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Small supernumerary marker chromosomes (sSMC) are chromosomal fragments difficult to characterize genomically. Here, we detail a proband with schizoaffective disorder and a mother with bipolar disorder with psychotic features who present with a marker chromosome that segregates with disease. We explored the architecture of this marker and investigated its temporal origin. Array comparative genomic hybridization (aCGH) analysis revealed three duplications and three triplications that spanned the short arm of chromosome 9, suggestive of a chromoanasynthesis-like event. Segregation of marker genotypes, phased using sSMC mosaicism in the mother, provided evidence that it was generated during a germline-level event in the proband's maternal grandmother. Whole-genome sequencing (WGS) was performed to resolve the structure and junctions of the chromosomal fragments, revealing further complexities. While structural variations have been previously associated with neuropsychiatric disorders and marker chromosomes, here we detail the precise architecture, human life-cycle genesis, and propose a DNA replicative/repair mechanism underlying formation.
Assuntos
Transtorno Bipolar/genética , Transtornos Cromossômicos/genética , Marcadores Genéticos , Transtornos Psicóticos/genética , Transtorno Bipolar/fisiopatologia , Aberrações Cromossômicas , Transtornos Cromossômicos/fisiopatologia , Duplicação Cromossômica/genética , Cromossomos Humanos Par 9/genética , Hibridização Genômica Comparativa , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Linhagem , Fenótipo , Transtornos Psicóticos/fisiopatologia , Sequenciamento Completo do GenomaRESUMO
Rare copy number variants (CNVs) have a prominent role in the aetiology of schizophrenia and other neuropsychiatric disorders. Substantial risk for schizophrenia is conferred by large (>500-kilobase) CNVs at several loci, including microdeletions at 1q21.1 (ref. 2), 3q29 (ref. 3), 15q13.3 (ref. 2) and 22q11.2 (ref. 4) and microduplication at 16p11.2 (ref. 5). However, these CNVs collectively account for a small fraction (2-4%) of cases, and the relevant genes and neurobiological mechanisms are not well understood. Here we performed a large two-stage genome-wide scan of rare CNVs and report the significant association of copy number gains at chromosome 7q36.3 with schizophrenia. Microduplications with variable breakpoints occurred within a 362-kilobase region and were detected in 29 of 8,290 (0.35%) patients versus 2 of 7,431 (0.03%) controls in the combined sample. All duplications overlapped or were located within 89 kilobases upstream of the vasoactive intestinal peptide receptor gene VIPR2. VIPR2 transcription and cyclic-AMP signalling were significantly increased in cultured lymphocytes from patients with microduplications of 7q36.3. These findings implicate altered vasoactive intestinal peptide signalling in the pathogenesis of schizophrenia and indicate the VPAC2 receptor as a potential target for the development of new antipsychotic drugs.
Assuntos
Variações do Número de Cópias de DNA/genética , Genes Duplicados/genética , Predisposição Genética para Doença/genética , Receptores Tipo II de Peptídeo Intestinal Vasoativo/genética , Esquizofrenia/genética , Linhagem Celular , Cromossomos Humanos Par 7/genética , Estudos de Coortes , AMP Cíclico/metabolismo , Feminino , Dosagem de Genes/genética , Estudo de Associação Genômica Ampla , Humanos , Padrões de Herança/genética , Masculino , Linhagem , Receptores Tipo II de Peptídeo Intestinal Vasoativo/metabolismo , Reprodutibilidade dos Testes , Esquizofrenia/metabolismo , Transdução de Sinais , Transcrição Gênica/genéticaRESUMO
Schizophrenia is a severe psychiatric disorder with strong heritability and marked heterogeneity in symptoms, course, and treatment response. There is strong interest in identifying genetic risk factors that can help to elucidate the pathophysiology and that might result in the development of improved treatments. Linkage and genome-wide association studies (GWASs) suggest that the genetic basis of schizophrenia is heterogeneous. However, it remains unclear whether the underlying genetic variants are mostly moderately rare and can be identified by the genotyping of variants observed in sequenced cases in large follow-up cohorts or whether they will typically be much rarer and therefore more effectively identified by gene-based methods that seek to combine candidate variants. Here, we consider 166 persons who have schizophrenia or schizoaffective disorder and who have had either their genomes or their exomes sequenced to high coverage. From these data, we selected 5,155 variants that were further evaluated in an independent cohort of 2,617 cases and 1,800 controls. No single variant showed a study-wide significant association in the initial or follow-up cohorts. However, we identified a number of case-specific variants, some of which might be real risk factors for schizophrenia, and these can be readily interrogated in other data sets. Our results indicate that schizophrenia risk is unlikely to be predominantly influenced by variants just outside the range detectable by GWASs. Rather, multiple rarer genetic variants must contribute substantially to the predisposition to schizophrenia, suggesting that both very large sample sizes and gene-based association tests will be required for securely identifying genetic risk factors.
