Intermediate Phenotype For Schizophrenia Research Articles

The Risk for Schizophrenia-Bipolar Spectrum: Does the Apple Fall Close to the Tree? A Narrative Review.

Schizophrenia (SCZ) and bipolar disorder (BD) are severe psychiatric disorders that share clinical features and several risk genes. Important information about their genetic underpinnings arises from intermediate phenotypes (IPs), quantifiable biological traits that are more prevalent in unaffected relatives (RELs) of patients compared to the general population and co-segregate with the disorders. Within IPs, neuropsychological functions and neuroimaging measures have the potential to provide useful insight into the pathophysiology of SCZ and BD. In this context, the present narrative review provides a comprehensive overview of the available evidence on deficits in neuropsychological functions and neuroimaging alterations in unaffected relatives of SCZ (SCZ-RELs) and BD (BD-RELs). Overall, deficits in cognitive functions including intelligence, memory, attention, executive functions, and social cognition could be considered IPs for SCZ. Although the picture for cognitive alterations in BD-RELs is less defined, BD-RELs seem to present worse performances compared to controls in executive functioning, including adaptable thinking, planning, self-monitoring, self-control, and working memory. Among neuroimaging markers, SCZ-RELs appear to be characterized by structural and functional alterations in the cortico-striatal-thalamic network, while BD risk seems to be associated with abnormalities in the prefrontal, temporal, thalamic, and limbic regions. In conclusion, SCZ-RELs and BD-RELs present a pattern of cognitive and neuroimaging alterations that lie between patients and healthy individuals. Similar abnormalities in SCZ-RELs and BD-RELs may be the phenotypic expression of the shared genetic mechanisms underlying both disorders, while the specificities in neuropsychological and neuroimaging profiles may be associated with the differential symptom expression in the two disorders.

Olfactory identification ability among schizophrenia patients, their first-degree relatives and healthy subjects.

Olfactory impairments, including identification, have been reported in patients with schizophrenia, while few studies have examined the olfactory function of unaffected first-degree relatives of patients with schizophrenia, and the sample sizes of first-degree relatives were relatively small. Here, we investigated olfactory identification ability among patients with schizophrenia, first-degree relatives and healthy controls (HCs) using relatively large sample sizes at a single institute. To assess olfactory identification ability, the open essence odorant identification test was administered to 172 schizophrenia patients, 75 first-degree relatives and 158 healthy controls. Differences in olfactory identification and correlations between olfactory ability and clinical variables were examined among these participants. We found a significant difference in olfactory identification ability among the diagnostic groups (p = 7.65 × 10-16). Schizophrenia patients displayed lower olfactory identification ability than first-degree relatives (Cohen's d = -0.57, p = 3.13 × 10-6) and healthy controls (d = -1.00, p = 2.19 × 10-16). Furthermore, first-degree relatives had lower olfactory identification ability than healthy controls (d = -0.29, p = 0.039). Olfactory identification ability moderately and negatively correlated with the duration of illness (r = -0.41, p = 1.88 × 10-8) and negative symptoms (r = -0.28, p = 1.99 × 10-4) in schizophrenia patients, although the correlation with the duration of illness was affected by aging (r = -0.24). Our results demonstrated that schizophrenia patients have impaired olfactory identification ability compared with first-degree relatives and healthy controls, and the impaired olfactory identification ability of first-degree relatives was intermediate between those in schizophrenia patients and healthy controls. Olfactory identification ability was relatively independent of clinical variables. Therefore, olfactory identification ability might be an intermediate phenotype for schizophrenia.

Over-representation of potential SP4 target genes within schizophrenia-risk genes

Reduction of Sp4 expression causes age-dependent hippocampal vacuolization and many other intermediate phenotypes of schizophrenia in Sp4 hypomorphic mice. Recent human genetic studies from both the Schizophrenia Exome Sequencing Meta-Analysis (SCHEMA) and the Genome-Wide Association Study (GWAS) validated SP4 as a schizophrenia-risk gene over the exome-wide or the genome-wide significance. Truncation of the human SP4 gene has an odds ratio of 9.37 (3.38–29.7) for schizophrenia. Despite successful identification of many schizophrenia-risk genes, it is unknown whether and how these risk genes may interact with each other in the development of schizophrenia. By taking advantage of the specific localization of the GC-boxes bound by SP4 transcription factors, I analyzed the relative abundance of these GC-boxes in the proximal promoter regions of schizophrenia-risk genes. I found that the GC-box containing genes are significantly over-represented within schizophrenia-risk genes, suggesting that SP4 is not only a high-risk gene for schizophrenia, but may also act as a hub of network in the regulation of many other schizophrenia-risk genes via these GC-boxes in the pathogenesis of schizophrenia.

