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1.
JAMA Psychiatry ; : 1-11, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31665216

RESUMO

Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities. Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance. Design, Setting, and Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019. Main Outcomes and Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort. Results: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (ß = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks. Conclusions and Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.

2.
Genes Brain Behav ; 18(8): e12602, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31385409

RESUMO

Variation in cognitive performance, which strongly predicts functional outcome in schizophrenia (SZ), has been associated with multiple immune-relevant genetic loci. These loci include complement component 4 (C4A), structural variation at which was recently associated with SZ risk and synaptic pruning during neurodevelopment and cognitive function. Here, we test whether this genetic association with cognition and SZ risk is specific to C4A, or extends more broadly to genes related to the complement system. Using a gene-set with an identified role in "complement" function (excluding C4A), we used MAGMA to test if this gene-set was enriched for genes associated with human intelligence and SZ risk, using genome-wide association summary statistics (IQ; N = 269 867, SZ; N = 105 318). We followed up this gene-set analysis with a complement gene-set polygenic score (PGS) regression analysis in an independent data set of patients with psychotic disorders and healthy participants with cognitive and genomic data (N = 1000). Enrichment analysis suggested that genes within the complement pathway were significantly enriched for genes associated with IQ, but not SZ. In a gene-based analysis of 90 genes, SERPING1 was the most enriched gene for the phenotype of IQ. In a PGS regression analysis, we found that a complement pathway PGS associated with IQ genome-wide association studies statistics also predicted variation in IQ in our independent sample. This association (observed across both patients and controls) remained significant after controlling for the relationship between C4A and cognition. These results suggest a robust association between the complement system and cognitive function, extending beyond structural variation at C4A.

3.
Psychol Med ; : 1-10, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31391132

RESUMO

BACKGROUND: Previous studies using resting-state functional neuroimaging have revealed alterations in whole-brain images, connectome-wide functional connectivity and graph-based metrics in groups of patients with schizophrenia relative to groups of healthy controls. However, it is unclear which of these measures best captures the neural correlates of this disorder at the level of the individual patient. METHODS: Here we investigated the relative diagnostic value of these measures. A total of 295 patients with schizophrenia and 452 healthy controls were investigated using resting-state functional Magnetic Resonance Imaging at five research centres. Connectome-wide functional networks were constructed by thresholding correlation matrices of 90 brain regions, and their topological properties were analyzed using graph theory-based methods. Single-subject classification was performed using three machine learning (ML) approaches associated with varying degrees of complexity and abstraction, namely logistic regression, support vector machine and deep learning technology. RESULTS: Connectome-wide functional connectivity allowed single-subject classification of patients and controls with higher accuracy (average: 81%) than both whole-brain images (average: 53%) and graph-based metrics (average: 69%). Classification based on connectome-wide functional connectivity was driven by a distributed bilateral network including the thalamus and temporal regions. CONCLUSION: These results were replicated across the three employed ML approaches. Connectome-wide functional connectivity permits differentiation of patients with schizophrenia from healthy controls at single-subject level with greater accuracy; this pattern of results is consistent with the 'dysconnectivity hypothesis' of schizophrenia, which states that the neural basis of the disorder is best understood in terms of system-level functional connectivity alterations.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31292938

RESUMO

Research into antibody-mediated disease, in response to immune dysfunction or to tumour development, has rapidly expanded in recent years. Antibodies binding to neuroreceptors can cause psychiatric features, including psychosis, in a minority of patients as well as neurological features. The responsiveness of some of these cases to immunotherapy supports the hypothesis that antibody-associated mechanisms play a role in the pathogenesis of psychotic diseases. The purpose of this chapter is to review autoantibodies that are most likely to be relevant for patients with psychotic symptoms. Herein, we describe receptor structure and mechanism of action, clinical and psychiatric features for the growing number of neuronal surface antibodies, including those to the N-methyl-D-aspartate (NMDA) receptor. The identification of a subgroup of patients with psychiatric features having antibody-mediated disease highlights the importance of considering the diagnosis, particularly in those patients presenting with a first episode of psychosis.

5.
Am J Psychiatry ; 176(8): 651-660, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31164008

RESUMO

OBJECTIVE: More than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium. METHODS: The samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders. RESULTS: Three genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%). CONCLUSIONS: This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.

