High Genetic Risk For Schizophrenia Research Articles

Impact of a microRNA MIR137 susceptibility variant on brain function in people at high genetic risk of schizophrenia or bipolar disorder.

A recent 'mega-analysis' combining genome-wide association study data from over 40,000 individuals identified novel genetic loci associated with schizophrenia (SCZ) at genome-wide significance level. The strongest finding was a locus within an intron of a putative primary transcript for microRNA MIR137. In the current study, we examine the impact of variation at this locus (rs1625579, G/T; where T is the common and presumed risk allele) on brain activation during a sentence completion task that differentiates individuals with SCZ, bipolar disorder (BD), and their relatives from controls. We examined three groups of individuals performing a sentence completion paradigm: (i) individuals at high genetic risk of SCZ (n=44), (ii) individuals at high genetic risk of BD (n=90), and (iii) healthy controls (n=81) in order to test the hypothesis that genotype at rs1625579 would influence brain activation. Genotype groups were assigned as 'RISK-' for GT and GG individuals, and 'RISK+' for TT homozygotes. The main effect of genotype was significantly greater activation in the RISK- individuals in the posterior right medial frontal gyrus, BA 6. There was also a significant genotype(*)group interaction in the left amygdala and left pre/postcentral gyrus. This was due to differences between the controls (where individuals with the RISK- genotype showed greater activation than RISK+ subjects) and the SCZ high-risk group, where the opposite genotype effect was seen. These results suggest that the newly identified SCZ locus may influence brain activation in a manner that is partly dependent on the presence of existing genetic susceptibility for SCZ.

Use of second-person pronouns and schizophrenia

A masked analysis of videotaped assessments of people at high genetic risk of schizophrenia revealed that those who subsequently went on to develop schizophrenia used significantly more second-person pronouns. This was evident before diagnosis, at two separate assessments approximately 18 months apart. This supports the view that people who go on to develop schizophrenia may have an abnormality in the deictic frame of interpersonal communication - that is, the distinction between concepts being self-generated or from elsewhere may be blurred prior to the onset of a diagnosis of schizophrenia.

Relationship Between Gyrification and Functional Connectivity of the Prefrontal Cortex in Subjects at High Genetic Risk of Schizophrenia

Measures of cortical folding ('gyrification') and connectivity are both reported to be disrupted in schizophrenia. There are also reports that increases in prefrontal gyrification may be predictive of subsequent illness in individuals at familial risk of the disorder. Such measures therefore have important potential clinical relevance. The nature of the relationship between cortical morphology and underlying connectivity is however unclear. In the current study we sought to explore the relationship between measures of gyrification and functional connectivity in a cohort of individuals at high genetic risk for the disorder. The theoretical background is based on the hypothesis that increased gyrification index (GI) in the prefrontal cortex may reflect increased short range regional connectivity. The cohort comprised 68 young unaffected relatives of schizophrenia patients and 21 healthy controls. Cortical folding was assessed using an automated Gyrification Index method (A-GI). Participants performed the Hayling sentence completion paradigm in the scanner and measures of functional connectivity were assessed using a correlation based approach. In the high risk subjects significant positive associations were found between prefrontal GI and prefrontal lateral-medial connectivity, while a negative correlation was found between prefrontal GI and prefrontal-thalamic connectivity. These associations indicate that measures describing morphological features of the brain surface relate to measures of underlying functional connectivity in the high risk subjects. Correlations in high risk people were more pronounced than in control subjects. We suggest our previous finding of increased prefrontal gyrification may therefore relate to increased local short range prefrontal connectivity and reduced long range connectivity.

