Polymorphisms of IKBKE gene are associated with major depressive disorder and panic disorder

Background The immune system has been increasingly implicated in the development of mood and anxiety disorders. Inhibitor of kappa light polypeptide gene enhancer in B cells, kinase epsilon (IKBKE) gene encodes IKKε protein that is involved in innate immunity, predominantly antiviral response generation. It also bears pro‐inflammatory properties that could affect psychiatric outcomes. In order to investigate the possible role of IKBKE gene in major depressive disorder (MDD) and panic disorder (PD), we conducted a case–control genetic association study concerning these disorders. Methods In all, 14 SNPs of IKBKE gene were genotyped in groups of 391 patients with MDD and 190 patients with PD together with respective 389 and 371 healthy control individuals. The given groups were further divided by gender for additional analyses. Results Substantial genetic associations were revealed between IKBKE SNPs and MDD (multiple testing adjusted P 0.05). In addition, two SNPs that were only associated with PD among males, also displayed significantly different allele frequencies compared to PD females. This may indicate a specific role of these SNPs in male PD, but caution should be applied here due to the small size of the studied PD males group. Conclusions The results of this study confirm our initial findings and indicate a possible role of IKBKE gene in mood and anxiety disorders

Role of CCK in anti-exploratory action of paroxetine, 5-HT reuptake inhibitor

The administration of paroxetine (0.5–8 mg/kg), a selective 5-HT reuptake inhibitor, induced a dose-dependent reduction of exploratory activity of rats in the motility test. In the elevated plus-maze paroxetine was less effective, only 8 mg/kg of paroxetine decreased the exploratory behaviour of rats. The doses of paroxetine (2–8 mg/kg) reducing the exploratory activity in the motility test increased the density of CCK receptors in the frontal cortex, but not in the hippocampus. The treatment of rats with the CCKB receptor antagonist LY288,513 (0.01–1 mg/kg) did not change the exploratory activity. However, the reduction of exploratory activity induced by the low dose of paroxetine (2 mg/kg), but not by the higher dose (8 mg/kg), was dose-dependently reversed by the administration of LY288,513. Moreover, LY288,513 did not affect the anti-exploratory action of paroxetine (8 mg/kg) in the elevated plus-maze. Diazepam at doses (0.5–1.0 mg/kg) not suppressing the locomotor activity did not change the anti-exploratory action of paroxetine in the motility test. It is likely that the anti-exploratory action of a low dose of paroxetine (2 mg/kg) is not related to the increase in anxiety, but rather to the reduction of exploratory drive. Evidence exists that this effect of paroxetine is mediated via the activation of CCK-ergic transmission

Associations between LSAMP gene polymorphisms and major depressive disorder and panic disorder

The purpose of this case–control genetic association study was to explore potential relationships between polymorphisms in the limbic system-associated membrane protein (LSAMP) gene and mood and anxiety disorders. A total of 21 single-nucleotide polymorphisms (SNPs) from the LSAMP gene were analyzed in 591 unrelated patients with the diagnoses of major depressive disorder (MDD) or panic disorder (PD) and in 384 healthy control subjects. The results showed a strong association between LSAMP SNPs and MDD, and a suggestive association between LSAMP SNPs and PD. This is the first evidence of a possible role of LSAMP gene in mood and anxiety disorders in humans

Analysis of SNP profiles in patients with major depressive disorder

The present study focused on 91 single-nucleotide polymorphisms (SNPs) in 21 candidate genes to find associations with major depressive disorder (MDD). In total, 160 healthy controls and 177 patients with MDD were studied. We applied arrayed primer extension (APEX) based genotyping technology followed by association and haplotype analysis. SNPs in CCKAR, DRD1, DRD2, and HTR2C genes showed nominally significant associations with MDD. None of these associations remained significant after adjustment for multiple testing. Haplotype analysis revealed CCKAR haplotypes to be associated with MDD (global p=0.004). More precisely, we found the GAGT haplotype to be associated with increased risk for MDD (OR 7.42, 95% CI 2.13–25.85, p=0.002). This haplotype effect remained significant after Bonferroni correction (p=0.04 after Bonferroni's adjustment). Altogether we were able to find some nominal associations, but due to small sample size these results should be taken as exploratory. However, the effect of GAGT haplotype on the CCKAR gene may be considered as increasing the risk for MDD

