Insights for disease modeling from single-cell transcriptomics of iPSC-derived Ngn2-induced neurons and astrocytes across differentiation time and co-culture.

BACKGROUND: Trans-differentiation of human-induced pluripotent stem cells into neurons via Ngn2-induction (hiPSC-N) has become an efficient system to quickly generate neurons a likely significant advance for disease modeling and in vitro assay development. Recent single-cell interrogation of Ngn2-induced neurons, however, has revealed some similarities to unexpected neuronal lineages. Similarly, a straightforward method to generate hiPSC-derived astrocytes (hiPSC-A) for the study of neuropsychiatric disorders has also been described. RESULTS: Here, we examine the homogeneity and similarity of hiPSC-N and hiPSC-A to their in vivo counterparts, the impact of different lengths of time post Ngn2 induction on hiPSC-N (15 or 21 days), and the impact of hiPSC-N/hiPSC-A co-culture. Leveraging the wealth of existing public single-cell RNA-seq (scRNA-seq) data in Ngn2-induced neurons and in vivo data from the developing brain, we provide perspectives on the lineage origins and maturation of hiPSC-N and hiPSC-A. While induction protocols in different labs produce consistent cell type profiles, both hiPSC-N and hiPSC-A show significant heterogeneity and similarity to multiple in vivo cell fates, and both more precisely approximate their in vivo counterparts when co-cultured. Gene expression data from the hiPSC-N show enrichment of genes linked to schizophrenia (SZ) and autism spectrum disorders (ASD) as has been previously shown for neural stem cells and neurons. These overrepresentations of disease genes are strongest in our system at early times (day 15) in Ngn2-induction/maturation of neurons, when we also observe the greatest similarity to early in vivo excitatory neurons. We have assembled this new scRNA-seq data along with the public data explored here as an integrated biologist-friendly web-resource for researchers seeking to understand this system more deeply: https://nemoanalytics.org/p?l=DasEtAlNGN2&g=NES . CONCLUSIONS: While overall we support the use of the investigated cellular models for the study of neuropsychiatric disease, we also identify important limitations. We hope that this work will contribute to understanding and optimizing cellular modeling for complex brain disorders.

Shared variance of oculomotor phenotypes in a large sample of healthy young men.

This study used canonical correlation analysis to investigate patterns of shared variance between parameters measured in seven different occulomotor function tasks, namely the visually guided saccade task, the antisaccade task, the closed-loop smooth-pursuit task, the open-loop smooth-pursuit task, and three active visual fixation tasks. These tasks were performed by 2130 young army recruits. Only a small percentage (1-10%) of shared variance existed between sets of parameters for all oculomotor function tasks measured. The most correlated tasks were the visually guided saccade and the antisaccade. The first common factor correlated with speed of performance between these tasks (latency), while the second and third correlated with accuracy of performance. Better performance in active visual fixation tasks correlated with better performance accuracy (lower error rate) and increased speed (lower latency) in the antisaccade and saccade tasks as well as better performance in the closed-loop smooth-pursuit task (increase in gain and decrease in the rate of unwanted saccades during pursuit). Better performance in the closed-loop smooth-pursuit task (increased gain and decreased number of unwanted saccades) also correlated with increased accuracy and increased speed of performing saccades and antisaccades. Finally, the open-loop fixation task had no correlation with all other oculomotor tasks except for a very weak negative correlation with the closed-loop pursuit task where better performance (increased gain) in one correlated with worse performance (decreased gain) in the other. The results of this analysis showed that a small percentage of variance is shared among different oculomotor function tasks. The structure of this shared variance could be used to derive common oculomotor function indices to study their relation to genetic and other sources of inter-subject variation.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

This corrects the article DOI: 10.1038/mp.2016.244.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10-8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.

The DPYSL2 gene connects mTOR and schizophrenia.

We previously reported a schizophrenia-associated polymorphic CT di-nucleotide repeat (DNR) at the 5'-untranslated repeat (UTR) of DPYSL2, which responds to mammalian target of Rapamycin (mTOR) signaling with allelic differences in reporter assays. Now using microarray analysis, we show that the DNR alleles interact differentially with specific proteins, including the mTOR-related protein HuD/ELAVL4. We confirm the differential binding to HuD and other known mTOR effectors by electrophoretic mobility shift assays. We edit HEK293 cells by CRISPR/Cas9 to carry the schizophrenia risk variant (13DNR) and observe a significant reduction of the corresponding CRMP2 isoform. These edited cells confirm the response to mTOR inhibitors and show a twofold shortening of the cellular projections. Transcriptome analysis of these modified cells by RNA-seq shows changes in 12.7% of expressed transcripts at a false discovery rate of 0.05. These transcripts are enriched in immunity-related genes, overlap significantly with those modified by the schizophrenia-associated gene, ZNF804A, and have a reverse expression signature from that seen with antipsychotic drugs. Our results support the functional importance of the DPYSL2 DNR and a role for mTOR signaling in schizophrenia.

