Altered cerebral response during cognitive control: a potential indicator of genetic liability for schizophrenia.
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ABSTRACT:
SUBMITTER: Sambataro F
PROVIDER: S-EPMC3671987 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ImportanceSchizophrenia is a clinically heterogeneous disorder. It is currently unclear how variability in symptom dimensions and cognitive ability is associated with genetic liability for schizophrenia.ObjectiveTo determine whether phenotypic dimensions within schizophrenia are associated with genetic liability to schizophrenia, other neuropsychiatric disorders, and intelligence.Design, setting, and participantsIn a genetic association study, 3 cross-sectional samples of 1220 individuals with a diagnosis of schizophrenia were recruited from community, inpatient, and voluntary sector mental health services across the UK. Confirmatory factor analysis was used to create phenotypic dimensions from lifetime ratings of the Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms, and the MATRICS Consensus Cognitive Battery. Analyses of polygenic risk scores (PRSs) were used to assess whether genetic liability to schizophrenia, other neuropsychiatric disorders, and intelligence were associated with these phenotypic dimensions. Data collection for the cross-sectional studies occurred between 1993 and 2016. Data analysis for this study occurred between January 2019 and March 2021.Main outcomes and measuresOutcome measures included phenotypic dimensions defined from confirmatory factor analysis relating to positive symptoms, negative symptoms of diminished expressivity, negative symptoms of motivation and pleasure, disorganized symptoms, and current cognitive ability. Exposure measures included PRSs for schizophrenia, bipolar disorder, major depression, attention-deficit/hyperactivity disorder, autism spectrum disorder, and intelligence.ResultsOf the 1220 study participants, 817 were men (67.0%). Participants' mean (SD) age at interview was 43.10 (12.74) years. Schizophrenia PRS was associated with increased disorganized symptom dimension scores in both a 5-factor model (β = 0.14; 95% CI, 0.07-0.22; P = 2.80 × 10-4) and a 3-factor model across all samples (β = 0.10; 95% CI, 0.05-0.15; P = 2.80 × 10-4). Current cognitive ability was associated with genetic liability to schizophrenia (β = -0.11; 95% CI, -0.19 to -0.04; P = 1.63 × 10-3) and intelligence (β = 0.23; 95% CI, 0.16-0.30; P = 1.52 × 10-10). After controlling for estimated premorbid IQ, current cognitive performance was associated with schizophrenia PRS (β = -0.08; 95% CI, -0.14 to -0.02; P = 8.50 × 10-3) but not intelligence PRS.Conclusions and relevanceThe findings of this study suggest that genetic liability for schizophrenia is associated with higher disorganized dimension scores but not other symptom dimensions. Cognitive performance in schizophrenia appears to reflect distinct contributions from genetic liabilities to both intelligence and schizophrenia.
| S-EPMC8340009 | biostudies-literature
Project description:Intensive computerized auditory training results in improved cognition for schizophrenia patients, but participants show variation in their cognitive gains and the biological factors that affect the response to training are unknown. Single nucleotide polymorphisms (SNPs) in the catechol-O-methyltransferase (COMT) gene have been related to cognitive function. Here we asked if functional variation in this gene has an impact on the response of schizophrenia patients to cognitive training. We genotyped 48 schizophrenia patients who completed 50 h of computerized cognitive training and analyzed the association between DNA variants in the COMT gene and the improvement in global cognition. Although conventional analyses did not reveal any significant associations, a set-based analysis examining the aggregate effect of common variation in the COMT gene (42 SNPs) suggested association with improvement in global cognition. Eight SNPs, mostly located in the 3' end of the COMT gene, were nominally associated with improvement in cognition. These data suggest that genotype influences the response to intensive cognitive training in schizophrenia, and may indicate that cognitive training regimens need to be personalized to the underlying biosignatures of each individual patient. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
| S-EPMC3448064 | biostudies-literature
Project description:The Psychiatric Genomics Consortium-Schizophrenia Workgroup (PGC-SCZ) recently identified 108 loci associated with increased risk for schizophrenia (SCZ). The vast majority of these variants reside within non-coding sequences of the genome and are predicted to exert their effects by affecting the mechanism of action of cis regulatory elements (CREs), such as promoters and enhancers. Although a number of large-scale collaborative efforts (e.g. ENCODE) have achieved a comprehensive mapping of CREs in human cell lines or tissue homogenates, it is becoming increasingly evident that many risk-associated variants are enriched for expression Quantitative Trait Loci (eQTLs) and CREs in specific tissues or cells. As such, data derived from previous research endeavors may not capture fully cell-type and/or region specific changes associated with brain diseases. Coupling recent technological advances in genomics with cell-type specific methodologies, we are presented with an unprecedented opportunity to better understand the genetics of normal brain development and function and, in turn, the molecular basis of neuropsychiatric disorders. In this review, we will outline ongoing efforts towards this goal and will discuss approaches with the potential to shed light on the mechanism(s) of action of cell-type specific cis regulatory elements and their putative roles in disease, with particular emphasis on understanding the manner in which the epigenome and CREs influence the etiology of SCZ.