Psychometric liability to psychosis and childhood adversities are associated with shorter telomere length: A study on schizophrenia patients, unaffected siblings, and non-clinical controls

Compared to the general population, individuals diagnosed with Schizophrenia (SCZ) experience a higher frequency and an earlier onset of chronic medical disorders, resulting in a reduction in life expectancy by an average of 15–25 years. Recently, it has been hypothesized that SCZ is a syndrome of accelerated aging. Childhood adversity was also associated with the pathogenesis and course of SCZ. Our hypothesis was that both SCZ patients and their unaffected siblings would have shorter telomere length (TL) compared to of non-clinical controls. Our additional goals were to determine (1) whether shorter TL correlates with intermediate phenotypes of SCZ (i.e. Psychosis-like symptoms and schizotypal traits); and (2) whether childhood adversities have a moderating role in TL shortening among SCZ and their unaffected siblings. To this end, SCZ patients (n = 100), their unaffected siblings (n = 100) and non-clinical controls (n = 100) were enrolled. The main variables were TL, measured by aTL-qPCR; psychotic-like and schizotypal symptoms, assessed by The Community Assessment of Psychic Experience (CAPE) and the Structured Interview for Schizotypy-Revised (SIS-R), respectively; and childhood adversities evaluated by the Childhood Experience of Care and Abuse (CECA)-Interview. Potentially relevant variables also included in the analyses were: Global Assessment of Functioning (GAF) scores, cognitive performance, and socio-demographic features. In contrast to our hypothesis patients had similar TL when compared to the non-clinical controls. Interestingly, unaffected siblings had longer TL compared to both patients and controls (p < 0.001). Independent from group status a negative correlation was observed between TL and psychotic-like symptoms as rated by the CAPE (p < 0.01). Childhood adversities, especially loneliness between ages 0 and 11 were also negatively associated with TL (p < 0.05). Our findings suggest that psychometric liability to psychosis and childhood adversities may be associated with shorter TL. Unaffected siblings had longer TL, suggesting the potential role of resilience on both the TL and the clinical presentation. These findings must be considered preliminary, calling for larger-scale replication efforts.

Altered DLPFC-Hippocampus Connectivity During Working Memory: Independent Replication and Disorder Specificity of a Putative Genetic Risk Phenotype for Schizophrenia.

Altered connectivity of dorsolateral prefrontal cortex (DLPFC) and hippocampus during working memory is considered an intermediate phenotype for schizophrenia (SCZ), but the relevance for other mental disorders with shared genetic background remains unknown. Here we investigated its presence in unaffected first-degree relatives of patients with bipolar disorder (BD) or major depressive disorder (MDD). Furthermore, we aimed to provide an independent replication of this phenotype in first-degree relatives of SCZ patients. We acquired functional magnetic resonance imaging (fMRI) data from 309 healthy controls and 218 healthy first-degree relatives of index patients with SCZ (n = 62), BD (n = 66) and MDD (n = 90), who completed the n-back working memory paradigm. We observed a significant group effect on DLPFC-hippocampus coupling (PFWE = .031, all P-values region of interest [ROI] corrected). Post hoc comparisons revealed that this effect was driven by the SCZ relatives, who showed a significant increase in the negative functional connectivity of the DLPFC and right hippocampus compared to controls (PFWE = .001), BD relatives (PFWE = .015) and trend-wise also MDD relatives (PFWE = .082). Comparison of BD and MDD relatives to the controls revealed no difference (PFWE-values > .451). Supplementary analyses suggested that the SCZ relatives finding is robust to a range of potential confounds, including structural differences. Our data further support altered DLPFC-hippocampus connectivity during working memory as an intermediate phenotype for SCZ. This suggests that this phenotype is relatively specific to SCZ and does not translate to other genetically related disorders in the mood-psychosis spectrum.

