ABSTRACT
Recent studies have reported a negative association between exposure to childhood trauma, including physical neglect, and cognitive functioning in patients with schizophrenia. Childhood trauma has been found to influence immune functioning, which may contribute to the risk of schizophrenia and cognitive symptoms of the disorder. In this study, we aimed to test the hypothesis that physical neglect is associated with cognitive ability, and that this association is mediated by a combined latent measure of inflammatory response, and moderated by higher genetic risk for schizophrenia. The study included 279 Irish participants, comprising 102 patients and 177 healthy participants. Structural equation modelling was used to perform mediation and moderation analyses. Inflammatory response was measured via basal plasma levels of IL-6, TNF-α, and CRP, and cognitive performance was assessed across three domains: full-scale IQ, logical memory, and the emotion recognition task. Genetic variation for schizophrenia was estimated using a genome-wide polygenic score based on genome-wide association study summary statistics. The results showed that inflammatory response mediated the association between physical neglect and all measures of cognitive functioning, and explained considerably more variance than any of the inflammatory markers alone. Furthermore, genetic risk for schizophrenia was observed to moderate the direct pathway between physical neglect and measures of non-social cognitive functioning in both patient and healthy participants. However, genetic risk did not moderate the mediated pathway associated with inflammatory response. Therefore, we conclude that the mediating role of inflammatory response and the moderating role of higher genetic risk may independently influence the association between adverse early life experiences and cognitive function in patients and healthy participants.
Subject(s)
Adverse Childhood Experiences , Schizophrenia , Humans , Genome-Wide Association Study , Healthy Volunteers , Cognition/physiologyABSTRACT
Next-generation sequencing studies are dependent on a high-quality reference genome for single nucleotide variant (SNV) calling. Although the two most recent builds of the human genome are widely used, position information is typically not directly comparable between them. Re-alignment gives the most accurate position information, but this procedure is often computationally expensive, and therefore, tools such as liftOver and CrossMap are used to convert data from one build to another. However, the positions of converted SNVs do not always match SNVs derived from aligned data, and in some instances, SNVs are known to change chromosome when converted. This is a significant problem when compiling sequencing resources or comparing results across studies. Here, we describe a novel algorithm to identify positions that are unstable when converting between human genome reference builds. These positions are detected independent of the conversion tools and are determined by the chain files, which provide a mapping of contiguous positions from one build to another. We also provide the list of unstable positions for converting between the two most commonly used builds GRCh37 and GRCh38. Pre-excluding SNVs at these positions, prior to conversion, results in SNVs that are stable to conversion. This simple procedure gives the same final list of stable SNVs as applying the algorithm and subsequently removing variants at unstable positions. This work highlights the care that must be taken when converting SNVs between genome builds and provides a simple method for ensuring higher confidence converted data. Unstable positions and algorithm code, available at https://github.com/cathaloruaidh/genomeBuildConversion.
Subject(s)
Algorithms , Gene Conversion , Genome, Human , Polymorphism, Single Nucleotide , Web Browser , High-Throughput Nucleotide Sequencing/methods , Human Genome Project , Humans , Whole Genome Sequencing/methodsABSTRACT
Tourette Syndrome (TS) is a heritable, early-onset neuropsychiatric disorder that typically begins in early childhood. Identifying rare genetic variants that make a significant contribution to risk in affected families may provide important insights into the molecular aetiology of this complex and heterogeneous syndrome. Here we present a whole-genome sequencing (WGS) analysis from the 11-generation pedigree (>500 individuals) of a densely affected Costa Rican family which shares ancestry from six founder pairs. By conducting an identity-by-descent (IBD) analysis using WGS data from 19 individuals from the extended pedigree we have identified putative risk haplotypes that were not seen in controls, and can be linked with four of the six founder pairs. Rare coding and non-coding variants present on the haplotypes and only seen in haplotype carriers show an enrichment in pathways such as regulation of locomotion and signal transduction, suggesting common mechanisms by which the haplotype-specific variants may be contributing to TS-risk in this pedigree. In particular we have identified a rare deleterious missense variation in RAPGEF1 on a chromosome 9 haplotype and two ultra-rare deleterious intronic variants in ERBB4 and IKZF2 on the same chromosome 2 haplotype. All three genes play a role in neurodevelopment. This study, using WGS data in a pedigree-based approach, shows the importance of investigating both coding and non-coding variants to identify genes that may contribute to disease risk. Together, the genes and variants identified on the IBD haplotypes represent biologically relevant targets for investigation in other pedigree and population-based TS data.