High-throughput sequencing of the synaptome in major depressive disorder.

Major depressive disorder (MDD) is among the leading causes of worldwide disability. Despite its significant heritability, large-scale genome-wide association studies (GWASs) of MDD have yet to identify robustly associated common variants. Although increased sample sizes are being amassed for the next wave of GWAS, few studies have as yet focused on rare genetic variants in the study of MDD. We sequenced the exons of 1742 synaptic genes previously identified by proteomic experiments. PLINK/SEQ was used to perform single variant, gene burden and gene set analyses. The GeneMANIA interaction database was used to identify protein-protein interaction-based networks. Cases were selected from a familial collection of early-onset, recurrent depression and were compared with screened controls. After extensive quality control, we analyzed 259 cases with familial, early-onset MDD and 334 controls. The distribution of association test statistics for the single variant and gene burden analyses were consistent with the null hypothesis. However, analysis of prioritized gene sets showed a significant association with damaging singleton variants in a Cav2-adaptor gene set (odds ratio=2.6; P=0.0008) that survived correction for all gene sets and annotation categories tested (empirical P=0.049). In addition, we also found statistically significant evidence for an enrichment of rare variants in a protein-based network of 14 genes involved in actin polymerization and dendritic spine formation (nominal P=0.0031). In conclusion, we have identified a statistically significant gene set and gene network of rare variants that are over-represented in MDD, providing initial evidence that calcium signaling and dendrite regulation may be involved in the etiology of depression.

Genetic determinants of neuroglobin transcription.

Neuroglobin (NGB) is a neuron-specific vertebrate globin shown to protect against hypoxia, ischemia, oxidative stress and the toxic effects of Amyloid-beta. Following on our and others' results highlighting the importance of NGB expression in disease, we searched for genetic determinants of its expression. We found that a microRNA expressed with the NGB transcript shows significant target enrichments in the angiogenesis pathway and the Alzheimer disease/presenilin pathway. Using reporter constructs we identified potential promoter/enhancer elements between the transcription start site and 1,142 bp upstream. Using 184 post-mortem temporal lobe samples we replicated the reported negative effect of age, and after genotyping tagging SNPs we found one (rs981471) showing a significant correlation with the gene's expression and another (rs8014408) showing an interaction with age, the rare C allele being correlated with higher expression and faster decline. The two SNPs are towards the 3' end of NGB within the same LD block, 52 Kb apart and modestly correlated (r (2) = 0.5). Next generation sequencing of the same 184 temporal lobe samples and 79 confirmed AD patients across the entire gene region (including >12 Kb on the 3' and 5' flank) revealed limited coding variation, suggesting purifying selection of NGB, but did not identify regulatory or disease associated rare variants. A dinucleotide repeat in intron 1 with extensive evidence of functionality showed interesting but inconclusive results, as it was not amenable to further molecular analysis.

Multiple variants aggregate in the neuregulin signaling pathway in a subset of schizophrenia patients.

Despite the strongly held view that schizophrenia (SZ) shows substantial genetic heterogeneity, pathway heterogeneity, as seen in cancer where different pathways are affected in similar tumors, has not been explored. We explore this possibility in a case-only study of the neuregulin signaling pathway (NSP), which has been prominently implicated in SZ and for which there is detailed knowledge on the ligand- and receptor-processing steps through ß- and γ-secretase cleavage. We hypothesize that more than one damaging variants in the NSP genes might be necessary to cause disease, leading to an apparent clustering of such variants in only the few patients with affected NSP. We analyze linkage and next-generation sequencing results for the genes encoding components of the pathway, including NRG1, NRG3, ERBB4, ß-secretase and the γ-secretase complex. We find multiple independent examples of supporting evidence for this hypothesis: (i) increased linkage scores over NSP genes, (ii) multiple positive interlocus correlations of linkage scores across families suggesting each family is linked to either many or none of the genes, (iii) aggregation of predicted damaging variants in a subset of individuals and (iv) significant phenotypic differences of the subset of patients carrying such variants. Collectively, our data strongly support the hypothesis that the NSP is affected by multiple damaging variants in a subset of phenotypically distinct patients. On the basis of this, we propose a general model of pathway heterogeneity in SZ, which, in part, may explain its phenotypic variability and genetic complexity.