Differences in social functioning among patients with major psychiatric disorders: Interpersonal communication is impaired in patients with schizophrenia and correlates with an increase in schizotypal traits

Impaired social functioning is a hallmark of major psychiatric disorders. The purpose of this study was to detect a disorder-specific factor of social dysfunction among patients with major psychiatric disorders (PSY), including schizophrenia (SCZ), bipolar disorder (BIP) and major depressive disorder (MDD). Social functioning was assessed in patients with SCZ (n=80), BIP (n=27) or MDD (n=29) and healthy controls (HC, n=68) using the Social Functioning Scale (SFS). Compared to HC, the SCZ, BIP and MDD patient groups showed lower total SFS scores. No differences in the total scores for social functioning were observed between patient groups. We next investigated seven subscales of the SFS among PSY and observed significant diagnostic effects on all subscales of the SFS. Notably, patients with SCZ have poorer interpersonal communication than patients with MDD. Furthermore, the poorer interpersonal communication score was significantly correlated with an increase in schizotypal personality traits, as assessed by the Schizotypal Personality Questionnaire (SPQ) in HC. Although there were no differences in overall social functioning among PSY, disorder-specific factors, such as interpersonal communication, were evident in SCZ. The correlation between poor interpersonal communication and the increase in schizotypal traits suggests that poor interpersonal communication may be an intermediate phenotype of SCZ.

Decreased white matter FA values in the left inferior frontal gyrus is a possible intermediate phenotype of schizophrenia: evidences from a novel group strategy.

Intermediate phenotype could be used to investigate genetic susceptibility. However, genetic and environmental heterogeneity may interfere with identification of intermediate phenotypes. In this study, we minimized these interferences by using a novel group strategy. A total of 22 drug-naive and first-episode schizophrenia (FES) patients, along with 22 of their kin healthy siblings (HS), 22 non-kin healthy siblings (nHS) of other schizophrenia patients and 22 healthy controls (HC), were recruited. Brain imaging was acquired from the participants. Voxel-based analysis was used to investigate differences in white matter integrity derived from diffusion tensor imaging among the four groups. Two cognitive tests related to our findings were selected to confirm the related phenotypic changes. All of the FES, HS, and nHS groups showed decreased fractional anisotropy (FA) values in the left inferior frontal gyrus (IFG) compared with the HC group (p<0.05, FDR corrected). The scores of Hopkins Verbal learning Test-Revised and Animal Naming in FES patients were significantly lower than in participants belonging to the other three groups (p<0.05). Significant correlation between Animal Naming scores and FA values in the left IFG was found in FES patients (r=0.53, p=0.01). Moreover, FES patients also showed decreased FA values in the left medial frontal gyrus, left inferior temporal gyrus, left parahippocampal gyrus, left posterior cingulate, and right middle temporal gyrus compared with HC (p<0.05, FDR corrected). Decreased FA values in the left IFG is a possible intermediate phenotype of schizophrenia, and this finding supports the hypothesis that disrupted connectivity of white matter may be the key substrate of schizophrenia.

Fast sleep spindle reduction in schizophrenia and healthy first-degree relatives: association with impaired cognitive function and potential intermediate phenotype.

Several studies in patients with schizophrenia reported a marked reduction in sleep spindle activity. To investigate whether the reduction may be linked to genetic risk of the illness, we analysed sleep spindle activity in healthy volunteers, patients with schizophrenia and first-degree relatives, who share an enriched set of schizophrenia susceptibility genes. We further investigated the correlation of spindle activity with cognitive function in first-degree relatives and whether spindle abnormalities affect both fast (12-15Hz) and slow (9-12Hz) sleep spindles. We investigated fast and slow sleep spindle activity during non-rapid eye movement sleep in a total of 47 subjects comprising 17 patients with schizophrenia, 13 healthy first-degree relatives and 17 healthy volunteers. Groups were balanced for age, gender, years of education and estimated verbal IQ. A subsample of relatives received additional testing for memory performance. Compared to healthy volunteers, fast spindle density was reduced in patients with schizophrenia and healthy first-degree relatives following a pattern consistent with an assumed genetic load for schizophrenia. The deficit in spindle density was specific to fast spindles and was associated with decreased memory performance. Our findings indicate familial occurrence of this phenotype and thus support the hypothesis that deficient spindle activity relates to genetic liability for schizophrenia. Furthermore, spindle reductions predict impaired cognitive function and are specific to fast spindles. This physiological marker should be further investigated as an intermediate phenotype of schizophrenia. It could also constitute a target for drug development, especially with regard to cognitive dysfunction.

