Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission.

Schizophrenia affects approximately 1% of the world population. Genetics, epigenetics, and environmental factors are known to play a role in this psychiatric disorder. While there is a high concordance in monozygotic twins, about half of twin pairs are discordant for schizophrenia. To address the question of how and when concordance in monozygotic twins occur, we have obtained fibroblasts from two pairs of schizophrenia discordant twins (one sibling with schizophrenia while the second one is unaffected by schizophrenia) and three pairs of healthy twins (both of the siblings are healthy). We have prepared iPSC models for these 3 groups of patients with schizophrenia, unaffected co-twins, and the healthy twins. When the study started the co-twins were considered healthy and unaffected but both the co-twins were later diagnosed with a depressive disorder. The reprogrammed iPSCs were differentiated into hippocampal neurons to measure the neurophysiological abnormalities in the patients. We found that the neurons derived from the schizophrenia patients were less arborized, were hypoexcitable with immature spike features, and exhibited a significant reduction in synaptic activity with dysregulation in synapse-related genes. Interestingly, the neurons derived from the co-twin siblings who did not have schizophrenia formed another distinct group that was different from the neurons in the group of the affected twin siblings but also different from the neurons in the group of the control twins. Importantly, their synaptic activity was not affected. Our measurements that were obtained from schizophrenia patients and their monozygotic twin and compared also to control healthy twins point to hippocampal synaptic deficits as a central mechanism in schizophrenia.

Integrative metabolomics-genomics analysis identifies key networks in a stem cell-based model of schizophrenia.

Schizophrenia (SCZ) is a neuropsychiatric disorder, caused by a combination of genetic and environmental factors. The etiology behind the disorder remains elusive although it is hypothesized to be associated with the aberrant response to neurotransmitters, such as dopamine and glutamate. Therefore, investigating the link between dysregulated metabolites and distorted neurodevelopment holds promise to offer valuable insights into the underlying mechanism of this complex disorder. In this study, we aimed to explore a presumed correlation between the transcriptome and the metabolome in a SCZ model based on patient-derived induced pluripotent stem cells (iPSCs). For this, iPSCs were differentiated towards cortical neurons and samples were collected longitudinally at various developmental stages, reflecting neuroepithelial-like cells, radial glia, young and mature neurons. The samples were analyzed by both RNA-sequencing and targeted metabolomics and the two modalities were used to construct integrative networks in silico. This multi-omics analysis revealed significant perturbations in the polyamine and gamma-aminobutyric acid (GABA) biosynthetic pathways during rosette maturation in SCZ lines. We particularly observed the downregulation of the glutamate decarboxylase encoding genes GAD1 and GAD2, as well as their protein product GAD65/67 and their biochemical product GABA in SCZ samples. Inhibition of ornithine decarboxylase resulted in further decrease of GABA levels suggesting a compensatory activation of the ornithine/putrescine pathway as an alternative route for GABA production. These findings indicate an imbalance of cortical excitatory/inhibitory dynamics occurring during early neurodevelopmental stages in SCZ. Our study supports the hypothesis of disruption of inhibitory circuits to be causative for SCZ and establishes a novel in silico approach that enables for integrative correlation of metabolic and transcriptomic data of psychiatric disease models.

Nrem Slow-Wave Activity In Adolescents Is Differentially Associated With Adhd Levels And Normalized By Pharmacological Treatment.