Assuntos
Exoma/genética , Predisposição Genética para Doença/genética , Esquizofrenia/genética , Sequência de Bases , Finlândia , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Dados de Sequência Molecular , Fatores de Risco , Alinhamento de Sequência , Análise de Sequência de DNA , Estados UnidosRESUMO
Several event-related potentials (ERP), including P3, sensory gating (P50), and gamma oscillation, are robustly impaired in patients with schizophrenia (SCZ) and bipolar disorder (BIP). Although these ERPs are known to be heritable, little is known about the specific genetic loci involved and the degree to which they overlap with loci influencing mood and psychotic disorders. In the present study, we conducted GWAS to a) identify common variants associated with ERP endophenotypes, and b) construct polygenic risk scores (PRS) to examine overlap between genetic components of ERPs and mood and psychotic disorders. The sample consisted of 271 patients with SCZ or psychotic BIP diagnosis and 128 controls for whom ERP and genomewide data were available. GWAS were conducted using the full sample. PRS, derived from the Psychiatric Genomics Consortium (PGC) analyses of SCZ, BIP, and major depressive disorder were applied to each ERP phenotype. We identified a region on chromosome 14 that was significantly associated with sensory gating (peak SNP rs10132223, P = 1.27 × 10(-9) ). This locus has not been previously associated with psychotic illness in PGC-GWAS. In the PRS analyses, patients with a higher load of SCZ risk alleles had reduced gamma response whereas patients with a higher load of BIP risk alleles had smaller P3 amplitude. We observed a genomewide significant locus on chromosome 14 for P50. This locus may influence P50 but not psychotic illness. Among patients with psychotic illness, PRS results indicated genetic overlap between SCZ loci and gamma oscillation and between BIP loci and P3 amplitude.
Assuntos
Transtorno Bipolar/genética , Transtorno Bipolar/patologia , Eletrofisiologia/métodos , Genoma Humano , Estudo de Associação Genômica Ampla , Esquizofrenia/genética , Esquizofrenia/patologia , Adulto , Endofenótipos , Feminino , Seguimentos , Predisposição Genética para Doença , Humanos , Masculino , PrognósticoRESUMO
A number of mixture modeling approaches assume both normality and independent observations. However, these two assumptions are at odds with the reality of many data sets, which are often characterized by an abundance of zero-valued or highly skewed observations as well as observations from biologically related (i.e., non-independent) subjects. We present here a finite mixture model with a zero-inflated Poisson regression component that may be applied to both types of data. This flexible approach allows the use of covariates to model both the Poisson mean and rate of zero inflation and can incorporate random effects to accommodate non-independent observations. We demonstrate the utility of this approach by applying these models to a candidate endophenotype for schizophrenia, but the same methods are applicable to other types of data characterized by zero inflation and non-independence.
Assuntos
Conjuntos de Dados como Assunto/estatística & dados numéricos , Modelos Estatísticos , Distribuição de Poisson , Adulto , Endofenótipos , Humanos , Pessoa de Meia-Idade , Razão de Chances , Esquizofrenia/genéticaRESUMO
Genome-wide association studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) as disease associated variants for schizophrenia (SCZ), bipolar disorder (BPD), or both. Although these results are statistically robust, the functional effects of these variants and their role in the pathophysiology of SCZ or BPD remain unclear. Dissecting the effects of risk genes on distinct domains of brain function can provide important biological insights into the mechanisms by which these genes may confer illness risk. This study used quantitative event related potentials to characterize the neurophysiological effects of well-documented GWAS-derived SCZ/BPD susceptibility variants in order to map gene effects onto important domains of brain function. We genotyped 199 patients with DSM-IV diagnoses of SCZ or BPD and 74 healthy control subjects for 19 risk SNPs derived from previous GWAS findings and tested their association with five neurophysiologic traits (P3 amplitude, P3 latency, N1 amplitude, P2 amplitude, and P50 sensory gating responses) known to be abnormal in psychosis. The TCF4 SNP rs17512836 risk allele showed a significant association with reduced auditory P3 amplitude (P = 0.00016) after correction for multiple testing. The same allele was also associated with delayed P3 latency (P = 0.005). Our results suggest that a SCZ risk variant in TCF4 is associated with neurophysiologic traits thought to index attention and working memory abnormalities in psychotic disorders. These findings suggest a mechanism by which TCF4 may contribute to the neurobiological basis of psychotic illness.
Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Transtorno Bipolar/genética , Esquizofrenia/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Idoso , Alelos , Ondas Encefálicas , Eletroencefalografia , Feminino , Frequência do Gene , Marcadores Genéticos , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Transtornos Psicóticos/genética , Risco , Fator de Transcrição 4 , Adulto JovemRESUMO
Recent studies have established an important role for rare genomic deletions and duplications in the etiology of schizophrenia. This research suggests that the genetic architecture of neuropsychiatric disorders includes a constellation of rare mutations in many different genes. Mutations that confer substantial risk for schizophrenia have been identified at several loci, most of which have also been implicated in other neurodevelopmental disorders, including autism. Genetic heterogeneity is a characteristic of schizophrenia; conversely, phenotypic heterogeneity is a characteristic of all schizophrenia-associated mutations. Both kinds of heterogeneity probably reflect the complexity of neurodevelopment. Research strategies must account for both genetic and clinical heterogeneity to identify the genes and pathways crucial for the development of neuropsychiatric disorders.
Assuntos
Mutação , Esquizofrenia/genética , Esquizofrenia/fisiopatologia , Animais , Variações do Número de Cópias de DNA , Predisposição Genética para Doença , HumanosRESUMO
Face recognition is impaired in autism spectrum disorders (ASDs), but the reason for this remains unclear. One possibility is that impairments in the ability to visually detect faces might be a factor. As a preliminary study in this vein, we measured face detection ability as a function of visual contrast level in 13 individuals with ASD, aged 13-18, and 18 neurotypical controls (NCs) in the same age range. We also measured contrast sensitivity, using sinusoidal grating stimuli, as a control task. Individuals with ASD did not differ from controls in face detection (p > 0.9) or contrast detection (p > 0.2) ability. Performance on contrast and face detection was significantly correlated in ASD but not in NC. Results suggest that the ability to visually detect faces is not altered in ASD overall, but that alterations in basic visual processing may affect face detection ability in some individuals with ASD.
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Semantic priming has long been used to investigate how concepts and ideas are related at the level of language, and has become a convenient tool for assessing conceptual and semantic dysfunction in cognitive disorders, including schizophrenia. The study of semantic priming in schizophrenia has led to diverse results: enhanced priming, reduced priming, and priming equivalent to that found in nonpsychiatric comparison groups. A number of hypotheses have been proposed to explain some of the observed deficits in schizophrenia patients. For example, difficulties in word recognition may be due to hyperactivation of too many lexical representations or to a failure to inhibit lexical competitors. One way to distinguish between these possible explanations is to move beyond reliance on behavior alone and to examine the neural processes involved in lexical recognition. Here we present a magnetoencephalographic study of semantic priming in schizophrenia. Importantly, schizophrenia patients and healthy controls did not differ in performance on a priming task. We show that normal behavioral performance can occur in a context of aberrant neural responses. These findings suggest that normal behavioral responses in schizophrenia can be achieved through neural mechanisms that differ from those seen in the psychiatrically well brain.
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Thought disorder as well as language and communication disturbances are associated with schizophrenia and are over-represented in clinically unaffected relatives of schizophrenics. All three kinds of dysfunction involve some element of deviant verbalizations, most notably, semantic anomalies. Of particular importance, thought disorder characterized primarily by deviant verbalizations has a higher recurrence in relatives of schizophrenic patients than schizophrenia itself. These findings suggest that deviant verbalizations may be more penetrant expressions of schizophrenia susceptibility genes than schizophrenia. This paper reviews the evidence documenting the presence of thought, language and communication disorders in schizophrenic patients and in their first-degree relatives. This familial aggregation potentially implicates genetic factors in the etiology of thought disorder, language anomalies, and communication disturbances in schizophrenia families. We also present two examples of ways in which thought, language and communication disorders can enrich genetic studies, including those involving schizophrenia.