Grey matter volume patterns in thalamic nuclei are associated with familial risk for schizophrenia

Previous evidence suggests reduced thalamic grey matter volume (GMV) in patients with schizophrenia (SCZ). However, it is not considered an intermediate phenotype for schizophrenia, possibly because previous studies did not assess the contribution of individual thalamic nuclei and employed univariate statistics. Here, we hypothesized that multivariate statistics would reveal an association of GMV in different thalamic nuclei with familial risk for schizophrenia. We also hypothesized that accounting for the heterogeneity of thalamic GMV in healthy controls would improve the detection of subjects at familial risk for the disorder.We acquired MRI scans for 96 clinically stable SCZ, 55 non-affected siblings of patients with schizophrenia (SIB), and 249 HC. The thalamus was parceled into seven regions of interest (ROIs). After a canonical univariate analysis, we used GMV estimates of thalamic ROIs, together with total thalamic GMV and premorbid intelligence, as features in Random Forests to classify HC, SIB, and SCZ. Then, we computed a Misclassification Index for each individual and tested the improvement in SIB detection after excluding a subsample of HC misclassified as patients.Random Forests discriminated SCZ from HC (accuracy=81%) and SIB from HC (accuracy=75%). Left anteromedial thalamic volumes were significantly associated with both multivariate classifications (p<0.05). Excluding HC misclassified as SCZ improved greatly HC vs. SIB classification (Cohen's d=1.39). These findings suggest that multivariate statistics identify a familial background associated with thalamic GMV reduction in SCZ. They also suggest the relevance of inter-individual variability of GMV patterns for the discrimination of individuals at familial risk for the disorder.

BDNF rs6265 methylation and genotype interact on risk for schizophrenia

Epigenetic mechanisms can mediate gene-environment interactions relevant for complex disorders. The BDNF gene is crucial for development and brain plasticity, is sensitive to environmental stressors, such as hypoxia, and harbors the functional SNP rs6265 (Val66Met), which creates or abolishes a CpG dinucleotide for DNA methylation. We found that methylation at the BDNF rs6265 Val allele in peripheral blood of healthy subjects is associated with hypoxia-related early life events (hOCs) and intermediate phenotypes for schizophrenia in a distinctive manner, depending on rs6265 genotype: in ValVal individuals increased methylation is associated with exposure to hOCs and impaired working memory (WM) accuracy, while the opposite is true for ValMet subjects. Also, rs6265 methylation and hOCs interact in modulating WM-related prefrontal activity, another intermediate phenotype for schizophrenia, with an analogous opposite direction in the 2 genotypes. Consistently, rs6265 methylation has a different association with schizophrenia risk in ValVals and ValMets. The relationships of methylation with BDNF levels and of genotype with BHLHB2 binding likely contribute to these opposite effects of methylation. We conclude that BDNF rs6265 methylation interacts with genotype to bridge early environmental exposures to adult phenotypes, relevant for schizophrenia. The study of epigenetic changes in regions containing genetic variation relevant for human diseases may have beneficial implications for the understanding of how genes are actually translated into phenotypes.

Contingent negative variation in patients with deficit schizophrenia or bipolar I disorder with psychotic features: Measurement and correlation with clinical characteristics

