Understanding the genetic liability to schizophrenia through the neuroepigenome.
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ABSTRACT:
SUBMITTER: Fullard JF
PROVIDER: S-EPMC4963306 | biostudies-literature | 2016 Nov
REPOSITORIES: biostudies-literature
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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: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:Genetic liability for schizophrenia is associated with psychopathology in early life. It is not clear if these associations are time dependent during childhood, nor if they are specific across different forms of psychopathology. Using genotype and questionnaire data on children (N = 15 105) from the Norwegian Mother, Father and Child Cohort Study, we used schizophrenia polygenic risk scores to test developmental stability in associations with measures of emotional and behavioral problems between 18 months and 5 years, and domain specificity in associations with symptoms of depression, anxiety, conduct problems, oppositionality, inattention, and hyperactivity at 8 years. We then sought to identify symptom profiles-across development and domains-associated with schizophrenia polygenic liability. We found evidence for developmental stability in associations between schizophrenia polygenic risk scores and emotional and behavioral problems, with the latter being mediated specifically via the rate of change in symptoms (β slope = 0.032; 95% CI: 0.007-0.057). At age 8, associations were better explained by a model of symptom-specific polygenic effects rather than effects mediated via a general psychopathology factor or by domain-specific factors. Overall, individuals with higher schizophrenia polygenic risk scores were more likely (OR = 1.310 [95% CIs: 1.122-1.528]) to have a profile of increasing behavioral and emotional symptoms in early childhood, followed by elevated symptoms of conduct disorder, oppositionality, hyperactivity, and inattention by age 8. Schizophrenia-associated alleles are linked to specific patterns of early-life psychopathology. The associations are small, but findings of this nature can help us better understand the developmental emergence of schizophrenia.
| S-EPMC8266611 | 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
Project description:Context-processing deficits have been shown in schizophrenia during first-episode, medication-naïve status, that persist after short-term antipsychotic treatment and also in first-degree relatives of individuals with schizophrenia. To confirm longer term persistence of deficits, we examined schizophrenia patients (n=63) during first-episode, medication-naïve status through to one-year follow-up, compared to healthy control (n=83) and non-schizophrenia psychosis comparison (n=47) groups, as well as unaffected first-degree relatives of individuals with schizophrenia (n=31). Context-processing ability was assessed by performance on the AX-CPT (Continuous Performance Test) at baseline, 8 weeks, 6 months, and 1 year (relatives only at baseline). Reaction time, error rates and signal detection indices (d'-context) of context processing were analyzed. Linear discriminant analyses (LDA) on early timepoints (baseline, 8 weeks) were conducted to predict confirmatory diagnosis (schizophrenia vs. psychosis control) at 6 months. Schizophrenia patients showed evidence of impaired context-processing relative to both the healthy and psychosis comparator groups at baseline and continued through to 1 year. While context-processing impairments persisted in schizophrenia patients through one year, the impairments in psychosis controls, which were more modest at baseline, remitted at follow-up. First-degree relatives showed deficits that were intermediate between the schizophrenia and healthy control groups. LDA showed 67% classification rates for distinguishing schizophrenia from non-schizophrenia psychosis. The persistence, diagnostic specificity and association with genetic liability give support for context processing impairments serving as a cognitive endophenotype for schizophrenia and evaluation of context processing could contribute to diagnostic assessments.
| S-EPMC3650125 | biostudies-literature
Project description:Childhood exposure to green space has previously been associated with lower risk of developing schizophrenia later in life. It is unclear whether this association is mediated by genetic liability or whether the 2 risk factors work additively. Here, we investigate possible gene-environment associations with the hazard ratio (HR) of schizophrenia by combining (1) an estimate of childhood exposure to residential-level green space based on the normalized difference vegetation index (NDVI) from Landsat satellite images, with (2) genetic liability estimates based on polygenic risk scores for 19 746 genotyped individuals from the Danish iPSYCH sample. We used information from the Danish registers of health, residential address, and socioeconomic status to adjust HR estimates for established confounders, ie, parents' socioeconomic status, and family history of mental illness. The adjusted HRs show that growing up surrounded by the highest compared to the lowest decile of NDVI was associated with a 0.52-fold (95% confidence interval [CI]: 0.40 to 0.66) lower schizophrenia risk, and children with the highest polygenic risk score had a 1.24-fold (95% CI: 1.18 to 1.30) higher schizophrenia risk. We found that NDVI explained 1.45% (95% CI: 1.07 to 1.90) of the variance on the liability scale, while polygenic risk score for schizophrenia explained 1.01% (95% CI: 0.77 to 1.46). Together they explained 2.40% (95% CI: 1.99 to 3.07) with no indication of a gene-environment interaction (P = .29). Our results suggest that risk of schizophrenia is associated additively with green space exposure and genetic liability, and provide no support for an environment-gene interaction between NDVI and schizophrenia.