6.
Schizophr Bull ; 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31206164

RESUMO

BACKGROUND: Cognitive impairment is a clinically important feature of schizophrenia. Polygenic risk score (PRS) methods have demonstrated genetic overlap between schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), educational attainment (EA), and IQ, but very few studies have examined associations between these PRS and cognitive phenotypes within schizophrenia cases. METHODS: We combined genetic and cognitive data in 3034 schizophrenia cases from 11 samples using the general intelligence factor g as the primary measure of cognition. We used linear regression to examine the association between cognition and PRS for EA, IQ, schizophrenia, BD, and MDD. The results were then meta-analyzed across all samples. A genome-wide association studies (GWAS) of cognition was conducted in schizophrenia cases. RESULTS: PRS for both population IQ (P = 4.39 × 10-28) and EA (P = 1.27 × 10-26) were positively correlated with cognition in those with schizophrenia. In contrast, there was no association between cognition in schizophrenia cases and PRS for schizophrenia (P = .39), BD (P = .51), or MDD (P = .49). No individual variant approached genome-wide significance in the GWAS. CONCLUSIONS: Cognition in schizophrenia cases is more strongly associated with PRS that index cognitive traits in the general population than PRS for neuropsychiatric disorders. This suggests the mechanisms of cognitive variation within schizophrenia are at least partly independent from those that predispose to schizophrenia diagnosis itself. Our findings indicate that this cognitive variation arises at least in part due to genetic factors shared with cognitive performance in populations and is not solely due to illness or treatment-related factors, although our findings are consistent with important contributions from these factors.

7.
Proc Natl Acad Sci U S A ; 116(19): 9604-9609, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31004051

RESUMO

Schizophrenia has been conceived as a disorder of brain connectivity, but it is unclear how this network phenotype is related to the underlying genetics. We used morphometric similarity analysis of MRI data as a marker of interareal cortical connectivity in three prior case-control studies of psychosis: in total, n = 185 cases and n = 227 controls. Psychosis was associated with globally reduced morphometric similarity in all three studies. There was also a replicable pattern of case-control differences in regional morphometric similarity, which was significantly reduced in patients in frontal and temporal cortical areas but increased in parietal cortex. Using prior brain-wide gene expression data, we found that the cortical map of case-control differences in morphometric similarity was spatially correlated with cortical expression of a weighted combination of genes enriched for neurobiologically relevant ontology terms and pathways. In addition, genes that were normally overexpressed in cortical areas with reduced morphometric similarity were significantly up-regulated in three prior post mortem studies of schizophrenia. We propose that this combined analysis of neuroimaging and transcriptional data provides insight into how previously implicated genes and proteins as well as a number of unreported genes in their topological vicinity on the protein interaction network may drive structural brain network changes mediating the genetic risk of schizophrenia.

8.
Mol Psychiatry ; 2019 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-30705424

RESUMO

Prior to and following the publication of this article the authors noted that the complete list of authors was not included in the main article and was only present in Supplementary Table 1. The author list in the original article has now been updated to include all authors, and Supplementary Table 1 has been removed. All other supplementary files have now been updated accordingly. Furthermore, in Table 1 of this Article, the replication cohort for the row Close relative in data set, n (%) was incorrect. All values have now been corrected to 0(0%). The publishers would like to apologise for this error and the inconvenience it may have caused.

9.
Am J Med Genet B Neuropsychiatr Genet ; 180(3): 223-231, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30801977

RESUMO

Genome-wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophrenia etiology but, with the exception of large copy number variants, are difficult to detect with GWAS. Exome and genome sequencing, which have accelerated the study of rare variants, are expensive so alternative methods are needed to aid detection of rare variants. Here we re-analyze an Irish schizophrenia GWAS dataset (n = 3,473) by performing identity-by-descent (IBD) mapping followed by exome sequencing of individuals identified as sharing risk haplotypes to search for rare risk variants in coding regions. We identified 45 rare haplotypes (>1 cM) that were significantly more common in cases than controls. By exome sequencing 105 haplotype carriers, we investigated these haplotypes for functional coding variants that could be tested for association in independent GWAS samples. We identified one rare missense variant in PCNT but did not find statistical support for an association with schizophrenia in a replication analysis. However, IBD mapping can prioritize both individual samples and genomic regions for follow-up analysis but genome rather than exome sequencing may be more effective at detecting risk variants on rare haplotypes.