BACKGROUND: A compelling hypothesis about ADHD etiopathogenesis is that the ADHD phenotype reflects a delay in cortical maturation. Slow-wave activity (SWA) of non-rapid eye movement (NREM) sleep electroencephalogram (EEG) is an electrophysiological index of sleep intensity reflecting cortical maturation. Available data on ADHD and SWA are conflicting and developmental differences, or the effect of pharmacological treatment are relatively unknown. METHODS: We examined, in samples (Mage=16.4, SD=1.2), of ever-medicated adolescents at-risk for ADHD (n=18, 72%boys), medication naïve adolescents at-risk for ADHD (n=15, 67%boys), and adolescents not at-risk for ADHD (n=31, 61%boys) matched for chronological age, whether controlling for non-ADHD pharmacotherapy, ADHD pharmacotherapy modulates the association between NREM SWA and ADHD risk in home sleep. RESULTS: Findings indicated medication naïve adolescents at-risk for ADHD exhibited greater first sleep cycle and entire night NREM SWA than both ever-medicated adolescents at-risk for ADHD and adolescents not at-risk for ADHD and no difference between ever-medicated, at-risk adolescents and not at-risk adolescents. CONCLUSIONS: Results support atypical cortical maturation in medication naïve adolescents at-risk for ADHD that appears to be normalized by ADHD pharmacotherapy in ever-medicated adolescents at-risk for ADHD. Greater NREM SWA may reflect a compensatory mechanism in middle-later adolescents at-risk for ADHD that normalizes an earlier occurring developmental delay.

Efficacy of a synbiotic in the management of adults with Attention-Deficit and Hyperactivity Disorder and/or Borderline Personality Disorder and high levels of irritability: Results from a multicenter, randomized, placebo-controlled, "basket" trial.

Irritability worsens prognosis and increases mortality in individuals with Attention-Deficit and Hyperactivity Disorder (ADHD) and/or Borderline Personality Disorder (BPD). However, treatment options are still insufficient. The aim of this randomized, double blind, placebo-controlled study was to investigate the superiority of a synbiotic over placebo in the management of adults with ADHD and/or BPD and high levels of irritability. The study was conducted between February 2019 and October 2020 at three European clinical centers located in Hungary, Spain and Germany. Included were patients aged 18-65 years old diagnosed with ADHD and/or BPD and high levels of irritability (i.e., an Affectivity Reactivity Index (ARI-S) ≥ 5, plus a Clinical Global Impression-Severity Scale (CGI-S) score ≥ 4). Subjects were randomized 1(synbiotic):1(placebo); the agent was administered each day, for 10 consecutive weeks. The primary outcome measure was end-of-treatment response (i.e., a reduction ≥ 30 % in the ARI-S total score compared to baseline, plus a Clinical Global Impression-Improvement (CGI-I) total score of < 3 (very much, or much improved) at week 10). Between-treatment differences in secondary outcomes, as well as safety were also investigated. Of the 231 included participants, 180 (90:90) were randomized and included in the intention-to-treat-analyses. Of these, 117 (65 %) were females, the mean age was 38 years, ADHD was diagnosed in 113 (63 %), BPD in 44 (24 %), both in 23 (13 %). The synbiotic was well tolerated. At week 10, patients allocated to the synbiotic experienced a significantly higher response rate compared to those allocated to placebo (OR: 0.2, 95 % CI:0.1 to 0.7; P = 0.01). These findings suggest that that (add-on) treatment with a synbiotic may be associated with a clinically meaningful improvement in irritability in, at least, a subgroup of adults with ADHD and/or BPD. A superiority of the synbiotic over placebo in the management of emotional dysregulation (-3.6, 95 % CI:-6.8 to -0.3; P = 0.03), emotional symptoms (-0.6, 95 % CI:-1.2 to -0.05; P = 0.03), inattention (-1.8, 95 % CI: -3.2 to -0.4; P = 0.01), functioning (-2.7, 95 % CI: -5.2 to -0.2; P = 0.03) and perceived stress levels (-0.6, 95 % CI: -1.2 to -0.05; P = 0.03) was also suggested. Higher baseline RANK-L protein levels were associated with a significantly lower response rate, but only in the synbiotic group (OR: 0.1, 95 % CI: -4.3 to - 0.3, P = 0.02). In the placebo group, higher IL-17A levels at baseline were significantly associated with a higher improvement in in particular, emotional dysregulation (P = 0.04), opening a door for new (targeted) drug intervention. However, larger prospective studies are warranted to confirm the findings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03495375.

MicroRNA-Mediated Suppression of Glial Cell Line-Derived Neurotrophic Factor Expression Is Modulated by a Schizophrenia-Associated Non-Coding Polymorphism.