| S-EPMC8496913 | biostudies-literature
Project description:BackgroundAlterations in intellectual ability and brain structure are important genetic markers for schizophrenia liability. How variations in these phenotypes interact with variance in schizophrenia liability due to genetic or environmental factors is an area of active investigation. Studying these genetic markers using a multivariate twin modeling approach can provide novel leads for (genetic) pathways of schizophrenia development.MethodsIn a sample of 70 twins discordant for schizophrenia and 130 healthy control twins, structural equation modeling was applied to quantify unique contributions of genetic and environmental factors on human brain structure (cortical thickness, cortical surface and global white matter fractional anisotropy [FA]), intellectual ability and schizophrenia liability.ResultsIn total, up to 28.1% of the genetic variance (22.8% of total variance) in schizophrenia liability was shared with intelligence quotient (IQ), global-FA, cortical thickness, and cortical surface. The strongest contributor was IQ, sharing on average 16.4% of the genetic variance in schizophrenia liability, followed by cortical thickness (6.3%), global-FA (4.7%) and cortical surface (0.5%). Furthermore, we found that up to 57.4% of the variation due to environmental factors (4.6% of total variance) in schizophrenia was shared with IQ (34.2%) and cortical surface (13.4%).ConclusionsIntellectual ability, FA and cortical thickness show significant and independent shared genetic variance with schizophrenia liability. This suggests that measuring brain-imaging phenotypes helps explain genetic variance in schizophrenia liability that is not captured by variation in IQ.
| S-EPMC4988741 | biostudies-literature
Project description:BackgroundThere is a wealth of literature on the observed association between childhood trauma and psychotic illness. However, the relationship between childhood trauma and psychosis is complex and could be explained, in part, by gene-environment correlation.MethodsThe association between schizophrenia polygenic scores (PGS) and experiencing childhood trauma was investigated using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Norwegian Mother, Father and Child Cohort Study (MoBa). Schizophrenia PGS were derived in each cohort for children, mothers, and fathers where genetic data were available. Measures of trauma exposure were derived based on data collected throughout childhood and adolescence (0-17 years; ALSPAC) and at age 8 years (MoBa).ResultsWithin ALSPAC, we found a positive association between schizophrenia PGS and exposure to trauma across childhood and adolescence; effect sizes were consistent for both child or maternal PGS. We found evidence of an association between the schizophrenia PGS and the majority of trauma subtypes investigated, with the exception of bullying. These results were comparable with those of MoBa. Within ALSPAC, genetic liability to a range of additional psychiatric traits was also associated with a greater trauma exposure.ConclusionsResults from two international birth cohorts indicate that genetic liability for a range of psychiatric traits is associated with experiencing childhood trauma. Genome-wide association study of psychiatric phenotypes may also reflect risk factors for these phenotypes. Our findings also suggest that youth at higher genetic risk might require greater resources/support to ensure they grow-up in a healthy environment.
| S-EPMC8381289 | biostudies-literature
Project description:Aberrant activity in brain regions underlying various aspects of executive cognition has been reported in patients with schizophrenia and in their healthy relatives, suggesting an association with genetic liability. The aim of this study was to investigate brain responses to selective aspects of cognitive control in unaffected siblings who are at increased genetic risk of schizophrenia. Altogether, 65 non-affected siblings, 70 patients with schizophrenia spectrum disorders, and 235 normal controls participated in this study. Blood-oxygen-level-dependent functional magnetic resonance imaging was conducted while participants performed a cognitive control task ('flanker task') to identify brain activity and connectivity associated with response inhibition and conflict monitoring, and suppression. Behaviorally, similar to patients with schizophrenia, siblings were less accurate when inhibiting prepotent responses relative to normal controls. During response inhibition, again similar to patients with schizophrenia, siblings showed decreased activity in the anterior cingulate (ACC), along with increased functional coupling with the dorsolateral prefrontal cortex (PFC) when compared to normal controls. Our findings show altered ACC activity and PFC connectivity in unaffected siblings and patients with schizophrenia during response inhibition. These results suggest that such changes in the neural activity underlying aspects of cognitive control may represent a potential intermediate phenotype for the investigation of the genetic basis of schizophrenia.
| S-EPMC3671987 | biostudies-literature
Project description:BackgroundResidential mobility during upbringing, and especially adolescence, is associated with multiple negative mental health outcomes. However, whether associations are confounded by unmeasured familial factors, including genetic liability, is unclear.AimsWe used a population-based case-cohort study to assess whether polygenic risk scores (PRSs) for schizophrenia, bipolar disorder and major depression were associated with mobility from ages 10-14 years, and whether PRS and parental history of mental disorder together explained associations between mobility and each disorder.MethodInformation on cases (n = 4207 schizophrenia, n = 1402 bipolar disorder, n = 18 215 major depression) and a random population sample (n = 17 582), born 1981-1997, was linked between Danish civil and psychiatric registries. Genome-wide data were obtained from the Danish Neonatal Screening Biobank and PRSs were calculated based on results of separate, large meta-analyses.ResultsPRSs for schizophrenia and major depression were weakly associated with moving once (odds ratio 1.07, 95% CI 1.00-1.16; and odds ratio 1.10, 95% CI 1.04-1.17, respectively), but not twice or three or more times. Mobility was positively associated with each disorder, with more moves associated with greater risk. Adjustment for PRS produced slight reductions in the magnitude of associations. Adjustment for PRS and parental history of mental disorder together reduced estimates by 5-11%. In fully adjusted models mobility was associated with all three disorders; hazard ratios ranged from 1.33 (95% CI 1.08-1.62; one move and bipolar disorder) to 3.05 (95% CI 1.92-4.86; three or more moves and bipolar disorder).ConclusionsAssociations of mobility with schizophrenia, bipolar disorder and depression do not appear to be attributable to genetic liability as measured here. Potential familial confounding of mobility associations may be predominantly environmental in nature.
| S-EPMC8130005 | biostudies-literature