10.
BMC Psychiatry ; 19(1): 27, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30646884

RESUMO

BACKGROUND: Evidence is accumulating that Cognitive Remediation Training (CRT) is effective for ameliorating cognitive deficits experienced by patients with schizophrenia and accompanying functional impairment. There has been no randomized controlled trial of CRT using a nationally representative population of forensic patients, despite the significant cognitive deficits frequently present within this group. METHODS: Sixty-five patients with schizophrenia or schizoaffective disorder were enrolled in a single blind randomized controlled trial of CRT versus treatment as usual (TAU); representing 94% of those eligible within a national forensic cohort. The primary outcome measure was the composite score of the MATRICS Consensus Cognitive Battery (MCCB). Secondary outcome measures included neurocognitive and social cognitive domains, symptoms, and 'real world' functioning. Patient satisfaction was examined using an exit interview. Participants were reassessed at 8 months follow up. All data were analyzed using an intention to treat design (ITT). RESULTS: For the primary outcome measure, the MCCB composite score, there were significant differences between those who participated in CRT and those receiving TAU at both end of treatment and 8 months follow up (Cohen's d = 0.34. Significant improvements were observed in visual and working memory. Mediation analysis found that those who cognitively benefited from CRT had corresponding improved functioning, and more net positive therapeutic moves i.e. moves to units with lower security within the hospital. Ninety-six percent believed their cognitive gains positively affected their daily lives. CONCLUSIONS: CRT may be an acceptable and efficacious intervention for forensic patients with schizophrenia or schizoaffective disorder. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02360813 . Trial registered Feb 4th 2015, last updated May 1st 2015.

11.
Biol Psychiatry ; 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30420267

RESUMO

BACKGROUND: Sequencing studies have pointed to the involvement in schizophrenia of rare coding variants in neuronally expressed genes, including activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-D-aspartate receptor (NMDAR) complexes; however, larger samples are required to reveal novel genes and specific biological mechanisms. METHODS: We sequenced 187 genes, selected for prior evidence of association with schizophrenia, in a new dataset of 5207 cases and 4991 controls. Included among these genes were members of ARC and NMDAR postsynaptic protein complexes, as well as voltage-gated sodium and calcium channels. We performed a rare variant meta-analysis with published sequencing data for a total of 11,319 cases, 15,854 controls, and 1136 trios. RESULTS: While no individual gene was significantly associated with schizophrenia after genome-wide correction for multiple testing, we strengthen the evidence that rare exonic variants in the ARC (p = 4.0 × 10-4) and NMDAR (p = 1.7 × 10-5) synaptic complexes are risk factors for schizophrenia. In addition, we found that loss-of-function variants and missense variants at paralog-conserved sites were enriched in voltage-gated sodium channels, particularly the alpha subunits (p = 8.6 × 10-4). CONCLUSIONS: In one of the largest sequencing studies of schizophrenia to date, we provide novel evidence that multiple voltage-gated sodium channels are involved in schizophrenia pathogenesis and confirm the involvement of ARC and NMDAR postsynaptic complexes.

12.
BMC Psychiatry ; 18(1): 289, 2018 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-30195335

RESUMO

BACKGROUND: We evaluated change in response to multi-modal psychosocial 'treatment as usual' programs offered within a forensic hospital. METHODS: Sixty nine patients with a diagnosis of schizophrenia or schizoaffective disorder were followed for up to four years. Patient progress was evaluated using the DUNDRUM-3, a measure of patient ability to participate and benefit from multi-modal psychosocial programs and the HCR-20 dynamic items, a measure of violence proneness. We report reliable change index (RCI) and reliable and clinically meaningful change (RMC). We assessed patients' cognition using the MCCB, psychopathology using the PANSS. The effect of cognition and psychopathology on change in DUNDRUM-3 was examined using hierarchical multiple regression with age, gender, and baseline DUNDRUM-3 scores. RESULTS: The DUNDRUM-3 changed significantly (p < 0.004, d = 0.367, RCI 32% of 69 cases, RMC 23%) and HCR-20-C (p < 0.003, d = 0.377, RCI 10%). Both cognition and psychopathology accounted for significant variance in DUNDRUM-3 at follow up. Those hospitalized for less than five years at baseline changed more than longer stay patients. Mediation analysis demonstrated that the relationship between cognition and change in violence proneness (HCR-20-C) was both directly affected and indirectly mediated by change in DUNDRUM-3. CONCLUSIONS: Change in response to multi-modal psychosocial programs (DUNDRUM-3) reduced a measure of violence proneness over four years. Forensic in-patients' ability to benefit from psychosocial treatment appears to be a function of the outcome measure used, unit of measurement employed, degree of cognitive impairment, psychopathology, and length of stay. Lower risk of re-offending may be partially attributable to participation and engagement in psychosocial interventions.