Wfs1-deficient mice display altered function of serotonergic system and increased behavioral response to antidepressants

It has been shown that mutations in the WFS1 gene make humans more susceptible to mood disorders. Besides that, mood disorders are associated with alterations in the activity of serotonergic and noradrenergic systems. Therefore, in this study, the effects of imipramine, an inhibitor of serotonin (5-HT) and noradrenaline (NA) reuptake, and paroxetine, a selective inhibitor of 5-HT reuptake, were studied in tests of behavioral despair. The tail suspension test (TST) and forced swimming test (FST) were performed in Wfs1-deficient mice. Simultaneously, gene expression and monoamine metabolism studies were conducted to evaluate changes in 5-HT- and NA-ergic systems of Wfs1-deficient mice. The basal immobility time of Wfs1-deficient mice in TST and FST did not differ from that of their wild-type littermates. However, a significant reduction of immobility time in response to lower doses of imipramine and paroxetine was observed in homozygous Wfs1-deficient mice, but not in their wild-type littermates. In gene expression studies, the levels of 5-HT transporter (SERT) were significantly reduced in the pons of homozygous animals. Monoamine metabolism was assayed separately in the dorsal and ventral striatum of naive mice and mice exposed for 30 min to brightly lit motility boxes. We found that this aversive challenge caused a significant increase in the levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of 5-HT, in the ventral and dorsal striatum of wild-type mice, but not in their homozygous littermates. Taken together, the blunted 5-HT metabolism and reduced levels of SERT are a likely reason for the elevated sensitivity of these mice to the action of imipramine and paroxetine. These changes in the pharmacological and neurochemical phenotype of Wfs1-deficient mice may help to explain the increased susceptibility of Wolfram syndrome patients to depressive states

Association of limbic system-associated membrane protein (LSAMP) to male completed suicide

<p>Abstract</p> <p>Background</p> <p>Neuroimaging studies have demonstrated volumetric abnormalities in limbic structures of suicide victims. The morphological changes might be caused by some inherited neurodevelopmental defect, such as failure to form proper axonal connections due to genetically determined dysfunction of neurite guidance molecules. Limbic system-associated membrane protein (LSAMP) is a neuronal adhesive molecule, preferentially expressed in developing limbic system neuronal dendrites and somata. Some evidence for the association between LSAMP gene and behavior has come from both animal as well as human studies but further investigation is required. In current study, polymorphic loci in human LSAMP gene were examined in order to reveal any associations between genetic variation in <it>LSAMP </it>and suicidal behaviour.</p> <p>Methods</p> <p>DNA was obtained from 288 male suicide victims and 327 healthy male volunteers. Thirty SNPs from LSAMP gene and adjacent region were selected by Tagger algorithm implemented in Haploview 3.32. Genotyping was performed using the SNPlex™ (Applied Biosystems) platform. Data was analyzed by Genemapper 3.7, Haploview 3.32 and SPSS 13.0.</p> <p>Results</p> <p>Chi square test revealed four allelic variants (rs2918215, rs2918213, rs9874470 and rs4821129) located in the intronic region of the gene to be associated with suicide, major alleles being overrepresented in suicide group. However, the associations did not survive multiple correction test. Defining the haplotype blocks using confidence interval algorithm implemented in Haploview 3.32, we failed to detect any associated haplotypes.</p> <p>Conclusion</p> <p>Despite a considerable amount of investigation on the nature of suicidal behaviour, its aetiology and pathogenesis remain unknown. This study examined the variability in LSAMP gene in relation to completed suicide. Our results indicate that LSAMP might play a role in pathoaetiology of suicidal behaviour but further studies are needed to understand its exact contribution.</p