Multidimensional Comparison of Personality Characteristics in Genetic High Risk for Schizophrenia, First Episode Psychosis and Healthy Controls

Objectives : Previous studies have suggested that some personality characteristics are associated with the onset, prognosis and so- cial function in schizophrenia patients. However few is known about the personality and affective characteristic of genetic high risk group (GHR) for schizophrenia. This study aimed to investigate the personality and the affective characteristic of GHR group for schizophrenia. Methods : Participants were 54 healthy controls (HC), 26 subjects with GHR for schizophrenia and 28 subjects with first episode psychosis (FEP). We performed three self-report questionnaires; NEO-Personality Inventory-Revised, State and Anger Expression Inventory and Positive Affect and Negative Affect Schedule. Results : The GHR group showed higher score in agreeableness item than the HC (p=0.028). In extraversion item, the FEP group showed significantly lower scores than the HC (p=0.001). The GHR group showed lower scores in neuroticism item com- pared with FEP group in trend level. The FEP group showed higher trait-anger, lower positive affect and higher negative affect compared with the others. Conclusion : The GHR group seem to share certain vulnerable personality and affective characteristics for schizophrenia with the FEP group. On the other hands, the GHR group appeared to be more agreeable than the other groups, which might act as the com- pensation for other impaired functions. (Korean J Schizophr Res 2012;15:73-80)

Impact of cannabis use on thalamic volume in people at familial high risk of schizophrenia

No longitudinal study has yet examined the association between substance use and brain volume changes in a population at high risk of schizophrenia. To examine the effects of cannabis on longitudinal thalamus and amygdala-hippocampal complex volumes within a population at high risk of schizophrenia. Magnetic resonance imaging scans were obtained from individuals at high genetic risk of schizophrenia at the point of entry to the Edinburgh High-Risk Study (EHRS) and approximately 2 years later. Differential thalamic and amygdala-hippocampal complex volume change in high-risk individuals exposed (n = 25) and not exposed (n = 32) to cannabis in the intervening period was investigated using repeated-measures analysis of variance. Cannabis exposure was associated with bilateral thalamic volume loss. This effect was significant on the left (F = 4.47, P = 0.04) and highly significant on the right (F= 7.66, P= 0.008). These results remained significant when individuals using other illicit drugs were removed from the analysis. These are the first longitudinal data to demonstrate an association between thalamic volume loss and exposure to cannabis in currently unaffected people at familial high risk of developing schizophrenia. This observation may be important in understanding the link between cannabis exposure and the subsequent development of schizophrenia.

Longitudinal Volume Reductions in People at High Genetic Risk of Schizophrenia as They Develop Psychosis

Structural differences between the brains of people with schizophrenia and control subjects are highly replicated but the timing and clinical correlates are unclear. In the Edinburgh High Risk Study, we have followed up 162 individuals at high genetic risk of schizophrenia and 36 healthy control subjects over 10 years. Participants received detailed clinical and up to five structural magnetic resonance imaging (MRI) assessments at 2-year intervals. All 436 MRI scans acquired were parcellated and adjusted for between-scanner differences. The trajectory of any structural MRI changes was then investigated using mixed effects analysis of variance. Seventeen of the 146 high-risk subjects who were scanned developed schizophrenia over the 8 years of the study. People at high genetic risk of schizophrenia had significantly greater reductions over time than the control group for whole brain volume and left and right prefrontal and temporal lobes. Greater prefrontal reductions were shown in high-risk subjects who subsequently became unwell compared with those who did not. These changes were significantly associated with increasing severity of psychotic symptoms. Individuals at high genetic risk of schizophrenia exhibited reductions in cerebral volume that were not found in control subjects. Changes in brain structure were also associated with increasing psychotic symptom severity as people developed schizophrenia. The progressive reductions found in those who went on to develop schizophrenia suggest an additional brain insult near to the time of onset.

Genetic vulnerability and premature death in schizophrenia spectrum disorders: A 28-year follow-up of adoptees in the Finnish Adoptive Family Study of Schizophrenia

Background: Excess mortality is widely reported among schizophrenia patients, but rarely examined in adoption study settings. Aim: We investigated whether genetic background plays a role in the premature death of adoptees with schizophrenia. Methods: Mortality among 382 adoptees in the Finnish Adoptive Family Study of Schizophrenia was monitored from 1977 to 2005 through the national causes-of-death register. The sample covered 190 adoptees with a high genetic risk of schizophrenia (HR) and 192 with a low risk (LR). Results: Overall mortality among the adoptees did not differ between the HR and LR groups, as 10% and 9% respectively had died during the follow-up, at mean ages of 45 and 46 years. Schizophrenia spectrum disorder was the most significant predictor of premature death in both groups, with dysfunction in the rearing family environment associated with mortality, unnatural deaths and suicides in the HR but not in the LR group. All the suicides involved HR cases. Conclusions: Mortality among the adoptees was not related to genetic factors but to environmental ones. The association of unnatural deaths and suicides with dysfunction in the rearing environment among the HR adoptees may indicate that they had a greater genetically determined vulnerability to environmental effects than their LR counterparts. The genetic and rearing environments can be disentangled in this setting because the biological parents give the offspring their genes and the adoptive parents give them their rearing environment. Our findings add to knowledge of the factors associated with the premature death of adoptees in mid-life.