Background: Schizophrenia is a highly heterogeneous disease. Event-related potentials have been regarded to establish intermediate phenotypes of schizophrenia. Our previous study found that patients with deficit schizophrenia (DS) are relatively homogeneous and show a significantly longer onset latency of contingent negative variation (CNV) expectancy wave. Aims: To further examine CNV in patients with first-episode and drug-naïve DS or bipolar I disorder (BP I) with psychotic features, and also investigate correlations between CNV and clinical characteristics in DS and BP I. Method: We elicited a CNV using an alarm (S1)-imperative (S2) paradigm in 30 DS patients or 33 BP I with psychotic features as well as 40 healthy controls. Results: CNV amplitude was significantly smaller and reaction time significantly longer in the DS and BP I groups than in healthy controls. Post-imperative negative variation (PINV) interval was significantly shorter in the DS group than in healthy controls. The onset latency of CNV expectancy wave was significantly longer and PINV area significantly smaller in the DS group than in the other groups. In the DS group, CNV amplitude and PINV interval correlated negatively with the subscale of negative symptoms on the Positive and Negative Syndrome Scale (PANSS); CNV amplitude also correlated negatively with disease duration. In the BP I group, CNV amplitude and reaction time showed no correlation with clinical features. Conclusions: CNV amplitude is a common trait marker for psychosis. The onset latency of CNV expectancy wave appears to be a specific trait marker and may be used to identify candidate genes for DS.

P.3.a.008 Effect of AMBRA1 polymorphism on a newly identified emotion-related connectomic intermediate phenotype for schizophrenia

P.3.a.008 Effect of AMBRA1 polymorphism on a newly identified emotion-related connectomic intermediate phenotype for schizophrenia

MB-COMT promoter DNA methylation is associated with working-memory processing in schizophrenia patients and healthy controls

Many genetic studies report mixed results both for the associations between COMT polymorphisms and schizophrenia and for the effects of COMT variants on common intermediate phenotypes of the disorder. Reasons for this may include small genetic effect sizes and the modulation of environmental influences. To improve our understanding of the role of COMT in the disease etiology, we investigated the effect of DNA methylation in the MB-COMT promoter on neural activity in the dorsolateral prefrontal cortex during working memory processing as measured by fMRI - an intermediate phenotype for schizophrenia. Imaging and epigenetic data were measured in 102 healthy controls and 82 schizophrenia patients of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia. Neural activity during the Sternberg Item Recognition Paradigm was acquired with either a 3T Siemens Trio or 1.5T Siemens Sonata and analyzed using the FMRIB Software Library (FSL). DNA methylation measurements were derived from cryo-conserved blood samples. We found a positive association between MB-COMT promoter methylation and neural activity in the left dorsolateral prefrontal cortex in a model using a region-of-interest approach and could confirm this finding in a whole-brain model. This effect was independent of disease status. Analyzing the effect of MB-COMT promoter DNA methylation on a neuroimaging phenotype can provide further evidence for the importance of COMT and epigenetic risk mechanisms in schizophrenia. The latter may represent trans-regulatory or environmental risk factors that can be measured using brain-based intermediate phenotypes.

Impaired Cerebellar-Dependent Eyeblink Conditioning in First-Degree Relatives of Individuals With Schizophrenia

Consistent with reports of cerebellar structural, functional, and neurochemical anomalies in schizophrenia, robust cerebellar-dependent delay eyeblink conditioning (dEBC) deficits have been observed in the disorder. Impaired dEBC is also present in schizotypal personality disorder, an intermediate phenotype of schizophrenia. The present work sought to determine whether dEBC deficits exist in nonpsychotic first-degree relatives of individuals with schizophrenia. A single-cue tone dEBC paradigm consisting of 10 blocks with 10 trials each (9 paired and 1 unpaired trials) was used to examine the functional integrity of cerebellar circuitry in schizophrenia participants, individuals with a first-degree relative diagnosed with schizophrenia, and healthy controls with no first-degree relatives diagnosed with schizophrenia. The conditioned stimulus (a 400ms tone) coterminated with the unconditioned stimulus (a 50ms air puff to the left eye) on paired trials. One relative and 2 healthy controls were removed from further analysis due to declining conditioned response rates, leaving 18 schizophrenia participants, 17 first-degree relatives, and 16 healthy controls. Electromyographic data were subsequently analyzed using growth curve models in hierarchical linear regression. Acquisition of dEBC conditioned responses was significantly impaired in schizophrenia and first-degree relative groups compared with controls. This finding that cerebellar-mediated associative learning deficits are present in first-degree relatives of individuals with schizophrenia provides evidence that dEBC abnormalities in schizophrenia may not be due to medication or course of illness effects. Instead, the present results are consistent with models of schizophrenia positing cerebellar-cortical circuit abnormalities and suggest that cerebellar abnormalities represent a risk marker for the disorder.