Promoter polymorphism -119C/G in MYG1 (C12orf10) gene is related to vitiligo susceptibility and Arg4Gln affects mitochondrial entrance of Myg1

<p>Abstract</p> <p>Background</p> <p><it>MYG1 </it>(<it>Melanocyte proliferating gene 1</it>, also C12orf10 in human) is a ubiquitous nucleo-mitochondrial protein, involved in early developmental processes and in adult stress/illness conditions. We recently showed that <it>MYG1 </it>mRNA expression is elevated in the skin of vitiligo patients. Our aim was to examine nine known polymorphisms in the <it>MYG1 </it>gene, to investigate their functionality, and to study their association with vitiligo susceptibility.</p> <p>Methods</p> <p>Nine single nucleotide polymorphisms (SNPs) in the <it>MYG1 </it>locus were investigated by SNPlex assay and/or sequencing in vitiligo patients (n = 124) and controls (n = 325). <it>MYG1 </it>expression in skin biopsies was detected by quantitative-real time PCR (Q-RT-PCR) and polymorphisms were further analysed using luciferase and YFP reporters in the cell culture.</p> <p>Results</p> <p>Control subjects with -119G promoter allele (rs1465073) exhibited significantly higher <it>MYG1 </it>mRNA levels than controls with -119C allele (<it>P </it>= 0.01). Higher activity of -119G promoter was confirmed by luciferase assay. Single marker association analysis showed that the -119G allele was more frequent in vitiligo patients (47.1%) compared to controls (39.3%, <it>P </it>< 0.05, OR 1.37, 95%CI 1.02-1.85). Analysis based on the stage of progression of the vitiligo revealed that the increased frequency of -119G allele occurred prevalently in the group of patients with active vitiligo (n = 86) compared to the control group (48.2% <it>versus </it>39.3%, <it>P </it>< 0.05; OR 1.44, 95%CI 1.02-2.03). Additionally, we showed that glutamine in the fourth position (in Arg4Gln polymorphism) completely eliminated mitochondrial entrance of YFP-tagged Myg1 protein in cell culture. The analysis of available EST, cDNA and genomic DNA sequences revealed that Myg1 4Gln allele is remarkably present in human populations but is never detected in homozygous state according to the HapMap database.</p> <p>Conclusions</p> <p>Our study demonstrated that both <it>MYG1 </it>promoter polymorphism -119C/G and Arg4Gln polymorphism in the mitochondrial signal of Myg1 have a functional impact on the regulation of the <it>MYG1 </it>gene and promoter polymorphism (-119C/G) is related with suspectibility for actively progressing vitiligo.</p

Animal models of major depressive disorder and the implications for drug discovery and development

Introduction: Depression is a highly debilitating psychiatric disorder that affects the global population and causes severe disabilities and suicide. Depression pathogenesis remains poorly understood, and the disorder is often treatment-resistant and recurrent, necessitating the development of novel therapies, models and concepts in this field. Areas covered: Animal models are indispensable for translational biological psychiatry, and markedly advance the study of depression. Novel approaches continuously emerge that may help untangle the disorder heterogeneity and unclear categories of disease classification systems. Some of these approaches include widening the spectrum of model species used for translational research, using a broader range of test paradigms, exploring new pathogenic pathways and biomarkers, and focusing more closely on processes beyond neural cells (e.g. glial, inflammatory and metabolic deficits). Expert opinion: Dividing the core symptoms into easily translatable, evolutionarily conserved phenotypes is an effective way to reevaluate current depression modeling. Conceptually novel approaches based on the endophenotype paradigm, cross-species trait genetics and ‘domain interplay concept’, as well as using a wider spectrum of model organisms and target systems will enhance experimental modeling of depression and antidepressant drug discovery. © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group