13.
Twin Res Hum Genet ; 21(5): 394-397, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30001766

RESUMO

Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88) presented a critique of our recently published paper in Cell Reports entitled 'Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets' (Lam et al., Cell Reports, Vol. 21, 2017, 2597-2613). Specifically, Hill offered several interrelated comments suggesting potential problems with our use of a new analytic method called Multi-Trait Analysis of GWAS (MTAG) (Turley et al., Nature Genetics, Vol. 50, 2018, 229-237). In this brief article, we respond to each of these concerns. Using empirical data, we conclude that our MTAG results do not suffer from 'inflation in the FDR [false discovery rate]', as suggested by Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88), and are not 'more relevant to the genetic contributions to education than they are to the genetic contributions to intelligence'.

14.
Nat Genet ; 50(7): 912-919, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29942086

RESUMO

Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.

15.
Eur J Neurosci ; 2018 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-29804303

RESUMO

Working memory-based cognitive remediation therapy (CT) for psychosis has recently been associated with broad improvements in performance on untrained tasks measuring working memory, episodic memory and IQ, and changes in associated brain regions. However, it is unclear whether these improvements transfer to the domain of social cognition and neural activity related to performance on social cognitive tasks. We examined performance on the Reading the Mind in the Eyes test (Eyes test) in a large sample of participants with psychosis who underwent working memory-based CT (N = 43) compared to a control group of participants with psychosis (N = 35). In a subset of this sample, we used functional magnetic resonance imaging (fMRI) to examine changes in neural activity during a facial emotion recognition task in participants who underwent CT (N = 15) compared to a control group (N = 15). No significant effects of CT were observed on Eyes test performance or on neural activity during facial emotion recognition, either at p < 0.05 family-wise error or at a p < 0.001 uncorrected threshold, within a priori social cognitive regions of interest. This study suggests that working memory-based CT does not significantly impact an aspect of social cognition which was measured behaviourally and neurally. It provides further evidence that deficits in the ability to decode mental state from facial expressions are dissociable from working memory deficits, and suggests that future CT programmes should target social cognition in addition to working memory for the purposes of further enhancing social function.

16.
Am J Med Genet B Neuropsychiatr Genet ; 177(3): 369-376, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29418072

RESUMO

Multiple genome-wide association studies of schizophrenia have implicated genetic variants within the gene encoding microRNA-137. As risk variants within or regulated by MIR137 have been implicated in memory performance, we investigated the additive effects of schizophrenia-associated risk variants in genes empirically regulated by MIR137 on brain regions associated with memory function. A polygenic risk score (PRS) was calculated (at a p = 0.05 threshold), using this empirically regulated MIR137 gene set, to investigate associations between this PRS and structural brain measures. These measures included total brain volume, cortical thickness, cortical surface area, and hippocampal volume, in a sample of 216 individuals consisting of healthy participants (n = 171) and patients with psychosis (n = 45). We did not observe a significant association between MIR137 PRS and these cortical thickness, surface area or hippocampal volume measures linked to memory function; a significant association between increasing PRS and decreasing total brain volume, independent of diagnosis status (R2 = 0.008, Beta = -0.09, p = 0.029), was observed. This did not survive correction for multiple testing. In conclusion, our study yielded only suggestive evidence that risk variants interacting with MIR137 impacts on cortical structure.

17.
Schizophr Res ; 195: 306-317, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-28982554

RESUMO

BACKGROUND: Schizophrenia has a large genetic component, and the pathways from genes to illness manifestation are beginning to be identified. The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium aims to clarify the role of genetic variation in brain abnormalities underlying schizophrenia. This article describes the GENUS Consortium sample collection. METHODS: We identified existing samples collected for schizophrenia studies consisting of patients, controls, and/or individuals at familial high-risk (FHR) for schizophrenia. Samples had single nucleotide polymorphism (SNP) array data or genomic DNA, clinical and demographic data, and neuropsychological and/or brain magnetic resonance imaging (MRI) data. Data were subjected to quality control procedures at a central site. RESULTS: Sixteen research groups contributed data from 5199 psychosis patients, 4877 controls, and 725 FHR individuals. All participants have relevant demographic data and all patients have relevant clinical data. The sex ratio is 56.5% male and 43.5% female. Significant differences exist between diagnostic groups for premorbid and current IQ (both p<1×10-10). Data from a diversity of neuropsychological tests are available for 92% of participants, and 30% have structural MRI scans (half also have diffusion-weighted MRI scans). SNP data are available for 76% of participants. The ancestry composition is 70% European, 20% East Asian, 7% African, and 3% other. CONCLUSIONS: The Consortium is investigating the genetic contribution to brain phenotypes in a schizophrenia sample collection of >10,000 participants. The breadth of data across clinical, genetic, neuropsychological, and MRI modalities provides an important opportunity for elucidating the genetic basis of neural processes underlying schizophrenia.