Genetic variation in GAD1 is associated with cortical thickness in the parahippocampal gyrus

Patients with schizophrenia show widespread cortical thickness reductions throughout the brain. Likewise, reduced expression of the γ-Aminobutyric acid (GABA) synthesizing enzyme glutamic acid decarboxylase (GAD1) and a single nucleotide polymorphism (SNP) rs3749034 in the corresponding gene have been associated with schizophrenia. We tested whether this SNP is associated with reduced cortical thickness, an intermediate phenotype for schizophrenia. Because of the well known interactions between the GABAergic and dopaminergic systems, we examined whether associations between GAD1 rs3749034 and cortical thickness are modulated by the catechol-O-methyltransferase (COMT) Val158Met genotype. Structural MRI and genotype data was obtained from 94 healthy subjects enrolled in the Mind Clinical Imaging Consortium study to examine the relations between GAD1 genotype and cortical thickness. Our data show a robust reduction of cortical thickness in the left parahippocampal gyrus (PHG) in G allele homozygotes of GAD1 rs3749034. When we stratified our analyses according to the COMT Val158Met genotype, cortical thickness reductions of G allele homozygotes were only found in the presence of the Val allele. Genetic risk variants of schizophrenia in the GABAergic system might interact with the dopaminergic system and impact brain structure and functioning. Our findings point to the importance of the GABAergic system in the pathogenesis of schizophrenia.

Psychopathology: genetics and the stress-vulnerability hypothesis

Since the findings of dopamine blockade by antipsychotics, a dysfunction of the dopamine system has been proposed to underly psychopathological symptoms in schizophrenia. In SPECT and PET imaging studies, radioligand binding to the dopamine receptor or transporter reflects the occupancy by dopamine itself or antipsychotics. Using dual-isotope imaging for the evaluation of pre- and postsynaptic site, Schmitt et al. [1] examined striatal dopamine transporter and dopamine D2 receptor availability in first-episode schizophrenia patients and patients with haloperidol treatment compared to healthy controls. In drug-naive patients with positive symptoms, dopamine transporter availability correlated negatively with psychopathology as did D2 receptor binding with disorganization and hallucinatory behavior, thus strengthening the dopamine hypothesis for positive symptoms. D2 receptor and dopamine transporter availability was lower in the haloperidol group which confirms previous dopamine blockade studies. However, response to antipsychotics is individual, and genetic factors may contribute to a different outcome. Mossner et al. [2] reported that patients homozygous for the risk allele ZNF804A show poorer improvement of positive symptoms compared to patients with a protective allele. Thus, identification of risk genes may help identifying patients with a different course of the disorder. A pharmacogenetic study of Crisafulli et al. [3] investigated 10 SNPs of genes related to pathophysiological pathways in Korean patients. They found a SNP within 5HTR1A associated with clinical improvement in both positive and negative symptoms. In schizophrenia patients, improvement of quality of life as treatment outcome among others is dependent on support in case of problems and assistance in coping with daily life demands. Landolt et al. [4] revealed that unmet needs changing to fulfilled ones enhanced quality of life. In this context, psychosocial functioning and psychotic symptoms may be influenced by alterations of theory of mind and empathy as underlying social-cognitive deficits and possibly are heritable. In first-degree relatives of schizophrenia patients, Montag et al. [5] showed impairment in cognitive skills, suggesting that social-cognitive abilities may serve as an intermediate phenotype for schizophrenia. In a re-analysis of AMDP data by nonmetric multidimensional scaling, Lage et al. [6] replicated clusters of psychopathological symptoms in two independent samples dating from 1980 and 2003. In individual’s health, the psychological well-being dimension and depressive symptoms are important variables and Morelatto de Souza and Paz Loayza Hidalgo [7] validated the WHO well-being index in a Brazilian population and showed this scale to be a useful tool for screening of depressive symptoms. Hagihara and Abe [8] highlight the influence of media reports on suicide and counteracting effects of stopping the sale of suicide-related products in Japan. Beside genetics, stressful experience and trauma are risk factors for the development of psychiatric diseases. Linden et al. [9] analyzed 100 case files of German servicemen during World War I and classified them in agreement with modern diagnoses. Most ancient diagnoses were “psychopathic constitution” or “hysteria.” Using contemporary diagnostics, some of these soldiers had symptoms of post-traumatic stress disorder. There was a high incidence of pseudoseizures that highlights different human responses to traumatic experience and stress in a historical context. Stressful experiences are known to increase vulnerability to schizophrenia. Rossi et al. [10] evaluated the Community Assessment of Psychic Experiences (CAPE) in students who survived an earthquake 2009 in Italy. Unexpectedly, earth quake survivors showed lower CAPE scores than nonexposed subjects. This is in line with the hypothesis that stressful events preceding psychosis are not derived from external traumatic experiences. In a previous study, Puustinen et al. [11] reported C-reactive protein, marker of cardiovascular disease, to be associated with psychological distress. However, in a cross-sectional and 3-year follow-up study in Japanese male workers, Kawada [12] failed to show this relationship, which is probably due to ethnicity. Life experience, stressful events and other environmental factors are known to influence the risk of developing mental diseases. The missing link between environment and neurobiology may be explained by epigenetic mechanisms, such as DNA methylation and acetylation in disease-related brain regions. Wiers [13] refers to an fMRI study of the COMT gene with the Val allele being associated with DNA methylation [14]. She proposes the use of genetic imaging in combination with investigations of epigenetic markers in blood cells to unravel gene-environmental interactions in severe psychiatric disorders.