Schizophrenia-related RGS4 gene variations specifically disrupt prefrontal control of saccadic eye movements.

BACKGROUND: The gene encoding the regulator of G-protein signaling subtype 4 (RGS4), located on chromosome 1q23-3, has been proposed as a possible susceptibility gene for schizophrenia and has been specifically linked to prefrontal cortical structural and functional integrity. METHOD: The effects of four core single nucleotide polymorphisms (SNPs) within the RGS4 gene on oculomotor parameters in a battery of oculomotor tasks (saccade, antisaccade, smooth eye pursuit, fixation) were investigated in a sample of 2243 young male military conscripts. RESULTS: The risk allele of RGS4SNP18 was found to be associated with two variables of antisaccade performance, increased error rate and variation in the correct antisaccade latency. By contrast, the same allele and also the risk allele of RGS4SNP4 led to an improvement in smooth eye pursuit performance (increased gain). Structural equation modeling confirmed that the combined gene variation of RGS4SNP4 and RGS4SNP18 was a significant predictor of antisaccade but not smooth eye pursuit performance. CONCLUSIONS: These results provide evidence for a specific effect of schizophrenia-related RGS4 genotype variations to prefrontal dysfunction measured by oculomotor indices of performance in normal individuals, further validating the hypothesis that RGS4 is related to prefrontal dysfunction in schizophrenia.

Alzheimer's risk variants in the clusterin gene are associated with alternative splicing.

Genetic variation in CLU encoding clusterin has been associated with Alzheimer's disease (AD) through replicated genome-wide studies, but the underlying mechanisms remain unknown. Following earlier reports that tightly regulated CLU alternative transcripts have different functions, we tested CLU single nucleotide polymorphisms (SNPs) including those associated with AD for quantitative effects on individual alternative transcripts. In 190 temporal lobe samples without pathology we found that the risk allele of the AD associated SNP rs9331888 increases the relative abundance of transcript NM_203339 (P=4.3×10(-12)). Using an independent set of 115 AD and control samples, we replicated this result (p=0.0014) and further observed that multiple CLU transcripts are at higher levels in AD compared to controls. The AD SNP rs9331888 is located in the first exon of NM_203339 and therefore, it is a functional candidate for the observed effects. We tested this hypothesis by in vitro dual luciferase assays using SK-N-SH cells and mouse primary cortical neurons and found allelic effects on enhancer function, consistent with our results on post-mortem human brain. These results suggest a biological mechanism for the genetic association of CLU with AD risk and indicate that rs9331888 is one of the functional DNA variants underlying this association.

Serotonin transporter gene variants and prediction of stress-induced risk for psychological distress.

The response to psychosocial stress is influenced by both psychosocial factors and genetic vulnerability. The most investigated gene in gene × environment studies in abnormal response to environmental stressors is the one coding for the serotonin transporter (SLC6A4). Variability within this gene has been associated with functional brain differences, personality dimensions, reactivity to stress and risk for various psychopathological conditions. In the present study, we set out to investigate the association of common genetic variants within SLC6A4 with state psychopathology in a community sample homogeneously exposed to stress, thus inquiring about potential genetic differences in stress sensitivity. One thousand eight hundred seventy-five young conscripts were evaluated for psychopathological distress with the 90-item Symptoms Checklist Revised in their first 2 weeks of admission to obligatory military service. Of these, 1594 were genotyped for the biallelic ins/del polymorphism (5-HTTLPR S/L) within the promoter region of SLC6A4, as well as the variation within the 'long' 5-HTTLPR allele (rs25531A/G). Homozygous for the 5-HTTLPR S allele reported significantly higher scores for paranoid ideation as compared with L-allele carriers. Slight effects on other subscales were observed, but were not significant after correction for multiple testing. Despite limitations linked to the evaluation of psychopathology by a single general scale and multiple comparisons, the present study support a role of SLC6A4 in modulating abnormal responses to environmental stress. In particular, variation within this gene may confer risk for paranoid/defensive reactions under conditions of environmental stress associated with military induction.

beta2-Adrenergic receptor gene variants and risk for autism in the AGRE cohort.