Subject(s)
Neurogenesis , Tourette Syndrome , Child, Preschool , Humans , Costa Rica , Haplotypes , Pedigree , Signal Transduction , Tourette Syndrome/genetics , Neurogenesis/genetics , Polymorphism, Genetic , Whole Genome Sequencing , Guanine Nucleotide-Releasing Factor 2/geneticsABSTRACT
The human genome contains regions that cannot be adequately assembled or aligned using next generation short-read sequencing technologies. More than 2500 genes are known contain such 'dark' regions. In this study, we investigate the negative consequences of dark regions on gene discovery across a range of disease and study types, showing that dark regions are likely preventing researchers from identifying genetic variants relevant to human disease.
Subject(s)
Genome, Human , High-Throughput Nucleotide Sequencing , Humans , Genome, Human/genetics , Sequence Analysis, DNAABSTRACT
Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3-2.8, one-sided p = 6.0 × 10-4), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ.
Subject(s)
Bipolar Disorder , Schizophrenia , Bipolar Disorder/genetics , Exome/genetics , Genetic Predisposition to Disease/genetics , Genetic Variation/genetics , Genome-Wide Association Study , Humans , Polymorphism, Single Nucleotide/genetics , Schizophrenia/geneticsABSTRACT
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.
Subject(s)
Brain , Gene Expression Regulation , Nerve Net , Neural Pathways , Neuroimaging , Psychotic Disorders , Schizophrenia , Adult , Brain/diagnostic imaging , Brain/metabolism , Brain/pathology , Case-Control Studies , Female , Humans , Male , Middle Aged , Nerve Net/diagnostic imaging , Nerve Net/metabolism , Nerve Net/pathology , Neural Pathways/metabolism , Neural Pathways/pathology , Psychotic Disorders/diagnostic imaging , Psychotic Disorders/metabolism , Psychotic Disorders/pathology , Schizophrenia/diagnostic imaging , Schizophrenia/metabolismABSTRACT
BACKGROUND: Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. AIMS: To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. METHOD: Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. RESULTS: Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (ß = -0.34 years, s.e. = 0.08), major depression (ß = -0.34 years, s.e. = 0.08), schizophrenia (ß = -0.39 years, s.e. = 0.08), and educational attainment (ß = -0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. CONCLUSIONS: AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
Subject(s)
Autism Spectrum Disorder , Bipolar Disorder , Depressive Disorder, Major , Age of Onset , Bipolar Disorder/diagnosis , Bipolar Disorder/epidemiology , Bipolar Disorder/genetics , Depressive Disorder, Major/genetics , Genome-Wide Association Study , Humans , Multifactorial InheritanceABSTRACT
OBJECTIVE: Exposure to childhood trauma (CT) is associated with cognitive impairment in schizophrenia, and deficits in social cognition in particular. Here, we sought to test whether IL-6 mediated the association between CT and social cognition both directly, and sequentially via altered default mode network (DMN) connectivity. METHODS: Three-hundred-and-eleven participants (104 patients and 207 healthy participants) were included, with MRI data acquired in a subset of nâ¯=â¯147. CT was measured using the childhood trauma questionnaire (CTQ). IL-6 was measured in both plasma and in toll like receptor (TLR) stimulated whole blood. The CANTAB emotion recognition task (ERT) was administered to assess social cognition, and cortical connectivity was assessed based on resting DMN connectivity. RESULTS: Higher IL-6 levels, measured both in plasma and in toll-like receptor (TLR-2) stimulated blood, were significantly correlated with higher CTQ scores and lower cognitive and social cognitive function. Plasma IL-6 was further observed to partly mediate the association between higher CT scores and lower emotion recognition performance (CTQ total: ßindirect -0.0234, 95% CI: -0.0573 to -0.0074; CTQ physical neglect: ßindirectâ¯=â¯-0.0316, 95% CI: -0.0741 to -0.0049). Finally, sequential mediation was observed between plasma IL-6 levels and DMN connectivity in mediating the effects of higher CTQ on lower social cognitive function (ßindirectâ¯=â¯-0.0618, 95% CI: -0.1523 to -0.285). CONCLUSION: This work suggests that previous associations between CT and social cognition may be partly mediated via an increased inflammatory response. IL-6's association with changes in DMN activity further suggest at least one cortical network via which CT related effects on cognition may be transmitted.