AS21-01 - Alterations of the early auditory evoked gamma-band response in patients with schizophrenia

There is growing evidence of abnormalities of high-frequency oscillations in the gamma range of the electroencephalography in schizophrenia. The generation of neural activity in the gammaband was shown to be critically related to a glutamatergic and GABAergic microcircuit which is also known to be involved in the pathophysiology of schizophrenia. One example of such gamma oscillations is the early auditory evoked gamma band response (aeGBR). We aimed to investigate whether there are altered aeGBR and activity of its sources in the anterior cingulate cortex and/or the auditory cortex (identified as sources of the GBR previously) in schizophrenic patients and in first-degree relatives of schizophrenia patients. We investigated the early aeGBR and its sources (LORETA source localisation) in 90 medicated patients with schizophrenia and in 17 unaffected first-degree relatives of patients with schizophrenia using an auditory reaction task (comparison with age-, gender- and educational-level-matched control groups). Evoked power and phase locking of the aeGBR was reduced in schizophrenia patients and healthy first-degree relatives of patients with schizophrenia. This effect was due to a reduced activity in the auditory cortex and the anterior cingulate cortex. The findings are in line with the hypothesis of a disturbed GABAergic interneural modulation of pyramidal cells in schizophrenia and findings of different schizophrenia risk genes associated with transmission at glutamatergic and GABAergic synapses. The results regarding the first-degree relatives of patients with schizophrenia point to the applicability of this marker as a heritable intermediate phenotype for schizophrenia.

Subtle deficits of cognitive theory of mind in unaffected first-degree relatives of schizophrenia patients

Alterations of theory of mind (ToM) and empathy were implicated in the formation of psychotic experiences, and deficits in psychosocial functioning of schizophrenia patients. Inspired by concepts of neurocognitive endophenotypes, the existence of a distinct, potentially neurobiologically based social-cognitive vulnerability marker for schizophrenia is a matter of ongoing debate. The fact that previous research on social-cognitive deficits in individuals at risk yielded contradictory results may partly be due to an insufficient differentiation between qualitative aspects of ToM. Thirty-four unaffected first-degree relatives of schizophrenia patients (21 parents, 8 siblings, 5 children; f/m: 30/4; mean age: 48.1 ± 12.7 years) and 34 controls subjects (f/m: 25/9; mean age: 45.9 ± 10.9 years) completed the 'Movie for the Assessment of Social Cognition'-a video-based ToM test-and an empathy questionnaire (Interpersonal Reactivity Index, IRI). Outcome parameters comprised (1) 'cognitive' versus 'emotional' ToM, (2) error counts representing 'undermentalizing' versus 'overmentalizing', (3) empathic abilities and (4) non-social neurocognition. MANCOVA showed impairments in cognitive but not emotional ToM in the relatives' group, when age, gender and neurocognition were controlled for. Relatives showed elevated error counts for 'undermentalizing' but not for 'overmentalizing'. No alterations were detected in self-rated dimensions of empathy. Of all measures of ToM and empathy, only the IRI subscale 'fantasy' was associated with measures of psychotic risk, i.e. a history of subclinical delusional ideation. The present study confirmed subtle deficits in cognitive, but not emotional ToM in first-degree relatives of schizophrenia patients, which were not explained by global cognitive deficits. Findings corroborate the assumption of distinct social-cognitive abilities as an intermediate phenotype for schizophrenia.