The beta2-adrenergic receptor is part of the catecholamine system, and variants at two polymorphic sites in the gene coding for the receptor (ADRB2) confer increased activity. Overstimulation of this receptor may alter brain development, and has been linked to autism in non-identical twins. The objective of this study was to determine whether alleles in ADRB2 are associated with diagnosis of autism in the Autism Genetic Resource Exchange (AGRE) population. Three hundred and thirty-one independent autism case-parent trios were included in the analysis. Subjects were genotyped at activity-related polymorphisms rs1042713 (codon 16) and rs1042714 (codon 27). Association between autism and genotypes at each polymorphic site was tested using genotype-based transmission disequilibrium tests, and effect modification by family and pregnancy characteristics was evaluated. Sensitivity to designation of the proband in each family was assessed by performing 1000 repeats of the analysis selecting affected children randomly. A statistically significant OR of 1.66 for the Glu27 homozygous genotype was observed. Increased associations with this genotype were observed among a subset of Autism Diagnostic Observation Schedule confirmed cases and a subset reporting experience of pregnancy-related stressors. In conclusion, the Glu27 allele of the ADRB2 gene may confer increased risk of autism and shows increased strength with exposure to pregnancy related stress.

Is the excess risk of psychosis-like experiences in urban areas attributable to altered cognitive development?

BACKGROUND: Rates of psychotic disorder and related attenuated psychotic experiences are higher in urban areas. We examined to what degree differences between urban and rural areas could be attributed to differences in cognitive development. METHOD: Scores on the nine subscales of the schizotypal personality questionnaire (SPQ) as well as IQ and specific neuropsychological functions of memory and attention were assessed in a representative sample of 943 young army conscripts from the 49 counties of Greece. RESULTS: Young men from urban areas had higher scores on the SPQ subscale Odd beliefs/magical thinking (OR = 1.99, 95% CI: 1.42, 2.78), but lower scores on Excessive social anxiety (OR = 0.63, 95 % CI: 0.49, 0.81) and No close friends (OR = 0.42, 95% CI: 0.29, 0.62). Adjustment for demographic factors, IQ and specific neuropsychological functions did not change the results. When the lower scores on Excessive social anxiety and No close friends were taken into account, the differences on the Odd beliefs/magical thinking subscale became even more pronounced (OR = 2.33, 95% CI: 1.56, 3.49). CONCLUSIONS: Young men from urban areas are socially more competent, but display higher levels of positive psychotic experiences, which are not mediated by lower IQ or higher levels of neuropsychological impairment.

Linkage of bipolar affective disorder on chromosome 8q24: follow-up and parametric analysis.

Our group first reported a linkage finding for bipolar (BP) disorder on chromosome 8q24 in a study of 50 multiplex pedigrees, with an HLOD score reaching 2.39. Recently, Cichon et al reported an LOD score of 3.62 in the same region using two-point parametric analysis. Subsequently, we published the results of a genome scan for linkage to BP disorder using a sample extended to 65 pedigrees in which chromosome 8q24 provided the best finding, an NPL score of 3.13, approaching the accepted score for suggestive linkage. We have now fine mapped this region of chromosome 8 in our 65 pedigrees by the addition of 19 microsatellite markers reaching a marker density of 0.8 cM and an information content of 0.84. After the addition of the new data, the original NPL score slightly increased to 3.25. Two-point parametric analysis using the model employed by Cichon et al obtained an LOD score of 3.32 for marker D8S256 at theta=0.14 exceeding the proposed threshold for genomewide significance. After adjusting the parameters in accordance with the 'common disease-common variant' hypothesis, multipoint parametric analysis resulted in an HLOD of 2.49 (alpha=0.78) between D8S529 and D8S256, and defined a 1-LOD interval corresponding to a 2.3 Mb region. No allelic association with the disease was observed for our set of microsatellite markers. Biologically, plausible candidate genes in this region include thyroglobulin, KCNQ3 coding for a voltage-gated potassium channel and the gene for brain adenyl-cyclase (ADCY8).

Active eye fixation performance in 940 young men: effects of IQ, schizotypy, anxiety and depression.

A total of 940 young men performed a task in which they actively maintained fixation for 50 s in three conditions: a). on a visual target, b). on a visual target while distracting targets appeared briefly on the periphery and c). with no visual target present. The same individuals completed psychometric evaluation tests measuring IQ, schizotypy and current state-dependent psychopathology. The proportion of fixation time decreased and saccade frequency increased in condition b compared wih condition a, and sequentially in condition c compared with condition b. A trend towards a decrease in proportion of fixation time and increase in saccade frequency was found as the subjects maintained fixation during the task and this time-dependent deterioration of performance was again most pronounced in condition c, less so in condition b and absent in condition a. Psychometric test scores were significantly correlated with fixation performance in the population. Worse performance in all three fixation conditions was observed for individuals with lower IQ scores. A deterioration of fixation performance with time in condition b was correlated with disorganization characteristics of schizotypy, suggesting that these individuals had difficulty maintaining active fixation in the presence of increased inhibitory load. A connection of such a difficulty with the frontal lobes and their role in the control of voluntary inhibitory functions is discussed.