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A linkage study of a qualitative disease endophenotype in a sample of sib pairs, consisting of one disease affected proband and one sibling is considered. The linkage statistic compares marker allele sharing with the proband in siblings with an abnormal endophenotype to siblings with the normal endophenotype. Expressions for the distribution of this linkage statistic, in terms of the recombination fraction are derived and (1) the genetic parameter values (allele frequency and endophenotype and disease penetrance) and (2) the abnormal endophenotype rates in the population and in classes of relatives of disease affected probands. It is then shown that when either the disease or the abnormal endophenotype has additive penetrance, the expressions simplify to a monotonic function of the difference between abnormal endophenotype rates in siblings and in the population. Thought disorder is considered as a putative schizophrenia endophenotype. Forty sets of genetic parameter values that correspond to the known prevalence values for thought disorder in schizophrenic patients, siblings of schizophrenics and the general population are evaluated. For these genetic parameter values, numerical results show that the test statistic has>70% power (α = 0.0001) in general with a sample of 200 or more proband-sibling pairs to detect the linkage between a marker (θ = 0.01), and a locus pleiotropic for schizophrenia and thought disorder.
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BACKGROUND: The increased mutational burden for rare structural genomic variants in schizophrenia and other neurodevelopmental disorders has so far not yielded therapies targeting the biological effects of specific mutations. We identified two carriers (mother and son) of a triplication of the gene encoding glycine decarboxylase, GLDC, presumably resulting in reduced availability of the N-methyl-D-aspartate receptor coagonists glycine and D-serine and N-methyl-D-aspartate receptor hypofunction. Both carriers had a diagnosis of a psychotic disorder. METHODS: We carried out two double-blind, placebo-controlled clinical trials of N-methyl-D-aspartate receptor augmentation of psychotropic drug treatment in these two individuals. Glycine was used in the first clinical trial, and D-cycloserine was used in the second one. RESULTS: Glycine or D-cycloserine augmentation of psychotropic drug treatment each improved psychotic and mood symptoms in placebo-controlled trials. CONCLUSIONS: These results provide two independent proof-of-principle demonstrations of symptom relief by targeting a specific genotype and explicitly link an individual mutation to the pathophysiology of psychosis and treatment response.
Assuntos
Transtornos Psicóticos Afetivos/genética , Glicinérgicos/farmacologia , Glicina Desidrogenase (Descarboxilante)/genética , Glicina/farmacologia , Transtornos Psicóticos/genética , Psicotrópicos/farmacologia , Receptores de N-Metil-D-Aspartato , Adulto , Variações do Número de Cópias de DNA , Método Duplo-Cego , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Glicina/administração & dosagem , Glicinérgicos/administração & dosagem , Humanos , Masculino , Estudo de Prova de Conceito , Psicotrópicos/administração & dosagem , Distribuição Aleatória , Estudos de Caso Único como AssuntoRESUMO
Tardive dyskinesia (TD) is an adverse movement disorder induced by chronic treatment with antipsychotics drugs. The contribution of common genetic variants to TD susceptibility has been investigated in recent years, but with limited success. The aim of the current study was to investigate the potential contribution of rare variants to TD vulnerability. In order to identify TD risk genes, we performed whole-exome sequencing (WES) and gene-based collapsing analysis focusing on rare (allele frequencyâ¯<â¯1%) and putatively deleterious variants (qualifying variants). 82 Jewish schizophrenia patients chronically treated with antipsychotics were included and classified as having severe TD or lack of any abnormal movements based on a rigorous definition of the TD phenotype. First, we performed a case-control, exome-wide collapsing analysis comparing 39 schizophrenia patients with severe TD to 3118 unrelated population controls. Then, we checked the potential top candidate genes among 43 patients without any TD manifestations. All the genes that were found to harbor one or more qualifying variants in patients without any TD features were excluded from the final list of candidate genes. Only one gene, regulating synaptic membrane exocytosis 2 (RIMS2), showed significant enrichment of qualifying variants in TD patients compared with unrelated population controls after correcting for multiple testing (Fisher's exact test pâ¯=â¯5.32E-08, logistic regression pâ¯=â¯2.50E-08). Enrichment was caused by a single variant (rs567070433) due to a frameshift in an alternative transcript of RIMS2. None of the TD negative patients had qualifying variants in this gene. In a validation cohort of 140 schizophrenia patients assessed for TD, the variant was also not detected in any individual. Some potentially suggestive TD genes were detected in the TD cohort and warrant follow-up in future studies. No significant enrichment in previously reported TD candidate genes was identified. To the best of our knowledge, this is the first WES study of TD, demonstrating the potential role of rare loss-of-function variant enrichment in this pharmacogenetic phenotype.