Plasma levels of glial cell line-derived neurotrophic factor (GDNF), a pivotal regulator of differentiation and survival of dopaminergic neurons, are reportedly decreased in schizophrenia. To explore the involvement of GDNF in the pathogenesis of the disease, a case-control association analysis was performed between five non-coding single nucleotide polymorphisms (SNP) across the GDNF gene and schizophrenia. Of them, the 'G' allele of the rs11111 SNP located in the 3' untranslated region (3'-UTR) of the gene was found to associate with schizophrenia. In silico analysis revealed that the rs11111 'G' allele might create binding sites for three microRNA (miRNA) species. To explore the significance of this polymorphism, transient co-transfection assays were performed in human embryonic kidney 293T (HEK293T) cells with a luciferase reporter construct harboring either the 'A' or 'G' allele of the 3'-UTR of GDNF in combination with the hsa-miR-1185-1-3p pre-miRNA. It was demonstrated that in the presence of the rs11111 'G' (but not the 'A') allele, hsa-miR-1185-2-3p repressed luciferase activity in a dose-dependent manner. Deletion of the miRNA binding site or its substitution with the complementary sequence abrogated the modulatory effect. Our results imply that the rs11111 'G' allele occurring more frequently in patients with schizophrenia might downregulate GDNF expression in a miRNA-dependent fashion.

Electrophysiological underpinnings of dysfunctional inhibitory control in adults with attention-deficit/hyperactivity disorder: evidence for reduced NoGo anteriorization.

Our aim was to delineate the electrophysiological basis of dysfunctional inhibitory control of adult ADHD via investigating the anteriorization of the P3 component of the event-related brain response associated with the NoGo task condition (i.e., NoGo anteriorization, NGA). NGA is a neurophysiological measure of brain topography for cognitive response control, which indexes an overall shift of the brain's electrical activity in anterior direction towards the prefrontal areas. While the NoGo P3 received considerable attention in the adult ADHD literature, the brain topography of this component, which reflects the inhibitory process, remains largely unaddressed. EEG recordings were obtained during a Go/NoGo task from 51 subjects (n = 26 adult patients with ADHD, n = 25 healthy controls) using a high-density, 128-channel BioSemi ActiveTwo recording system. ADHD patients had significantly lower P3 NGA response compared to controls. The decrease in NGA was related to impulsivity scores as measured by the Conners' Adult ADHD Rating Scale: patients with higher impulsivity scores had significantly lower NGA. Treatment with stimulant medication, as compared to the lack of such treatment, was associated with a correction of the lower NGA response in ADHD patients. The current study revealed a lower NGA in adult ADHD, a finding which is consistent with the inhibitory control and frontal lobe dysfunctions described in the disorder. Our finding of the inverse relationship between NGA and impulsivity suggests that clinically more severe impulsivity is linked to a more pronounced frontal dysfunction in adult ADHD subjects.

Differential neurocognitive profiles in adult attention-deficit/hyperactivity disorder subtypes revealed by the Cambridge Neuropsychological Test Automated Battery.

Adult attention-deficit/hyperactivity disorder (aADHD) represents a heterogeneous entity incorporating different subgroups in terms of symptomatology, course, and neurocognition. Although neurocognitive dysfunction is generally associated with aADHD, its severity, association with self-reported symptoms, and differences between subtypes remain unclear. We investigated 61 outpatients (65.6% male, mean age 31.5 ± 9.5) diagnosed using DSM-5 criteria together with age-, sex-, and education-matched healthy controls (HC) (n = 58, 63.8% male, mean age 32.3 ± 9.6). Neurocognitive alterations were assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB) and compared between groups using the generalized linear model (GLM) method. Multivariate effects were tested by principal component analysis combined with multivariate pattern analysis. Self-reported symptom severity was tested for correlations with neurocognitive performance. GLM analyses revealed nominally significant differences between the aADHD and HC groups in several domains, however, only the Rapid Visual Information Processing measures survived correction, indicating impaired sustained attention and response inhibition in the aADHD group. Comparison of the predominantly inattentive and the hyperactive-impulsive/combined subtypes yielded nominally significant differences with higher levels of dysfunction in the inattentive group. In the stepwise discriminant analysis aADHD and HC groups were best separated with 2 factors representing sustained attention and reaction time. We found only weak correlations between symptom severity and CANTAB factors. aADHD patients are neuropsychologically heterogeneous and subtypes show different neurocognitive profiles. Differences between the aADHD and HC groups were driven primarily by the inattentive subtype. Sustained attention and its factor derivative showed the most significant alterations in aADHD patients.

