosis
2016, Neuropeptides
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by brain inflammation, demyelination and axonal loss. Neuropeptide Y (NPY) has a critical role in the maintenance of homeostasis in the immune system and coping of stress condition. In the current study we analyzed 188 patients suffering from MS and 204 unrelated healthy controls for two functional single nucleotide polymorphisms (SNPs), NPY 20T > C (rs16139) and NPY -485 T > C (rs16147) using PCR-RFLP and Mismatch PCR-RFLP methods. Our results demonstrated that homozygocity in the minor allele for NPY -485 T > C polymorphism is associated with the MS risk in patients in compare with healthy controls (CC vs. TT, P = 0.033; CC vs. TT + TC, P = 0.02). In addition, by comparison with allele T, the frequency of NPY -485C allele was higher in cases than in control subjects and present increased risk of MS, but statistically significant was borderline (P = 0.053). The stratification for disease progression revealed a significant difference in the allelic and genotypic distribution between subgroups of MS and controls. The frequency of the CC genotype and C allele was higher in the primary progressive MS patients when compared with control group (CC vs. TT, P = 0.019; CC vs. TT + TC, P = 0.008; C vs. T, P = 0.022). In addition, the frequency of CC genotype was higher in the relapsing remitting MS patients when compared with control group (CC vs. TT, P = 0.034; CC vs. TT + TC, P = 0.016). Haplotype analysis demonstrated that the haplotype 3 (CT) is more common in RR MS (P = 0.041), and PP MS (P = 0.031) than control group. In conclusion, the obtained results demonstrate the probable role of NPY SNPs in susceptibility to MS within the Iranian population.
Neuropeptide Y associated with asthma in young adults
2016, Neuropeptides
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The only other study which investigated the role of NPY gene variation in asthma among Finnish young adults found that rs16147 was associated with an increased risk for self-reported asthma in overweight (BMI ≥ 25 kg/m2) individuals (Jaakkola et al., 2012), suggesting an interaction between NPY gene polymorphism and obesity. Genetic variation at the NPY loci has been demonstrated to be associated with multiple conditions including cardiovascular disease and high blood pressure (rs16147, rs16139, rs3037354), (Jaakkola et al., 2009; Shah et al., 2009; Zhang et al., 2012) responses to stress and emotional challenge (rs16147), (Zhou et al., 2008) alcohol dependence (rs16139, rs17149106), (Lappalainen et al., 2002; Mottagui-Tabar et al., 2005) obesity (rs3037354), (Bray et al., 2000) ischemic stroke (rs16147), (Yu et al., 2010) schizophrenia (rs16147), (Itokawa et al., 2003) and early-onset atherosclerosis (rs16147) (Shah et al., 2009). In this study, we explored NPY gene polymorphism as a possible genetic predisposing factor for prevalent asthma using a candidate gene approach, and investigated the interaction between NPY gene polymorphism and obesity in predicting the likelihood of prevalent asthma.
Neuropeptide Y, a widely circulating neurotransmitter, plays a pivotal role in energy balance, immunomodulation and asthma, and several NPY polymorphisms are promising genetic risk factors for asthma and obesity. We explored the associations of candidate NPY gene polymorphisms with prevalent asthma and its relationship with obesity in young adult asthma patients free of other chronic medical morbidity.
Five common gene variants of NPY (rs16147 (− 399T/C), rs17149106 (− 602G/T), rs16140 (+ 1000C/G), rs5573 (+ 1201A/G), rs5574 (+ 5327C/T)) previously validated to account for most of the NPY expression in vitro and in vivo were investigated in 126 physician-diagnosed asthma patients without other chronic medical morbidity and 182 healthy controls (21–35 years). Plasma levels of NPY, adiponectin, and CRP were determined using ELISA, and IL-6 was measured by Luminex in a subgroup of 70 patients and 69 age- and sex-matched healthy controls.
In logistic regression models controlling for gender and obesity, the CT genotype of rs5574 (OR = 0.54, 95%CI: 0.30–0.89) and the GT genotype of rs17149106 (OR = 5.58, 95%CI: 1.09–28.54) were significantly associated with asthma. No significant interaction between NPY SNP polymorphisms and obesity were detected. Plasma NPY level was correlated with adiponectin levels (p < 0.05). Compared with the healthy controls, patients with asthma had higher BMI (p < 0.001), adiponectin (p < 0.05), IL-6 (p = 0.001) and CRP (p < 0.001), and lower NPY levels (p < 0.01).
The CT genotype of rs5574 and the GT genotype of rs17149106 are significantly associated with prevalent asthma.
Social feeding in Caenorhabditis elegans is modulated by antipsychotic drugs and calmodulin and may serve as a protophenotype for asociality