Assuntos
Discinesia Induzida por Medicamentos/genética , Sequenciamento do Exoma/estatística & dados numéricos , Adulto , Idoso , Antipsicóticos/efeitos adversos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/complicações , Esquizofrenia/tratamento farmacológico , Adulto JovemRESUMO
The "co-familiality" criterion for an endophenotype has two requirements: (1) clinically unaffected relatives as a group should show both a shift in mean performance and an increase in variance compared with controls; (2) performance scores should be heritable. Performance on the antisaccade task is one of several candidate endophenotypes for schizophrenia. In this paper we examine whether the various measures of performance on the standard version of the antisaccade task meet the co-familiality criterion for an endophenotype. The three measures of performance-reflexive saccade errors, latency of correct antisaccades, and gain-show a wide range of effect sizes and variance ratios as well as evidence of significant or near significant heterogeneity. The estimated mean effect sizes [Cohen's d: error rate: 0.34 (SD: 0.29); latency: 0.33 (SD: 0.30); gain: 0.54 (SD: 0.38)] are significantly greater than 0, but the magnitude of the departures from 0 is relatively small, corresponding to modest effect sizes. The width of the 95% confidence intervals for the estimated effect sizes (error rate: 0.2-0.49; latency: 0.17-0.50; gain: 0.23-0.85) and the coefficients of variation in effect sizes (error rate: 85.3%; latency: 90.9%; gain: 68.4%) reflect heterogeneity in effect sizes. The effect sizes for error rate showed statistically significant heterogeneity and those for latency (P=.07) and gain (P=.09) showed a trend toward heterogeneity. These results indicate that the effect sizes are not consistent with a single mean and that the average effect size may be a biased estimate of the magnitude of differences in performance between relatives of schizophrenics and controls. Relatives of schizophrenics show a small but significant increase in variance in error rate, but the confidence interval is broad, perhaps reflecting the heterogeneity in effect size. The variance ratios for latency and gain did not differ in relatives of schizophrenics and controls. Performance, as measured by error rate, is moderately heritable. The data do not provide compelling support for a consistent shift in mean or variance in relatives of schizophrenia patients compared with nonpsychiatric controls, both of which are required for a major gene involved in co-familial transmission. This set of findings suggests that although intra-familial resemblance in antisaccade performance is due in part to genetic factors, it may not be related to a schizophrenia genotype. Based on the current literature, it would be premature to conclude that any of the measures of antisaccade performance unambiguously meets the co-familiality criterion for an endophenotype.
Assuntos
Família , Tempo de Reação/fisiologia , Movimentos Sacádicos/fisiologia , Esquizofrenia/fisiopatologia , Predisposição Genética para Doença , Humanos , Testes Neuropsicológicos/normas , Fenótipo , Desempenho Psicomotor/fisiologia , Tempo de Reação/genética , Movimentos Sacádicos/genética , Esquizofrenia/diagnóstico , Esquizofrenia/genética , Análise e Desempenho de TarefasRESUMO
P50 suppression deficit has been reported in patients with psychotic bipolar disorder. In our previous report on twin pairs concordant and discordant for bipolar disorder, we found significant genetic overlap between bipolar disorder and P50 sensory gating. However, the sample size in that study was relatively small. A separate study, the Maudsley Bipolar Family Study, reported diminished P50 gating in unaffected relatives of psychotic bipolar patients. However, genetic and environmental influences are confounded in family studies due to lack of monozygotic (MZ) twin pairs. The current study combines the twin sample and the family sample in order to improve statistical power and study design, with the aims of: (1) substantiating the association between psychotic bipolar disorder and diminished P50 suppression and (2) verifying the genetic overlap between the two traits reported in the twin sample. We also assessed the relationship between bipolar disorder and an alternative suppression index, the P50 Condition-Testing (C-T) amplitude difference. A total of 309 subjects was included in this study, comprising 91 twin pairs, 31 bipolar families, and 45 unrelated healthy controls. Statistical analyses were based on structural equation modeling. Bipolar disorder was significantly associated with a diminished P50 suppression ratio and decreased C-T amplitude difference. Shared genetic factors were the main source of these associations. Suppression impairment was due to larger, poorly gated, T amplitude responses. The results provide further evidence that impaired P50 suppressions are promising endophenotypes for psychotic bipolar disorder. The non-specificity of impaired P50 suppression may reflect the impact of shared psychosis susceptibility genes.