Effects of the BDNF val66met polymorphism on prefrontal brain function in a population at high genetic risk of schizophrenia

A single nucleotide polymorphism (val66met) in the brain derived neurotrophic factor (BDNF) gene has been shown to be a risk factor for a number of psychiatric disorders, including schizophrenia. This polymorphism has also been shown to have effects on prefrontal brain morphology and function. This study aims to clarify the effects of the val66met polymorphism on prefrontal brain function in a population at high genetic risk for schizophrenia. The Edinburgh High Risk Study has followed young individuals who had one first- or second-degree relative with schizophrenia and a minimum of one further genetic relative with the illness. A sample of 62 individuals provided both genetic and functional imaging data using the Hayling sentence completion task. Individuals with the BDNF ValVal (presumed risk) genotype (n = 41) showed relatively increased activation of the anterior cingulate cortex in relation to Met carrier individuals (n = 21) during sentence completion conditions versus baseline, against a background of similar levels of task performance. It appeared from further investigation that this relatively increased activation was attributable to a failure to disengage or suppress activation in the high risk ValVal group during the task condition, suggesting that BDNF may contribute to the abnormal default network reported in schizophrenia. These results suggest that this gene affects prefrontal brain function in those at high genetic risk for the disorder, unconfounded by medication effects. BDNF may therefore be one of the heritable factors involved in the development of abnormal prefrontal function in schizophrenia. © 2010 Wiley-Liss, Inc.

Functional magnetic resonance imaging of BDNF val66met polymorphism in unmedicated subjects at high genetic risk of schizophrenia performing a verbal memory task

Multiple strands of evidence suggest a role for Brain Derived Neurotrophic Factor (BDNF) in the pathophysiology of schizophrenia. It is not yet clear, however, how BDNF may contribute to altered brain function seen in the disorder, or in those at high genetic risk. The current study examines functional imaging correlates of the BDNF val66met polymorphism in a population at high genetic risk of schizophrenia. Subjects at high genetic risk for the disorder ( n = 58) provided both BDNF genotyping and fMRI data while performing a verbal memory task. During encoding, participants were presented with a word and asked to make a ‘living’/‘non-living’ classification. During retrieval, individuals were requested to make an ‘old’/‘new’ word classification. For encoding, we report decreased activation of the inferior occipital cortex and a trend in the cingulate cortex in Val homozygote individuals relative to Met carriers. For retrieval, we report decreases in activation in the prefrontal, cingulate cortex and bilateral posterior parietal regions in Val homozygote individuals versus Met carriers. These findings add to previous evidence suggesting that genetic variation in the BDNF gene modulates prefrontal and limbic functioning and suggests that it may contribute to differences in brain function seen in those at high risk of the disorder.

Orbitofrontal morphology in people at high risk of developing schizophrenia

Background Abnormalities of orbitofrontal cortex (OFC) sulcogyral patterns have been reported in schizophrenia, but it is not known if these predate psychosis. Methods Hundred and forty-six subjects at high genetic risk of schizophrenia, 34 first episode of schizophrenia patients (SZ) and 36 healthy controls were scanned and clinically assessed. Utilising the classification system proposed by Chiavaras, we categorised OFC patterns and compared their distribution between the groups, as well as between those high risk subjects who did, and did not develop schizophrenia. The relationship between OFC pattern and schizotypy was explored in high risk subjects. Results We refined Chiavaras’ classification system, with the identification of a previously unreported variant of OFC surface structure. There were significant differences in distribution of OFC patterns between high risk subjects who did or did not develop schizophrenia as well as between the first episode of schizophrenia group and healthy controls. Within the high risk group, possession of OFC Type III was associated with higher ratings on the Structured Inventory for Schizotypy (SIS) psychotic factor. Conclusions Our results suggest that OFC Type III is associated with psychotic features before the development of schizophrenia. Characterisation of OFC morphology may have a role in the identification of those at greatest risk of developing schizophrenia.