Subject(s)
Adverse Childhood Experiences , Schizophrenia , Brain , Brain Mapping , Cognition , Humans , Interleukin-6 , Magnetic Resonance Imaging , Neuropsychological Tests , Schizophrenia/diagnostic imagingABSTRACT
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.
ABSTRACT
Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (ß = -0.71 to -1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (ß = -0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10-6, 1.7 × 10-9, 3.5 × 10-12 and 1.0 × 10-4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.
Subject(s)
Autistic Disorder/genetics , Basal Ganglia/pathology , Chromosome Disorders/genetics , DNA Copy Number Variations/genetics , Intellectual Disability/genetics , Adult , Autism Spectrum Disorder/genetics , Brain/pathology , Chromosome Deletion , Chromosome Duplication , Chromosomes, Human, Pair 16/genetics , Databases, Factual , Female , Globus Pallidus/pathology , Humans , Image Processing, Computer-Assisted/methods , Magnetic Resonance Imaging/methods , Male , Middle Aged , Neurodevelopmental Disorders/genetics , Organ Size/genetics , Putamen/pathology , Schizophrenia/geneticsABSTRACT
OBJECTIVE: This study investigated associations between childhood trauma, parental bonding, and social cognition (i.e., Theory of Mind and emotion recognition) in patients with schizophrenia and healthy adults. METHODS: Using cross-sectional data, we examined the recollections of childhood trauma experiences and social cognitive abilities in 74 patients with schizophrenia and 116 healthy adults. RESULTS: Patients had significantly higher scores compared with healthy participants on childhood trauma, and lower scores on parental bonding and social cognitive measures. Physical neglect was found to be the strongest predictor of emotion recognition impairments in both groups. Optimal parental bonding attenuated the impact of childhood trauma on emotion recognition. CONCLUSION: The present study provides evidence of an association between physical neglect and emotion recognition in patients with schizophrenia and healthy individuals and shows that both childhood trauma and parental bonding may influence social cognitive development. Psychosocial interventions should be developed to prevent and mitigate the long-term effects of childhood adversities.
Subject(s)
Schizophrenia , Theory of Mind , Adult , Cognition , Cross-Sectional Studies , Emotions , Humans , Parents , Social Cognition , Social PerceptionABSTRACT
Schizophrenia is a severe psychiatric disorder associated with both structural and functional brain abnormalities. In the past few years, there has been growing interest in the application of machine learning techniques to neuroimaging data for the diagnostic and prognostic assessment of this disorder. However, the vast majority of studies published so far have used either structural or functional neuroimaging data, without accounting for the multimodal nature of the disorder. Structural MRI and resting-state functional MRI data were acquired from a total of 295 patients with schizophrenia and 452 healthy controls at five research centers. We extracted features from the data including gray matter volume, white matter volume, amplitude of low-frequency fluctuation, regional homogeneity and two connectome-wide based metrics: structural covariance matrices and functional connectivity matrices. A support vector machine classifier was trained on each dataset separately to distinguish the subjects at individual level using each of the single feature as well as their combination, and 10-fold cross-validation was used to assess the performance of the model. Functional data allow higher accuracy of classification than structural data (mean 82.75% vs. 75.84%). Within each modality, the combination of images and matrices improves performance, resulting in mean accuracies of 81.63% for structural data and 87.59% for functional data. The use of all combined structural and functional measures allows the highest accuracy of classification (90.83%). We conclude that combining multimodal measures within a single model is a promising direction for developing biologically informed diagnostic tools in schizophrenia.