Assuntos
Transtornos Cognitivos/etiologia , Predisposição Genética para Doença/genética , Imagem por Ressonância Magnética , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Transtornos Cognitivos/diagnóstico por imagem , Endofenótipos , Feminino , Genótipo , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Esquizofrenia/complicações , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/genética , Estatísticas não Paramétricas , Adulto Jovem
18.
Schizophr Res ; 193: 468-469, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28716450

RESUMO

Forensic patients with schizophrenia who had carried out a homicide scored higher on a measure of moral cognition (MFQ-30) than other violent patients. Neurocognitive impairment was associated with homicide by mediation via higher scores for in-group loyalty.


Assuntos
Transtornos Cognitivos/psicologia , Princípios Morais , Transtornos Psicóticos/psicologia , Esquizofrenia , Psicologia do Esquizofrênico , Comportamento Social , Violência/psicologia , Análise de Variância , Estudos de Coortes , Estudos Transversais , Humanos , Masculino , Testes Neuropsicológicos , Inquéritos e Questionários
19.
Curr Psychiatry Rep ; 19(9): 61, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28741255

RESUMO

PURPOSE OF REVIEW: This is an era where we have significantly advanced the understanding of the genetic architecture of schizophrenia. In this review, we consider how this knowledge may translate into advances that will improve patient care. RECENT FINDINGS: Large-scale genome-wide association studies (GWAS) have identified more than a hundred loci each making a small contribution to illness risk. Meta-analysis of copy number variants (CNVs) in the Psychiatric Genomics Consortium (PGC) dataset has confirmed that some variants have a moderate or large impact on risk, although these are rare in the population. Genome sequencing advances allow a much more comprehensive evaluation of genomic variation. We describe the key findings from whole exome studies to date. These studies are happening against a backdrop of growing understanding of the regulation and expression of genes and better functional tools to investigate molecular mechanisms in model systems. We provide an overview of how recent approaches in schizophrenia genetics are converging and consider how they could impact on diagnostics, the development of personalized medicine, and drug discovery.


Assuntos
Predisposição Genética para Doença/genética , Esquizofrenia/genética , Variações do Número de Cópias de DNA , Descoberta de Drogas/métodos , Estudo de Associação Genômica Ampla , Genômica , Humanos , Medicina de Precisão/métodos , Esquizofrenia/diagnóstico
20.
Neuropsychopharmacology ; 42(13): 2612-2622, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28607492

RESUMO

With >100 common variants associated with schizophrenia risk, establishing their biological significance is a priority. We sought to establish cognitive effects of risk variants at loci implicated in synaptic transmission by (1) identifying GWAS schizophrenia variants whose associated gene function is related to synaptic transmission, and (2) testing for association between these and measures of neurocognitive function. We selected variants, reported in the largest GWAS to date, associated with genes involved in synaptic transmission. Associations between genotype and cognitive test score were analyzed in a discovery sample (988 Irish participants, including 798 with psychosis), and replication samples (528 UK patients with schizophrenia/schizoaffective disorder; 921 German participants including 362 patients with schizophrenia). Three loci showed significant associations with neuropsychological performance in the discovery samples. This included an association between the rs2007044 (risk allele G) within CACNA1C and poorer working memory performance (increased errors B (95% CI)=0.635-4.535, p=0.012), an effect driven mainly by the psychosis groups. In an fMRI analysis of working memory performance (n=84 healthy participants, a subset of the discovery sample), we further found evidence that the same CACNA1C allele was associated with decreased functional connectivity between the right dorsolateral prefrontal cortex and right superior occipital gyrus/cuneus and anterior cingulate cortex. In conclusion, these data provide evidence to suggest that the CACNA1C risk variant rs2007044 is associated with poorer memory function that may result from risk carriers' difficulty with top-down initiated responses caused by dysconnectivity between the right DLPFC and several cortical regions.


Assuntos
Canais de Cálcio Tipo L/genética , Cognição , Predisposição Genética para Doença , Memória de Curto Prazo , Esquizofrenia/genética , Transmissão Sináptica/genética , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Mapeamento Encefálico , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Imagem por Ressonância Magnética , Masculino , Memória de Curto Prazo/fisiologia , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiologia , Testes Neuropsicológicos , Polimorfismo de Nucleotídeo Único , Transtornos Psicóticos/genética
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