The impact of substance use on brain structure in people at high risk of developing schizophrenia.

Ventricular enlargement and reduced prefrontal volume are consistent findings in schizophrenia. Both are present in first episode subjects and may be detectable before the onset of clinical disorder. Substance misuse is more common in people with schizophrenia and is associated with similar brain abnormalities. We employ a prospective cohort study with nested case control comparison design to investigate the association between substance misuse, brain abnormality, and subsequent schizophrenia. Substance misuse history, imaging data, and clinical information were collected on 147 subjects at high risk of schizophrenia and 36 controls. Regions exhibiting a significant relationship between level of use of alcohol, cannabis or tobacco, and structure volume were identified. Multivariate regression then elucidated the relationship between level of substance use and structure volumes while accounting for correlations between these variables and correcting for potential confounders. Finally, we established whether substance misuse was associated with later risk of schizophrenia. Increased ventricular volume was associated with alcohol and cannabis use in a dose-dependent manner. Alcohol consumption was associated with reduced frontal lobe volume. Multiple regression analyses found both alcohol and cannabis were significant predictors of these abnormalities when simultaneously entered into the statistical model. Alcohol and cannabis misuse were associated with an increased subsequent risk of schizophrenia. We provide prospective evidence that use of cannabis or alcohol by people at high genetic risk of schizophrenia is associated with brain abnormalities and later risk of psychosis. A family history of schizophrenia may render the brain particularly sensitive to the risk-modifying effects of these substances.

Relationship between clinical and neuropsychological characteristics in child and adolescent first degree relatives of subjects with schizophrenia

Studies have shown higher rates of psychopathology and cognitive difficulties among relatives of schizophrenia patients than among the general population. This study aimed to analyze the relationship between clinical and neuropsychological characteristics in children and adolescents at high genetic risk for schizophrenia. Participants were 26 children and adolescent first-degree relatives of subjects diagnosed with schizophrenia (high-risk [HR] group) and 20 controls whose parents and siblings did not meet DSM-IV criteria for any psychotic disorder. These two groups were matched by age, sex and socio-economic status and clinical and neuropsychological assessments were completed by all participants. Among HR children 42.3% were diagnosed with one or more DSM-IV axis I psychiatric disorders. The most common diagnoses were attention deficit/hyperactivity disorder (ADHD) (34.6%) and generalized anxiety disorder (3.8%) There were significant differences between HR children and controls with respect to prodromal symptoms, behavioral problems and premorbid adjustment, as well as on the majority of intelligence subscales, working memory and logical memory. When differences between HR with ADD (HR-ADD), HR without ADD (HR-NADD) and controls were analyzed, significantly higher scores on clinical scales of prodromal symptoms, behavioral problems and premorbid adjustment were found in HR-ADD than in HR-NADD or controls. There were no significant differences in cognitive domains between HR-ADD and HR-NADD, but there were between HR-ADD and controls and between HR-NADD and controls on the Verbal Comprehension Index, Perceptual Reasoning Index, Working Memory Index and GAI. Compared to controls, HR children showed more clinical symptoms and cognitive abnormalities. HR children with ADD had worse clinical symptoms than did HR without ADD, although there were no differences in terms of cognitive abnormalities. Both HR groups seem to have similar deficits in neuropsychological performance.

The volumetric differences of the fronto-temporal region in young offspring of schizophrenic patients

The aim of this study is to examine the volumetric differences of the fronto-temporal region in the offspring of schizophrenic patients in comparison to normal. Twenty-six offspring of chronic schizophrenic patients aged between 8 and 15 years and 23 control children were matched with respect to cranial MRI. Chronic schizophrenic patients were reevaluated with SCID-I to confirm their diagnosis. Parents of children in the control group completed SCL-90-R and were evaluated by clinical interview to exclude any psychotic disorder. The diagnoses of psychiatric disorders in all of the children were established by DSM-IV-based clinical interviews with children and parents. They underwent IQ evaluation by WISC-R and evaluated with cranial MRI. Hippocampus, thalamus, amygdala, corpus callosum, frontal, and temporal lobe volumes were measured and compared by using MANCOVA. After covarying whole brain volume, age and gender, statistically significant decrease in the measurements of corpus callosum and hippocampi, and a non-significant trend toward smaller temporal lobes were observed in the high-risk children. The structure of hippocampal formation and corpus callosum were impaired in the children of the schizophrenic patients which suggests a neurodevelopmental abnormality in subjects with genetic high risk for schizophrenia.