Concurrent and Prospective Associations of Reward Response with Affective and Alcohol Problems: ADHD-Related Differential Vulnerability.

Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous disorder. Data on the role of transdiagnostic, intermediate phenotypes in ADHD-relevant characteristics and outcomes are needed to advance conceptual understanding and approaches to precision psychiatry. Specifically, the extent to which the association between neural response to reward and ADHD-associated affective, externalizing, internalizing, and substance use problems differ depending on ADHD status is unknown. Aims were to examine, in 129 adolescents, whether concurrent and prospective associations of fMRI-measured initial response to reward attainment (relative to loss) with affectivity and externalizing, internalizing, and alcohol use problems differs between youth at-risk for (i.e., subclinical) (n = 50) and not at-risk for ADHD. Adolescents were, on average, 15.29 years old (SD = 1.00; 38% female), 50 were at-risk for (Mage = 15.18 years, SD = 1.04; 22% female) and 79 not at-risk for (Mage = 15.37 years, SD = 0.98; 48.1% female) ADHD. Both concurrent and prospective relations differed given ADHD risk: across analyses, in at-risk youth, greater superior frontal gyrus response was associated with lower concurrent depressive problems but in not at-risk youth, these characteristics were not related. Controlling for baseline use, in at-risk youth, greater putamen response was associated with greater 18-month hazardous alcohol use, whereas in not at-risk youth, greater putamen response was associated with lower use. Where in brain and for which outcomes modulate (direction of) observed relations: superior frontal gyrus response is relevant for depressive problems whereas putamen response is relevant for alcohol problems and greater neural responsivity is linked to less depressive but to more alcohol problems in adolescents at-risk for ADHD and less alcohol problems in adolescents not at-risk. Differences in neural response to reward differentially confer vulnerability for adolescent depressive and alcohol problems depending on ADHD risk.

Potential Role of the Antidepressants Fluoxetine and Fluvoxamine in the Treatment of COVID-19.

Mapping non-canonical cellular pathways affected by approved medications can accelerate drug repurposing efforts, which are crucial in situations with a global impact such as the COVID-19 pandemic. Fluoxetine and fluvoxamine are well-established and widely-used antidepressive agents that act as serotonin reuptake inhibitors (SSRI-s). Interestingly, these drugs have been reported earlier to act as lysosomotropic agents, inhibitors of acid sphingomyelinase in the lysosomes, and as ligands of sigma-1 receptors, mechanisms that might be used to fight severe outcomes of COVID-19. In certain cases, these drugs were administered for selected COVID-19 patients because of their antidepressive effects, while in other cases, clinical studies were performed to assess the effect of these drugs on treating COVID-19 patients. Clinical studies produced promising data that encourage the further investigation of fluoxetine and fluvoxamine regarding their use in COVID-19. In this review, we summarize experimental data and the results of the performed clinical studies. We also provide an overview of previous knowledge on the tissue distribution of these drugs and by integrating this information with the published experimental results, we highlight the real opportunity of using these drugs in our fight against COVID-19.

Impaired early information processing in adult ADHD: a high-density ERP study.

BACKGROUND: Children with attention-deficit/hyperactivity disorder (ADHD) often demonstrate sensory processing difficulties in the form of altered sensory modulation, which may contribute to their symptomatology. Our objective was to investigate the neurophysiological correlates of sensory processing deficits and the electrophysiological characteristics of early information processing in adult ADHD, measured by the P1 event-related potential (ERP). METHODS: We obtained ERPs during a Go/NoGo task from 26 adult patients with ADHD and 25 matched controls using a high-density 128-channel BioSemi ActiveTwo recording system. RESULTS: ADHD patients had a significantly reduced P1 component at occipital and inferotemporal scalp areas compared to controls. The reduction was associated with inattention and hyperactivity symptom severity, as measured by the Conners' Adult ADHD Rating Scale. ADHD patients with higher inattention scores had significantly smaller P1 amplitudes at posterior scalp sites, while higher hyperactivity scores were associated with higher P1 amplitudes. CONCLUSIONS: Deficits in early sensory processing, as measured by the P1 ERP component, are present in adult ADHD patients and are associated with symptom severity. These findings are suggestive of bottom-up cognitive deficits in ADHD driven by impairments in early visual processing, and provide evidence that sensory processing problems are present at the neurophysiological level in this population.