SMARCA2 and other genome-wide supported schizophrenia-associated genes: regulation by REST/NRSF, network organization and primate-specific evolution

The SMARCA2 gene, which encodes BRM in the SWI/SNF chromatin-remodeling complex, was recently identified as being associated with schizophrenia (SZ) in a genome-wide approach. Polymorphisms in SMARCA2, associated with the disease, produce changes in the expression of the gene and/or in the encoded amino acid sequence. We show here that an SWI/SNF-centered network including the Smarca2 gene is modified by the down-regulation of REST/NRSF in a mouse neuronal cell line. REST/NRSF down-regulation also modifies the levels of Smarce1, Smarcd3 and SWI/SNF interactors (Hdac1, RcoR1 and Mecp2). Smarca2 down-regulation generates an abnormal dendritic spine morphology that is an intermediate phenotype of SZ. We further found that 8 (CSF2RA, HIST1H2BJ, NOTCH4, NRGN, SHOX, SMARCA2, TCF4 and ZNF804A) out of 10 genome-wide supported SZ-associated genes are part of an interacting network (including SMARCA2), 5 members of which encode transcription regulators. The expression of 3 (TCF4, SMARCA2 and CSF2RA) of the 10 genome-wide supported SZ-associated genes is modified when the REST/NRSF-SWI/SNF chromatin-remodeling complex is experimentally manipulated in mouse cell lines and in transgenic mouse models. The REST/NRSF-SWI/SNF deregulation also results in the differential expression of genes that are clustered in chromosomes suggesting the induction of genome-wide epigenetic changes. Finally, we found that SMARCA2 interactors and the genome-wide supported SZ-associated genes are considerably enriched in genes displaying positive selection in primates and in the human lineage which suggests the occurrence of novel protein interactions in primates. Altogether, these data identify the SWI/SNF chromatin-remodeling complex as a key component of the genetic architecture of SZ.

SPECIFIC PROGRAM FOR INTERVENTION IN INCIPIENT PSYCHOSIS INTRODUCED IN CATALONIA(SPAIN)

Background: Elevated presynaptic striatal dopamine is thought to be a final common effect of multiple specific aetiologies, which in turn gives risk to psychosis through the disruption of incentive salience. In contrast to psychosis, negative symptoms are thought to emerge from the disruption of multiple neurophysiological systems (Howes & Kapur, 2009, Schizophr. Bull., 35, 549-62). We tested this model by examining the relationship of an ecologically valid measure of reward learning with anhedonia and intermediate phenotypes of schizophrenia, while controlling for neuropsychological impairment. Methods: Undergraduates (n=84) completed the stimulus chase task (SCT), which provided a measure of sensitivity to reward, selfreport measures of hedonic capacity, and self-report (Schizotypal Personality Questionnaire [SPQ]) and performance (psychobabble task) measures of intermediate phenotypes of schizophrenia. Motor reaction time, attention, and frontal functions were assessed with a small battery of neuropsychological tests. Results: After controlling for neuropsychological functioning, higher cognitive-perceptual SPQ scores predicted poorer performance on the SCT (r=-0.27, p<0.01). Higher interpersonal SPQ scores also predicted poorer SCT performance (r=-0.26, p<0.01). However, anhedonia and disorganization features were not associated with SCT scores. Discussion: The theoretical link between salience, or the efficacy of reward learning, and psychosis is evident at the level of the intermediate phenotypes of schizophrenia reported by ostensibly healthy individuals. However, an equally strong association of salience with intermediate phenotypes of negative symptoms complicates this picture. The observed associations are not attributable to neuropsychological impairment or anhedonia.