Assuntos
Transtorno Bipolar/genética , Doenças em Gêmeos/genética , Potenciais Evocados Auditivos/fisiologia , Transtornos Psicóticos/genética , Gêmeos/genética , Adulto , Transtorno Bipolar/fisiopatologia , Doenças em Gêmeos/fisiopatologia , Eletroencefalografia , Feminino , Humanos , Masculino , Transtornos Psicóticos/fisiopatologia , Gêmeos/metabolismo , Gêmeos Monozigóticos/genética , Gêmeos Monozigóticos/fisiologiaRESUMO
OBJECTIVES: Gamma oscillation is important for cortico-cortical coordination and the integration of information across neural networks. The 40â¯Hz auditory steady-state response (ASSR), which reflects neural synchrony in the gamma band (30-100â¯Hz), is abnormal in patients with schizophrenia (SZ). The present study used the ASSR at multiple frequencies to examine (1) gamma dysfunction in patients with SZ, schizoaffective (SA), and bipolar disorder (BD) compared with controls, (2) the relationship between ASSR measures and clinical symptom severity, and (3) the relationship between ASSR measures and real-life community functioning. METHODS: EEG was recorded from 75 controls, 52 SZ, 55 SA, and 89 BD patients during 20-30-40-Hz binaural click trains. ANCOVA was used to compare ASSR measures between groups controlling for age, sex, and education. Associations between ASSR measures, symptom severity, and community functioning were examined using linear regression and Pearson partial correlations. RESULTS: ASSR deficits at gamma frequency were observed in all patient groups. SA patients showed additional specific deficit in the 20â¯Hz ASSR. Severity of manic, depressive, and anxiety symptoms mediated ASSR deficits. Severity of hallucinatory symptom and community functioning, particularly independent living/meaningful activity, were significantly and independently associated with the 40â¯Hz ASSR. CONCLUSIONS: SZ, SA and BD patients are likely to share the same abnormalities in neural processes that generate gamma oscillations. 40â¯Hz ASSR are associated with community functioning across patients and may serve as a biomarker for predicting functional outcome.
Assuntos
Percepção Auditiva/fisiologia , Transtorno Bipolar/fisiopatologia , Encéfalo/fisiopatologia , Ritmo Gama/fisiologia , Transtornos Psicóticos/fisiopatologia , Esquizofrenia/fisiopatologia , Adulto , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/psicologia , Estudos de Coortes , Potenciais Evocados Auditivos , Feminino , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/psicologia , Esquizofrenia/tratamento farmacológico , Psicologia do Esquizofrênico , Índice de Gravidade de Doença , Processamento de Sinais Assistido por Computador , Habilidades SociaisRESUMO
Variants in CNTNAP2, a member of the neurexin family of genes that function as cell adhesion molecules, have been associated with multiple neuropsychiatric conditions such as schizophrenia, autism spectrum disorder and intellectual disability; animal studies indicate a role for CNTNAP2 in axon guidance, dendritic arborization and synaptogenesis. We previously reprogrammed fibroblasts from a family trio consisting of two carriers of heterozygous intragenic CNTNAP2 deletions into human induced pluripotent stem cells (hiPSCs) and described decreased migration in the neural progenitor cells (NPCs) differentiated from the affected CNTNAP2 carrier in this trio. Here, we report the effect of this heterozygous intragenic deletion in CNTNAP2 on global gene expression and neuronal activity in the same cohort. Our findings suggest that heterozygous CNTNAP2 deletions affect genes involved in neuronal development and neuronal activity; however, these data reflect only one family trio and therefore more deletion carriers, with a variety of genetic backgrounds, will be needed to understand the molecular mechanisms underlying CNTNAP2 deletions.