Functional Comparison of Blood-Derived Human Neural Progenitor Cells.

Induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs) are promising tools to model complex neurological or psychiatric diseases, including schizophrenia. Multiple studies have compared patient-derived and healthy control NPCs derived from iPSCs in order to investigate cellular phenotypes of this disease, although the establishment, stabilization, and directed differentiation of iPSC lines are rather expensive and time-demanding. However, interrupted reprogramming by omitting the stabilization of iPSCs may allow for the generation of a plastic stage of the cells and thus provide a shortcut to derive NPSCs directly from tissue samples. Here, we demonstrate a method to generate shortcut NPCs (sNPCs) from blood mononuclear cells and present a detailed comparison of these sNPCs with NPCs obtained from the same blood samples through stable iPSC clones and a subsequent neural differentiation (classical NPCs-cNPCs). Peripheral blood cells were obtained from a schizophrenia patient and his two healthy parents (a case-parent trio), while a further umbilical cord blood sample was obtained from the cord of a healthy new-born. The expression of stage-specific markers in sNPCs and cNPCs were compared both at the protein and RNA levels. We also performed functional tests to investigate Wnt and glutamate signaling and the oxidative stress, as these pathways have been suggested to play important roles in the pathophysiology of schizophrenia. We found similar responses in the two types of NPCs, suggesting that the shortcut procedure provides sNPCs, allowing an efficient screening of disease-related phenotypes.

Characterization of calcium signals in human induced pluripotent stem cell-derived dentate gyrus neuronal progenitors and mature neurons, stably expressing an advanced calcium indicator protein.

Pluripotent stem cell derived human neuronal progenitor cells (hPSC-NPCs) and their mature neuronal cell culture derivatives may efficiently be used for central nervous system (CNS) drug screening, including the investigation of ligand-induced calcium signalization. We have established hippocampal NPC cultures derived from human induced PSCs, which were previously generated by non-integrating Sendai virus reprogramming. Using established protocols these NPCs were differentiated into hippocampal dentate gyrus neurons. In order to study calcium signaling without the need of dye loading, we have stably expressed an advanced calcium indicator protein (GCaMP6fast) in the NPCs using the Sleeping Beauty transposon system. We observed no significant effects of the long-term GCaMP6 expression on NPC morphology, gene expression pattern or neural differentiation capacity. In order to compare the functional properties of GCaMP6-expressing neural cells and the corresponding parental cells loaded with calcium indicator dye Fluo-4, a detailed characterization of calcium signals was performed. We found that the calcium signals induced by ATP, glutamate, LPA, or proteases - were similar in these two systems. Moreover, the presence of the calcium indicator protein allowed for a sensitive, repeatable detection of changes in calcium signaling during the process of neurogenesis and neuronal maturation.

Development of quality indicators for mental healthcare in the Danube region.