| S-EPMC4963306 | biostudies-literature
Project description:Although there is a vast literature linking education and later health outcomes, the mechanisms underlying these associations are relatively unknown. In the spirit of some medical literature that leverages developmental abnormalities to understand mechanisms of normative functioning, we explore the ability of higher educational attainments to "rescue" biological/genetic liabilities in brain function through inheritance of a variant of the APOE gene shown to lead to cognitive decline, dementia, and Alzheimer's disease in old age. Deploying a between-sibling design that allows quasi-experimental variation in genotype and educational attainment within a standard gene-environment interaction framework, we show evidence that the genetic effects of the "risky" APOE variant on old-age cognitive decline are absent in individuals who complete college (vs. high school graduates). Auxiliary analyses suggest that the likely mechanisms of education are most consistent through changing brain processes (i.e., "how we think") and potentially building cognitive reserves, rather than alleviating old age cognitive decline through the channels of higher socioeconomic status and resources over the life course.
| S-EPMC4286526 | biostudies-literature
Project description:Disruption of visual percepts by a subsequent stimulus (ie, backward masking) has been consistently noted in schizophrenia, with some evidence that this fragility in early perception is present in people with genetic liability for the disorder. Given the potential of backward masking paradigms to mark neural processes that confer risk for schizophrenia, it is important to test the diagnostic specificity of abnormalities in visual perception. To more fully assess whether masking visual stimuli reveals a marker of genetic liability (ie, endophenotype) specific to schizophrenia, we tested 44 people with the disorder, 29 people with bipolar disorder, 56 first-degree biological relatives of people with schizophrenia, 26 first-degree biological relatives of people with bipolar disorder, and 43 nonpsychiatric control participants using a magnocellular-biased visual backward masking procedure that included target-to-mask onset asynchronies ranging from 0 to 80 ms. Relatives of people with schizophrenia who were without schizophrenia spectrum disorders exhibited impaired performance compared with nonpsychiatric control participants and relatives of people with bipolar disorder when a visual mask interrupted early perception (eg, 27 ms). A similar vulnerability of early processes was noted in people with schizophrenia, yet they also had impaired performance when masks occurred at later time points (ie, 80 ms). Performance deficits were not attributable to intellectual function, measures of attention and memory, symptomatology, or medication dosage. Bipolar patients and their relatives failed to exhibit deficits on the backward masking task. Fragility of early visual percepts appears to mark genetic liability specific to schizophrenia and may serve as an endophenotype for the disorder.
| S-EPMC3686444 | biostudies-literature
Project description:As evidenced by a multitude of studies, abnormalities in Theory of Mind (ToM) and its neural processing might constitute an intermediate phenotype of schizophrenia. If so, neural alterations during ToM should be observable in unaffected relatives of patients as well, since they share a considerable amount of genetic risk. While behaviorally, impaired ToM function is confirmed meta-analytically in relatives, evidence on aberrant function of the neural ToM network is sparse and inconclusive. The present study therefore aimed to further explore the neural correlates of ToM in relatives of schizophrenia. About 297 controls and 63 unaffected first-degree relatives of patients with schizophrenia performed a ToM task during functional magnetic resonance imaging. Consistent with the literature relatives exhibited decreased activity of the medial prefrontal cortex. Additionally, increased recruitment of the right middle temporal gyrus and posterior cingulate cortex was found, which was related to subclinical paranoid symptoms in relatives. These results further support decreased medial prefrontal activation during ToM as an intermediate phenotype of genetic risk for schizophrenia. Enhanced recruitment of posterior ToM areas in relatives might indicate inefficiency mechanisms in the presence of genetic risk.
| S-EPMC4733339 | biostudies-literature
Project description:Many studies have shown abnormal cerebral blood flow (CBF) in schizophrenia; however, it remains unclear how topological properties of CBF network are altered in this disorder. Here, arterial spin labeling (ASL) MRI was employed to measure resting-state CBF in 96 schizophrenia patients and 91 healthy controls. CBF covariance network of each group was constructed by calculating across-subject CBF covariance between 90 brain regions. Graph theory was used to compare intergroup differences in global and nodal topological measures of the network. Both schizophrenia patients and healthy controls had small-world topology in CBF covariance networks, implying an optimal balance between functional segregation and integration. Compared with healthy controls, schizophrenia patients showed reduced small-worldness, normalized clustering coefficient and local efficiency of the network, suggesting a shift toward randomized network topology in schizophrenia. Furthermore, schizophrenia patients exhibited altered nodal centrality in the perceptual-, affective-, language-, and spatial-related regions, indicating functional disturbance of these systems in schizophrenia. This study demonstrated for the first time that schizophrenia patients have disrupted topological properties in CBF covariance network, which provides a new perspective (efficiency of blood flow distribution between brain regions) for understanding neural mechanisms of schizophrenia.