Cortical thickness in a cohort of individuals at high genetic risk of schizophrenia.

Cortical thickness in a cohort of individuals at high genetic risk of schizophrenia.

Proton magnetic resonance spectroscopy in subjects with high genetic risk of schizophrenia: Investigation of anterior cingulate, dorsolateral prefrontal cortex and thalamus

Objective Reduced N-acetylaspartate levels in regions of the frontal cortex, including the anterior cingulate cortex, dorsolateral prefrontal cortex, and thalamus, involved in the pathophysiology of schizophrenia suggest that brain metabolite abnormalities may be a marker of genetic vulnerability to schizophrenia. We used proton magnetic resonance spectroscopy (H-MRS) to acquire absolute concentrations of brain metabolites in subjects with a high genetic risk of schizophrenia to investigate the potential relationship between unexpressed genetic liability to schizophrenia and neuronal dysfunction. Method Included in the study were 22 subjects who had at least two relatives with schizophrenia (high genetic risk group) and 22 controls with no second-degree relatives with schizophrenia. Absolute concentrations of N-acetylaspartate, creatine, choline, glutamate/glutamine, and myo-inositol and the ratios of metabolites in the anterior cingulate cortex, left dorsolateral prefrontal cortex, and left thalamus were measured using H-MRS at 1.5 Tesla. Results Relative to the controls, the high genetic risk group showed significant differences in absolute metabolite levels in the spectra of the regions of the left thalamus, including significant decreases in N-acetylaspartate, creatine, and choline concentrations. Conclusions The study points to neuronal dysfunction, and in particular thalamic dysfunction, as a key region of the vulnerability marker of schizophrenia. Further studies should examine the nature of the thalamus more intensively to further our understanding of thalamic dysfunction as a vulnerability marker.

Language pathway abnormalities in schizophrenia: a review of fMRI and other imaging studies

Schizophrenia is a severe mental disorder with substantial genetic vulnerability. This review discusses recent neuroimaging studies reporting on impairment in brain functioning relevant to language processing in individuals with schizophrenia and those who are at a genetic risk for its development. Studies have shown that schizophrenia is associated with deficits in language function, as well as structural and functional abnormalities in brain regions that are involved with language perception and processing. Individuals who are at genetic high risk for schizophrenia also have structural and functional deficits in brain pathways for language processing. These studies consistently suggest that the normal pattern of left hemisphere dominance of language processing is significantly disturbed. This review suggests that future studies should examine the underlying mechanism for producing this disturbance in language processing and that prospective studies should be carried out that aim to follow individuals over time to determine whether these anomalies eventually lead to clinical symptoms of schizophrenia.

FMRI changes over time and reproducibility in unmedicated subjects at high genetic risk of schizophrenia

Functional brain abnormalities have been repeatedly demonstrated in schizophrenia but there is little data concerning their progression. For such studies to have credibility it is first important to establish the reproducibility of functional imaging techniques. The current study aimed to examine these factors in healthy controls and in unmedicated subjects at high genetic risk of the disorder: (i) to examine the reproducibility of task-related activation patterns, (ii) to determine if there were any progressive functional changes in high-risk subjects versus controls reflecting inheritance of the schizophrenic trait, and (iii) to examine changes over time in relation to fluctuating positive psychotic symptoms (i.e. state effects). Subjects were scanned performing the Hayling sentence completion test on two occasions 18 months apart. Changes in activation were examined in controls and high-risk subjects (n=16, n=63). Reproducibility was assessed for controls and high-risk subjects who remained asymptomatic at both time points (n=16, n=32). Intra-class correlation values indicated good agreement between scanning sessions. No significant differences over time were seen between the high-risk and control group; however, comparison of high-risk subjects who developed symptoms versus those who remained asymptomatic revealed activation increases in the left middle temporal gyrus (p=0.026). The current results suggest that functional changes over time occur in the lateral temporal cortex as high genetic risk subjects become symptomatic, further, they indicate the usefulness of functional imaging tools for investigating progressive changes associated with state and trait effects in schizophrenia.