2015, Neuropharmacology
Citation Excerpt :
Social feeding in C. elegans is regulated largely by the npr-1 gene that encodes the ortholog of the human neuropeptide Y (NPY) receptor (de Bono and Bargmann, 1998). It is noteworthy that reductions in NPY mRNA and protein levels in the brain have been documented in schizophrenic patients (Frederiksen et al., 1991; Kuromitsu et al., 2001; Morris et al., 2009), and the NPY gene may represent a risk locus for schizophrenia (Itokawa et al., 2003). NPY is anxiolytic in mammals (Kask et al., 1998; Sajdyk et al., 2002) and also regulates feeding (Beck, 2006).
Here, we define a protophenotype as an endophenotype that has been conserved during evolution. Social feeding in Caenorhabditis elegans may be an example of a protophenotype related to asociality in schizophrenia. It is regulated by the highly conserved neuropeptide Y receptor, NPR-1, and we speculated that social feeding should be affected by antipsychotic drugs. The social feeding strain, npr-1(g320), was exposed to antipsychotic drugs, dopamine or calmodulin antagonists on plates with bacterial lawns, and the number of aggregates on the plates was counted as a measure of social feeding. First-generation antipsychotics, chlorpromazine, trifluoperazine, fluphenazine, and haloperidol, and the second-generation drug, olanzapine, inhibited social feeding. Dopamine accelerated aggregation, whereas selective D2 dopamine receptor antagonists, sulpiride and raclopride, were inhibitory. Calmodulin antagonists effectively inhibited social feeding, as did RNAi knockdown of calmodulin (cmd-1) expression. In addition, gap junction inhibitors prevented aggregation, which is consistent with the hub-and-spoke arrangement of neurons that regulate social feeding via functional gap junctions. The studies described here revealed novel connections between dopaminergic signaling, the NPY receptor, calmodulin, and gap junctions in the regulation of social behavior in C. elegans. These pathways are evolutionarily-conserved, and have also been implicated in the pathogenesis of schizophrenia.
NPY2-receptor variation modulates iconic memory processes
2014, European Neuropsychopharmacology
Citation Excerpt :
The single nucleotide polymorphisms (SNPs) in this study were selected based on their established functional effects. The promoter variations in NPY (rs16147) and NPY2R have previously been shown to affect gene expression (Buckland et al., 2005, 2004; Itokawa et al., 2003; Kloster et al., 2013; Zhou et al., 2008). A sample of N=199 healthy adults (mean age: 23.79 years, SD: 2.88; 98 women; 101 men) of Caucasian descent was recruited for the study.
Sensory memory systems are modality-specific buffers that comprise information about external stimuli, which represent the earliest stage of information processing. While these systems have been the subject of cognitive neuroscience research for decades, little is known about the neurobiological basis of sensory memory. However, accumulating evidence suggests that the glutamatergic system and systems influencing glutamatergic neural transmission are important. In the current study we examine if functional promoter variations in neuropeptide Y (NPY) and its receptor gene NPY2R affect iconic memory processes using a partial report paradigm. We found that iconic memory decayed much faster in individuals carrying the rare promoter NPY2R G allele which is associated with increased expression of the Y2 receptor. Possibly this effect is due to altered presynaptic inhibition of glutamate release, known to be modulated by Y2 receptors. Altogether, our results provide evidence that the functionally relevant single nucleotide polymorphism (SNP) in the NPY2R promoter gene affect circumscribed processes of early sensory processing, i.e. only the stability of information in sensory memory buffers. This leads us to suggest that especially the stability of information in sensory memory buffers depends on glutamatergic neural transmission and factors modulating glutamatergic turnover.

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Association between a novel polymorphism in the promoter region of the neuropeptide Y gene and schizophrenia in humans

Abstract

Section snippets

Acknowledgements

Biol. Psychiatry

Gene Expr. Patt.

Neuropeptides

The single nucleotide polymorphism T1128C in the signal peptide of neuropeptide Y (NPY) was not identified in a Korean population

J. Clin. Pharm. Ther.

No leucine(7)-to-proline(7) polymorphism in the signal peptide of neuropeptide Y in Japanese population or Japanese with alcoholism

Psychiatr. Genet.

Reduced concentrations of galanin, arginine vasopressin, neuropeptide Y and peptide YY in the temporal cortex but not in the hypothalamus of brains from schizophrenics

Acta Psychiatr. Scand.

Schizophrenia Genetics: The Origin of Madness