Subject(s)
Machine Learning , Multimodal Imaging/methods , Neuroimaging/methods , Schizophrenia/diagnostic imaging , Adult , Connectome , Diffusion Tensor Imaging , Female , Gray Matter/diagnostic imaging , Humans , Image Processing, Computer-Assisted/methods , Magnetic Resonance Imaging , Male , Middle Aged , Neural Pathways/diagnostic imaging , Reproducibility of Results , Rest , Support Vector Machine , White Matter/diagnostic imaging , Young AdultABSTRACT
BACKGROUND: Copy number variants (CNVs) play a significant role in disease pathogenesis in a small subset of individuals with schizophrenia (~2.5%). Chromosomal microarray testing is a first-tier genetic test for many neurodevelopmental disorders. Similar testing could be useful in schizophrenia. AIMS: To determine whether clinically identifiable phenotypic features could be used to successfully model schizophrenia-associated (SCZ-associated) CNV carrier status in a large schizophrenia cohort. METHOD: Logistic regression and receiver operating characteristic (ROC) curves tested the accuracy of readily identifiable phenotypic features in modelling SCZ-associated CNV status in a discovery data-set of 1215 individuals with psychosis. A replication analysis was undertaken in a second psychosis data-set (n = 479). RESULTS: In the discovery cohort, specific learning disorder (OR = 8.12; 95% CI 1.16-34.88, P = 0.012), developmental delay (OR = 5.19; 95% CI 1.58-14.76, P = 0.003) and comorbid neurodevelopmental disorder (OR = 5.87; 95% CI 1.28-19.69, P = 0.009) were significant independent variables in modelling positive carrier status for a SCZ-associated CNV, with an area under the ROC (AUROC) of 74.2% (95% CI 61.9-86.4%). A model constructed from the discovery cohort including developmental delay and comorbid neurodevelopmental disorder variables resulted in an AUROC of 83% (95% CI 52.0-100.0%) for the replication cohort. CONCLUSIONS: These findings suggest that careful clinical history taking to document specific neurodevelopmental features may be informative in screening for individuals with schizophrenia who are at higher risk of carrying known SCZ-associated CNVs. Identification of genomic disorders in these individuals is likely to have clinical benefits similar to those demonstrated for other neurodevelopmental disorders.
Subject(s)
DNA Copy Number Variations/genetics , Medical History Taking , Schizophrenia/diagnosis , Schizophrenia/genetics , Female , Humans , Logistic Models , Male , Neurodevelopmental Disorders/diagnosis , Neurodevelopmental Disorders/genetics , ROC Curve , Retrospective Studies , Young AdultABSTRACT
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.
Subject(s)
Brain/physiopathology , Connectome , Schizophrenia/diagnostic imaging , Adult , Case-Control Studies , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Schizophrenia/physiopathology , Severity of Illness Index , Support Vector Machine , Young AdultABSTRACT
Multiple genome-wide association studies of schizophrenia have reported associations between genetic variants within the MHC region and disease risk, an association that has been partially accounted for by alleles of the complement component 4 (C4) gene. Following on previous findings of association between both C4 and other complement-related variants and memory function, we tested the hypothesis that polygenic scores calculated based on identified schizophrenia risk alleles within the "complement" system would be broadly associated with memory function and associated brain structure. We tested this using a polygenic risk score (PRS) calculated for complement genes, but excluding C4 variants. Higher complement-based PRS scores were observed to be associated with lower memory scores for the sample as a whole (N = 620, F change = 8.25; p = .004). A significant association between higher PRS and lower hippocampal volume was also observed (N = 216, R2 change = 0.016, p = .015). However, after correcting for further testing of association with the more general indices of cortical thickness, surface area or total brain volume, none of which were associated with complement, the association with hippocampal volume became non-significant. A post-hoc analysis of hippocampal subfields suggested an association between complement PRS and several hippocampal subfields, findings that appeared to be particularly driven by the patient sample. In conclusion, our study yielded suggestive evidence of association between complement-based schizophrenia PRS and variation in memory function and hippocampal volume.