A diffusion tensor MRI study of white matter integrity in subjects at high genetic risk of schizophrenia

Diffusion tensor imaging (DTI) has previously shown compromised white matter integrity in frontotemporal white matter fibers in patients with schizophrenia, as indicated by reduced fractional anisotropy (FA). In the present study we investigated whether reduced white matter FA is also present in relatives of individuals with schizophrenia who are at high risk (HR) for genetic reasons. Twenty-two HR subjects, 31 patients with schizophrenia and 51 control subjects underwent DTI. We compared FA between the three groups in the cingulum cingulate gyri, the uncinate and the arcuate fasciculi and the anterior limb of the internal capsules (ALIC). A voxel-based analysis showed lower FA in patients with schizophrenia compared to controls in left and right uncinate ( p < 0.03), the left arcuate ( p < 0.03) and left and right ALIC ( p < 0.01). Using an automatic region-of-interest analysis, less sensitive to potential misregistration errors, produced essentially the same results, as well as reduced FA of the ALIC in the HR group compared to controls ( p < 0.05). This study replicates previous findings showing lower FA in frontotemporal white matter fibers of schizophrenia patients. We also found reduced FA in the ALIC of both patients and subjects at high risk of schizophrenia when compared to controls. This may be a possible indicator of the higher vulnerability of relatives to develop the disorder.

A DTI study of white matter microstructure in individuals at high genetic risk for schizophrenia

Structural brain developmental anomalies, particularly those in frontotemporal white matter pathways, may have a genetic component and place people at increased risk for schizophrenia. The current study employed Diffusion Tensor Imaging (DTI) to measure fractional anisotropy (FA) as a quantitative indicator of white matter integrity. We examined twenty-two participants at high genetic risk for schizophrenia (HR), 23 people with schizophrenia (most of whom were family members of those at HR) and 37 non-psychiatric controls for comparison. In those at HR, reduced FA was observed in the cingulate and angular gyri bilaterally. In a few regions, FA was higher in HR participants than in comparison participants. These regional variations in FA might reflect differences in white matter development from comparison participants. Our data provide some evidence that abnormal white matter integrity may be detectable before the onset of a psychotic illness, although longitudinal studies are necessary to determine whether these individuals at genetic risk with abnormal FA will develop illness and whether these changes are associated with the genetic risk for the disorder.

Different psychological effects of cannabis use in adolescents at genetic high risk for schizophrenia and with attention deficit/hyperactivity disorder (ADHD)

Background Controversy exists regarding whether young people at risk for schizophrenia are at increased risk of adverse mental effects of cannabis use. Methods We examined cannabis use and mental health functioning in three groups of young people aged 14–21; 36 non-psychotic siblings of adolescents with schizophrenia (genetic high risk group), 25 adolescents with attention deficit hyperactivity disorder (ADHD) and 72 healthy controls. The groups were sub-divided into ‘users’ and ‘non-users’ of cannabis based on how often they had used cannabis previously. Mental health functioning was quantified by creating a composite index derived from scores on the Schizotypal Personality Questionnaire (SPQ), Strengths and Difficulties Questionnaire (SDQ) and Global Assessment of Function (GAF). Results A significant positive association between cannabis use and mental health disturbance was confined to young people at genetic high risk for schizophrenia. To determine whether the relationship was specific to particular dimensions of mental health function, a second composite index was created based on scores from the SPQ Disorganisation and SDQ hyperactivity-inattention sub-scales. Again, there was a significant positive association between cannabis use and factor scores which was specific to the genetic high risk group. There was a trend for this association to be negative in the ADHD group ( p = 0.07). Conclusions The findings support the view that young people at genetic high risk for schizophrenia are particularly vulnerable to mental health problems associated with cannabis use. Further research is needed to investigate the basis of relationships between cannabis and mental health in genetically vulnerable individuals.