BACKGROUND: Quality indicators are quality assurance instruments for the evaluation of mental healthcare systems. Quality indicators can be used to measure the effectiveness of mental healthcare structure and process reforms. This project aims to develop quality indicators for mental healthcare systems in Bulgaria, the Czech Republic, Hungary and Serbia to provide monitoring instruments for the transformation of mental healthcare systems in these countries. METHODS: Quality indicators for mental healthcare systems were developed in a systematic, multidisciplinary approach. A systematic literature study was conducted to identify quality indicators that are used internationally in mental healthcare. Retrieved quality indicators were systematically selected by means of defined inclusion and exclusion criteria. Quality indicators were subsequently rated in a two-stage Delphi study for relevance, validity and feasibility (data availability and data collection effort). The Delphi panel included 22 individuals in the first round, and 18 individuals in the second and final round. RESULTS: Overall, mental healthcare quality indicators were rated higher in relevance than in validity (Mean relevance=7.6, SD=0.8; Mean validity=7.1, SD=0.7). There was no statistically significant difference in scores between the four countries for relevance (X2 (3)=3.581, p=0.310) and validity (X2 (3)=1.145, p=0.766). For data availability, the appraisal of "YES" (data are available) ranged from 6% for "assisted housing" to 94% for "total beds for mental healthcare per 100,000 population" and "availability of mental health service facilities". CONCLUSION: Quality indicators were developed in a systematic and multidisciplinary development process. There was a broad consensus among mental healthcare experts from the participating countries in terms of relevance and validity of the proposed quality indicators. In a next step, the feasibility of these twenty-two indicators will be evaluated in a pilot study in the participating countries.

[Review of the psychiatric aspects of anti-NMDA (N-methyl-D-aspartic acid) receptor encephalitis, case report, and our plans for a future study]. / Anti-NMDA (N-metil-D-aszparaginsav) receptor enkefalitisz: irodalmi összefoglaló, esetismertetés és kutatási terv.

Anti-NMDAR (N-methyl-D-aspartic acid receptor) encephalitis, first described in 2007, is a rare, autoimmune limbic encephalitis. In half of the cases anti-NMDAR antibodies are paraneoplastic manifestations of an underlying tumor (mostly ovarian teratoma). In the early stage of the disease psychiatric symptoms are prominent, therefore 60-70% of the patients are first treated in a psychiatric department. In most of the cases, typical neurological symptoms appear later. Besides the clinical picture and typical symptoms, verifying presence of IgG antibodies in the serum or CSF is necessary to set up the diagnosis. Other diagnostic tools, including laboratory tests, MRI, lumbar puncture or EEG are neither specific, nor sensitive enough. Therapy is based on supportive care, plasma exchange and immune suppression, intensive care administration can be necessary. If there is an underlying tumor, tumor removal is the first-line treatment. The disease can cause fatal complications in the acute phase but with adequate therapy long-term prognosis is good, although rehabilitation can last for months. In the past few years besides the typical clinical picture and illness course an increasing number of case reports described no typical neurological symptoms, only psychiatric symptoms, including psychosis, disorganized behavior, and catatonic symptoms. Immune suppressive treatment was still effective in most of these cases. Such cases present a difficult diagnostic challenge. These patients may receive unnecessary antipsychotic treatment because of the suspected schizophrenia, although they often suffer from serious extrapyramidal side effects. A few years ago there was a hypothesis that a small part of the patients who are treated with therapy-resistant schizophrenia may suffer from anti-NMDAR encephalitis, so they require a different kind of medication. Evidence from the latest publications did not confirm this hypothesis, although the connection between anti-NMDAR antibodies and disorders with psychotic symptoms is still not clear. After reviewing the most important studies regarding the psychiatric aspects of anti-NMDAR encephalitis, we present a case report of a patient with a pure psychiatric manifestation of this disease. We conclude with a short outline of the design and plan of our future study.

[Modeling neurological and psychiatric disorders in vitro using induced pluripotent stem cells: highlighting findings in Alzheimer's disease and schizophrenia]. / Neurológiai és pszichiátriai betegségek in vitro modellezése indukált pluripotens ossejtek felhasználásával: fókuszban az Alzheimer-kór és a szkizofrénia.