Subject(s)
Brain/pathology , Cerebral Cortex/pathology , Genetic Markers , Immunologic Factors/genetics , Multifactorial Inheritance , Polymorphism, Single Nucleotide , Psychotic Disorders/pathology , Adult , Brain/metabolism , Case-Control Studies , Cerebral Cortex/metabolism , Complement C4/genetics , Female , Follow-Up Studies , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Ireland/epidemiology , Male , Prognosis , Psychotic Disorders/epidemiology , Psychotic Disorders/genetics , Risk FactorsABSTRACT
Bacteremia (bacterial bloodstream infection) is a major cause of illness and death in sub-Saharan Africa but little is known about the role of human genetics in susceptibility. We conducted a genome-wide association study of bacteremia susceptibility in more than 5,000 Kenyan children as part of the Wellcome Trust Case Control Consortium 2 (WTCCC2). Both the blood-culture-proven bacteremia case subjects and healthy infants as controls were recruited from Kilifi, on the east coast of Kenya. Streptococcus pneumoniae is the most common cause of bacteremia in Kilifi and was thus the focus of this study. We identified an association between polymorphisms in a long intergenic non-coding RNA (lincRNA) gene (AC011288.2) and pneumococcal bacteremia and replicated the results in the same population (p combined = 1.69 × 10(-9); OR = 2.47, 95% CI = 1.84-3.31). The susceptibility allele is African specific, derived rather than ancestral, and occurs at low frequency (2.7% in control subjects and 6.4% in case subjects). Our further studies showed AC011288.2 expression only in neutrophils, a cell type that is known to play a major role in pneumococcal clearance. Identification of this novel association will further focus research on the role of lincRNAs in human infectious disease.
Subject(s)
Bacteremia/genetics , Pneumonia, Pneumococcal/genetics , Polymorphism, Genetic/genetics , RNA, Long Noncoding/genetics , Streptococcus pneumoniae/genetics , Adolescent , Bacteremia/microbiology , Bacteremia/pathology , Case-Control Studies , Child , Child, Preschool , Genome-Wide Association Study , Humans , Infant , Infant, Newborn , Kenya/epidemiology , Pneumonia, Pneumococcal/microbiology , Pneumonia, Pneumococcal/pathology , Risk FactorsABSTRACT
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.
Subject(s)
Cognitive Remediation/methods , Forensic Psychiatry/methods , Psychotic Disorders/psychology , Psychotic Disorders/therapy , Schizophrenia/therapy , Schizophrenic Psychology , Adult , Cohort Studies , Female , Follow-Up Studies , Humans , Male , Middle Aged , Patient Satisfaction , Single-Blind Method , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: People with schizophrenia are ten times more likely to commit homicide than a member of the general population. The relationship between symptoms of schizophrenia and acts of violence is unclear. There has also been limited research on what determines the seriousness and form of violence, such as reactive or instrumental violence. Moral cognition may play a paradoxical role in acts of violence for people with schizophrenia. Thoughts which have moral content arising from psychotic symptoms may be a cause of serious violence. METHOD: We investigated if psychotic symptoms and moral cognitions at the time of a violent act were associated with acts of violence using a cross-sectional national forensic cohort (n = 55). We examined whether moral cognitions were associated with violence when controlling for neurocognition and violence proneness. We explored the association between all psychotic symptoms present at the time of the violent act, psychotic symptoms judged relevant to the violent act and moral cognitions present at that time. Using mediation analysis, we examined whether moral cognitions were the missing link between symptoms and the relevance of symptoms for violence. We also investigated if specific moral cognitions mediated the relationship between specific psychotic symptoms, the seriousness of violence (including homicide), and the form of violence. RESULTS: Psychotic symptoms generally were not associated with the seriousness or form of violence. However, specific moral cognitions were associated with the seriousness and form of violence even when controlling for neurocognition and violence proneness. Specific moral cognitions were associated with specific psychotic symptoms present and relevant to violence. Moral cognitions mediated the relationship between the presence of specific psychotic symptoms and their relevance for violence, homicide, seriousness of violence, and the form of violence. CONCLUSIONS: Moral cognitions including the need to reduce suffering, responding to an act of injustice or betrayal, the desire to comply with authority, or the wish to punish impure or disgusting behaviour, may be a key mediator explaining the relationship between psychotic symptoms and acts of violence. Our findings may have important implications for risk assessment, treatment and violence prevention.
Subject(s)
Cognition , Morals , Psychotic Disorders/psychology , Violence/psychology , Adult , Cohort Studies , Cross-Sectional Studies , Female , Homicide/psychology , Humans , Male , Middle AgedABSTRACT
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.
Subject(s)
Exome Sequencing/methods , Schizophrenia/genetics , Sequence Analysis, DNA/methods , Adult , Case-Control Studies , Chromosome Mapping , DNA Copy Number Variations , Databases, Genetic , Exome/genetics , Female , Genetic Predisposition to Disease/genetics , Genome-Wide Association Study/methods , Genotype , Haplotypes , Humans , Male , Middle Aged , Risk Factors , Schizophrenia/metabolismABSTRACT
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.