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Thought disorder (TD) has long been associated with schizophrenia (SZ) and is now widely recognized as a symptom of mania and other psychotic disorders as well. Previous studies have suggested that the TD found in the clinically unaffected relatives of SZ, schizoaffective and bipolar probands is qualitatively similar to that found in the probands themselves. Here, we examine which quantitative measures of TD optimize the distinction between patients with diagnoses of SZ and bipolar disorder with psychotic features (BP) from nonpsychiatric controls (NC) and from each other. In addition, we investigate whether these same TD measures also distinguish their respective clinically unaffected relatives (RelSZ, RelBP) from controls as well as from each other. We find that deviant verbalizations are significantly associated with SZ and are co-familial in clinically unaffected RelSZ, but are dissociated from, and are not co-familial for, BP disorder. In contrast, combinatory thinking was nonspecifically associated with psychosis, but did not aggregate in either group of relatives. These results provide further support for the usefulness of TD for identifying potential non-penetrant carriers of SZ-risk genes, in turn enhancing the power of genetic analyses. These findings also suggest that further refinement of the TD phenotype may be needed in order to be suitable for use in genetic studies of bipolar disorder.
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Transtornos Psicóticos Afetivos/fisiopatologia , Transtorno Bipolar/fisiopatologia , Endofenótipos , Transtornos Psicóticos/fisiopatologia , Esquizofrenia/fisiopatologia , Pensamento/fisiologia , Adulto , Transtornos Psicóticos Afetivos/genética , Transtorno Bipolar/genética , Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Psicóticos/genética , Esquizofrenia/genéticaRESUMO
In the process of generating presumably clonal human induced pluripotent stem cells (hiPSCs) from two carriers of a complex structural rearrangement, each having a psychotic disorder, we also serendipitously generated isogenic non-carrier control hiPSCs, finding that the rearrangement occurs as an extrachromosomal marker (mar) element. All confirmed carrier hiPSCs and differentiated neural progenitor cell lines were found to be mosaic. We caution that mar elements may be difficult to functionally evaluate in hiPSC cultures using currently available methods, as it is difficult to distinguish cells with and without mar elements in live mosaic cultures.
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Cromossomos Humanos , Marcadores Genéticos , Células-Tronco Pluripotentes Induzidas/metabolismo , Transtornos Psicóticos/genética , Duplicação Cromossômica , Cromossomos Humanos Par 9 , Hibridização Genômica Comparativa , Estudos de Associação Genética , Predisposição Genética para Doença , Heterozigoto , Humanos , Regiões de Interação com a Matriz/genética , Mosaicismo , TrissomiaRESUMO
BACKGROUND: Since Kraepelin's early distinction between bipolar disorder and schizophrenia, it has been assumed that these disorders represent two different pathophysiological processes, although they share many clinical symptoms. Previous studies showed that velocity discrimination, a sensitive psychophysiological measure of the visual motion system, is deficient in schizophrenia. Here we examined whether the motion processing impairment found in schizophrenia also occurs in bipolar disorder. METHODS: We compared 16 bipolar patients, 25 schizophrenic patients, and 25 normal controls on a velocity discrimination task. We measured the psychophysical threshold for velocity discrimination and contrast detection (as a control task) in all subjects. RESULTS: Bipolar patients showed normal velocity discrimination thresholds at intermediate velocities, the range in which velocity cues dominate velocity discrimination, and at low velocities. Schizophrenic patients, however, showed elevated velocity discrimination thresholds at intermediate and low velocities. At higher velocities, both bipolar and schizophrenic patients showed elevated thresholds. All subjects showed normal contrast detection thresholds. CONCLUSIONS: Normal velocity discrimination in the intermediate range of velocity indicates unimpaired motion processing in bipolar disorder. The abnormal velocity discrimination of both schizophrenic and bipolar patients at higher velocities may reflect impaired temporal processing rather than impaired motion processing per se. These results suggest that the pathophysiological processes of bipolar disorder and schizophrenia diverge at the stage of visual motion processing, a sensory component mediated primarily in the extrastriate cortex.