Over the past decade we witnessed the birth of a new scientific area that lies at the borders of developmental biology, stem cell biology, basic and clinical neuroscience. In vitro disease modeling refers to the approach that exploits the capacity of stem cells for self-renewal and pluripotency by generating specific cell types that are relevant for a given disorder. Based on this method, neurological and psychiatric disorders can be investigated by differentiating stem cells into neurons in a dish, and studying the relevant neuronal populations affected in the pathophysiology of the disorder in terms of specific cellular phenotypes. The advent of induced pluripotent stem cells (IPSCs) has made it possible to reprogram IPSCs from somatic cells of patients carrying specific genetic risk variants, and to analyze the in vitro cellular findings in the context of the clinical picture. Pluripotent stem cell based disease modeling offers an alternative solution for invasive and mostly not performable central nervous system biopsies in neuropsychiatric disorders, and is an appealing laboratory method for studying biomarkers of these disorders and for future drug development. This review summarizes the pluripotent stem cell based disease modeling literature in two important neuropsychiatric disorders, Alzheimer's disease and schizophrenia.

[An attempt to identify 22q11.2 microdeletions in samples of the Hungarian schizophrenia DNA bank by multiplex ligation-based probe amplification (MLPA): literature review, methodology and results]. / 22q11.2 deléciók azonosítási kísérlete magyar szkizofrénia biobank mintákon multiplex ligációs alapú próba amplifikáció (MLPA) módszerrel: irodalmi összefoglalás, módszertani leírás és eredmények.

Schizophrenia is a severe debilitating psychiatric disorder, with a typical onset in adolescence or early adulthood. This condition is characterized by heterogeneous symptoms (hallucinations, delusions, disorganized behaviour, affective flattening, and social isolation) and a life-time prevalence of 0.5-1.2%. In spite of the efforts to uncover the etiology of the disorder, its pathogenesis and neurobiological background are poorly understood. Given the high heritability in schizophrenia, genetic research remains an important area of focus. Besides the common variations of low penetrance - single nucleotid polymorphisms (SNPs) -, rare variants, mainly copy number variations (CNVs) play a role in the genetic architecture of the disorder. The most frequent CNV associated with schizophrenia is the hemizygous deletion of the 22q11.2 region. According to previous research this genetic variant occurs in 1% of the patients and conversely, 25% of the carriers of the 22q11.2 microdeletion will develop schizophrenia. The 22q11.2 deletion syndrome (22Q11DS, velocardiofacial (VCFS) syndrome, DiGeorge-syndrome) is usually a childhood diagnosis. Its prevalence is 1:2000-4000 considering all births. Patients can demonstrate heart developmental disorders, craniofacial (elongated face, hypertelorism), immunological (thymus-hypoplasia), endocrinological (hypocalcaemia) abnormalities, and neurodevelopmental alterations, but only a proportion will have these abnormalities due to incomplete penetrance. The variable symptoms complicate the recognition of the syndrome in the day to day medical practice. 25% of the known 22Q11DS patients develop schizophrenia but the risk of neuropsychiatric problems, like autism, ADHD and childhood conduct disorder is also increased, while early onset Parkinson's disease in also more frequent in adults. The schizophrenia phenotype is not distinguishable at the moment in patients with or without the 22q11 deletion. But emerging evidence suggests that early onset Parkinson's disease is more frequent in 22Q11DS and the effects of clozapine treatment could be different in schizophrenia with 22Q11DS. The question arises what is the incidence rate of the 22q11.2 microdeletion among our Hungarian DNA samples with schizophrenia. To answer the question, we utilized a new method used in routine genetic diagnostics, multiplex ligation-based probe amplification (MLPA). Although we genotyped the DNA of 315 Hungarian schizophrenia patients, we found no 22Q11DS in this cohort. The findings are discussed in terms of basic research and their translation into everyday clinical practice.

[Investigation of CNTF, COMT, DDR1, DISC1, DRD2, DRD3, and DTNBP1 candidate genes in schizophrenia: Results from the Hungarian SCHIZOBANK Consortium]. / CNTF, COMT, DDR1, DISC1, DRD2, DRD3 és DTNBP1 kandidáns gének vizsgálata szkizofréniában: eredmények a Magyar SCHIZOBANK Konzorcium vizsgálatából.