| S-EPMC4927570 | biostudies-literature
Project description:Structural and diffusion tensor imaging studies implicate gray and white matter (WM) abnormalities and disruptions of neural circuitry in schizophrenia. However, the structural integrity of the superficial WM, comprising short-range association (U-fibers) and intracortical axons, has not been investigated in schizophrenia.High-resolution structural and diffusion tensor images and sophisticated cortical pattern matching methods were used to measure and compare global and local variations in superficial WM fractional anisotropy between schizophrenia patients and their relatives and community comparison subjects and their relatives (n = 150).Compared with control subjects, patients showed reduced superficial WM fractional anisotropy distributed across each hemisphere, particularly in left temporal and bilateral occipital regions (all p < .05, corrected). Furthermore, by modeling biological risk for schizophrenia in patients, patient relatives, and control subjects, fractional anisotropy was shown to vary in accordance with relatedness to a patient in both hemispheres and in the temporal and occipital lobes (p < .05, corrected). However, effects did not survive correction procedures for two-group comparisons between patient relatives and control subjects.Results extend previous findings restricted to deep WM pathways to demonstrate that disturbances in corticocortical connectivity are associated with schizophrenia and might indicate a genetic predisposition for the disorder. Because the structural integrity of WM plays a crucial role in the functionality of networks linking gray matter regions, disturbances in the coherence and organization of fibers at the juncture of the neuropil might relate to features of schizophrenia at least partially attributable to disease-related genetic factors.
| S-EPMC3838300 | biostudies-literature
Project description:To better understand cognitive control impairment in schizophrenia, it is vital to determine the extent of dysfunctional connectivity in the associated fronto-striatal brain network, with a focus on the connections with the anterior cingulate cortex (ACC), prior to the potential confounding effect of medication. It is also essential to determine the effects following antipsychotic medication and the relationship of those effects on psychosis improvement. Twenty-two patients with schizophrenia, initially unmedicated and after a 6-week course of risperidone, and 20 matched healthy controls (HC) performed a fMRI task twice, six weeks apart. We investigated group and longitudinal differences in ACC-related functional connectivity during performance of a Stroop color task as well as connectivity patterns associated with improvement in psychosis symptoms. Unmedicated patients with schizophrenia showed greater functional connectivity between ACC and bilateral caudate and midbrain and lower connectivity with left putamen compared to healthy controls. At baseline, greater functional connectivity between ACC and bilateral putamen predicted subsequent better treatment response. Change in functional connectivity between ACC and left putamen positively correlated with better treatment response. These results suggest that patterns of functional connectivity in fronto-striatal networks can be utilized to predict potential response to antipsychotic medication. Prior to treatment, brain function may be structured with a predisposition that favors or not treatment response.
| S-EPMC7909720 | biostudies-literature
Project description:BackgroundIndividuals with schizophrenia are at higher risk of physical illnesses, which are a major contributor to their 20-year reduced life expectancy. It is currently unknown what causes the increased risk of physical illness in schizophrenia.AimsTo link genetic data from a clinically ascertained sample of individuals with schizophrenia to anonymised National Health Service (NHS) records. To assess (a) rates of physical illness in those with schizophrenia, and (b) whether physical illness in schizophrenia is associated with genetic liability.MethodWe linked genetic data from a clinically ascertained sample of individuals with schizophrenia (Cardiff Cognition in Schizophrenia participants, n = 896) to anonymised NHS records held in the Secure Anonymised Information Linkage (SAIL) databank. Physical illnesses were defined from the General Practice Database and Patient Episode Database for Wales. Genetic liability for schizophrenia was indexed by (a) rare copy number variants (CNVs), and (b) polygenic risk scores.ResultsIndividuals with schizophrenia in SAIL had increased rates of epilepsy (standardised rate ratio (SRR) = 5.34), intellectual disability (SRR = 3.11), type 2 diabetes (SRR = 2.45), congenital disorders (SRR = 1.77), ischaemic heart disease (SRR = 1.57) and smoking (SRR = 1.44) in comparison with the general SAIL population. In those with schizophrenia, carrier status for schizophrenia-associated CNVs and neurodevelopmental disorder-associated CNVs was associated with height (P = 0.015-0.017), with carriers being 7.5-7.7 cm shorter than non-carriers. We did not find evidence that the increased rates of poor physical health outcomes in schizophrenia were associated with genetic liability for the disorder.ConclusionsThis study demonstrates the value of and potential for linking genetic data from clinically ascertained research studies to anonymised health records. The increased risk for physical illness in schizophrenia is not caused by genetic liability for the disorder.
| S-EPMC7745237 | biostudies-literature