Schizophrenia is a chronic, debilitating psychiatric disorder characterized by heterogeneous clinical symptoms. Although the pathogenesis of this disorder is poorly understood, several lines of evidence support the role of both common and rare genetic variants in the etiology of schizophrenia. Common variants, single nucleotide polymorphisms can be investigated by candidate gene association studies or genome-wide association studies, while rare variants, single nucleotide variants are assessable by means of candidate gene resequencing or whole-exome and genome sequencing using next generation sequencing. In this study we investigated polymorphisms of 7 candidate genes in a Hungarian schizophrenia cohort. Candidate genes were chosen on the basis of previous results and biological plausibility. 390 patients were recruited in 5 centers in the framework of the Hungarian SCHIZOBANK Consortium, the schizophrenia sample was contrasted to 1069 healthy control individuals. In this sample SNPs of DDR1 and DRD2 genes demonstrated significant association with schizophrenia. The role of DDR1 and DRD2 genes in the etiology of schizophrenia warrant further investigation, based on their genomic localization and biological functions.

Multimarker analysis suggests the involvement of BDNF signaling and microRNA biosynthesis in suicidal behavior.

Despite moderate heritability estimates the genetics of suicidal behavior remains unclear, genome-wide association and candidate gene studies focusing on single nucleotide associations reported inconsistent findings. Our study explored biologically informed, multimarker candidate gene associations with suicidal behavior in mood disorders. We analyzed the GAIN Whole Genome Association Study of Bipolar Disorder version 3 (n = 999, suicidal n = 358) and the GAIN Major Depression: Stage 1 Genomewide Association in Population-Based Samples (n = 1,753, suicidal n = 245) datasets. Suicidal behavior was defined as severe suicidal ideation or attempt. Candidate genes were selected based on literature search (Geneset1, n = 35), gene expression data of microRNA genes, (Geneset2, n = 68) and their target genes (Geneset3, n = 11,259). Quality control, dosage analyses were carried out with PLINK. Gene-based associations of Geneset1 were analyzed with KGG. Polygenic profile scores of suicidal behavior were computed in the major depression dataset both with PRSice and LDpred and validated in the bipolar disorder data. Several nominally significant gene-based associations were detected, but only DICER1 associated with suicidal behavior in both samples, while only the associations of NTRK2 in the depression sample reached family wise and experiment wise significance. Polygenic profile scores negatively predicted suicidal behavior in the bipolar sample for only Geneset2, with the strongest prediction by PRSice at Pt < 0.03 (Nagelkerke R(2) = 0.01, P < 0.007). Gene-based association results confirmed the potential involvement of the BDNF-NTRK2-CREB pathway in the pathogenesis of suicide and the cross-disorder association of DICER1. Polygenic risk prediction of the selected miRNA genes indicates that the miRNA system may play a mediating role, but with considerable pleiotropy. © 2016 Wiley Periodicals, Inc.

Common variants conferring risk of schizophrenia.

Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.

Glycogen synthase kinase 3 beta gene structural variants as possible risk factors of bipolar depression.

The glycogen synthase kinase 3B (GSK3B) is an important target protein of several antidepressants, such as lithium, a mood stabilizer. Recent studies associated structural variations of the GSK3B gene to bipolar disorder (BP), although replications were not conclusive. Here we present data on copy number variations (CNVs) of the GSK3B gene probing the 9th exon region in 846 individuals (414 controls, 172 patients with major depressive disorder (MDD) and 260 with BP). A significant accumulation (odds ratio: 5.5, P = 0.00051) of the amplified exon 9 region was found in patients (22 out of 432) compared to controls (4 of 414). Analyzing patient subgroups, GSK3B structural variants were found to be risk factors of BP particularly (P = 0.00001) with an odds ratio of 8.1 while no such effect was shown in the MDD group. The highest odds (19.7 ratio) for bipolar disorder was observed in females with the amplified exon 9 region. A more detailed analysis of the identified GSK3B CNV by a set of probes covering the GSK3B gene and the adjacent NR1I2 and C3orf15 genes showed that the amplified sequences contained 3' (downstream) segments of the GSK3B and NR1I2 genes but none of them involved the C3orf15 gene. Therefore, the copy number variation of the GSK3B gene could be described as a complex set of structural variants involving partial duplications and deletions, simultaneously. In summary, here we confirmed significant association of the GSK3B CNV and bipolar disorder pointing out that the copy number and extension of the CNV varies among individuals.