Effects of direction on saccadic performance in relation to lateral preferences.

A sample of 676 healthy young males performed visually guided saccades and antisaccades and completed the Porac-Coren questionnaire measuring lateral preferences. There was no difference in mean latency between rightward versus leftward saccades or for saccades executed in the left versus right hemispace. There was also no right/left asymmetry for individuals with left or right dominance as assessed by the lateral preferences questionnaire. The same results were observed for the latency of antisaccades and for the error rate in the antisaccade task. Finally, we did not confirm any substantial subpopulation of individuals with idiosyncratic left/right latency asymmetries that persisted both in the saccade and antisaccade task. These results suggest that neither latency nor antisaccade error rate are good indicators of lateral preferences in these tasks. Other oculomotor tasks might be more sensitive to hemifield differences, or cerebral hemispheric asymmetry is not present at the level of cortical organization of saccades and antisaccades.

The antisaccade task in a sample of 2,006 young men. I. Normal population characteristics.

A population of 2,075 young men aged 18-25 years selected from the conscripts of the Greek Air Force performed an antisaccade task as part of a prospective study for the identification of risk factors in the development of psychoses. The aim of this study, which is ongoing, is to follow this population and investigate the possible predictive value of oculomotor, cognitive, and psychometric factors for the development of psychosis and other psychiatric conditions. In this report we present data concerning the antisaccade task in this population. We measured performance indices, including the percentage of errors (PE), the latencies of different eye movement responses (latency for correct antisaccades, errors, corrections), and performance in perseveration-prone trials. These indices were also evaluated with respect to IQ (measured by the Raven progressive matrices test) and educational level. Mean PE was 23%, with 17% variance. This large variance is of particular importance whenever the detection of a putative deviant behavior is explored. As mean latency of the first eye movement decreased, the PE increased, as did the latency variance. While the negative correlation between percentage of error and mean latency is well established, the relationship of the latency variability of the first response to error production has not been studied before. Thus, optimal performance appears to require both an intermediate mean latency and a small variability. Furthermore, performance seems to be affected by IQ (the higher the IQ score, the lower the percentage of errors). This report offers an analysis of the interindividual variation in the performance of the antisaccade task and discusses some of the sources of this variation.

The antisaccade task in a sample of 2,006 young males. II. Effects of task parameters.

Antisaccade performance was investigated in a sample of 2,006 young males as part of a large epidemiological study investigating psychosis proneness. This report summarizes the effects of task parameters on performance using a sample of 55,678 antisaccade trials collected from a subpopulation of 947 individuals. Neither the amplitude nor the latency of an error prosaccade in the antisaccade task was correlated with the latency of the ensuing corrective antisaccade that almost always followed an error. However, the latency of the corrective antisaccade decreased with increasing stimulus distance. Concerning the effects of specific task parameters, trials with stimuli closer to the central fixation point and trials preceded by shorter fixation intervals resulted in more errors and longer latencies for the antisaccades. Finally, there were learning and fatigue effects reflected mainly in the error rate, which was greater at the beginning and at the end of the 5-min task. We used a model to predict whether an error or a correct antisaccade would follow a particular trial. All task parameters were significant predictors of the trial outcome but their power was negligible. However, when modeled alone, response latency of the first movement predicted 40% of errors. In particular, the smaller this latency was, the higher the probability of an error. These findings are discussed in light of current hypotheses on antisaccade production mechanisms involving mainly the superior colliculus.

Higher scores of self reported schizotypy in healthy young males carrying the COMT high activity allele.

The gene for COMT is located on chromosome 22q11, an area that has been implicated in the pathogenesis of schizophrenia through linkage studies and through the detection of deletions in schizophrenics and velocardiofacial syndrome patients that often present psychotic symptomatology. Additionally catechol-O-methyl transferase activity has been found increased in schizophrenia and a functional polymorphism in the COMT gene itself has been associated with the disease, as well as with aggression in patients. We tested the hypothesis that COMT genotype for the functional Val158Met might contribute to the variance of self reported schizotypy and aggression scores in the normal population. We genotyped 379 healthy 18- to 24-year-old male individuals who had completed the PAS, SPQ and AQ questionnaires. Our results showed that self-reported schizotypy scores in both questionnaires were significantly related to COMT genotype (P = 0.028 for the PAS and P = 0.015 for the SPQ) with individuals homozygous for the high activity allele showing the highest scores. No significant differences were detected for AQ scores. We conclude that the COMT genotype for the functional Val158Met polymorphism is correlated to self-reported schizotypy in healthy males. This finding is in the same direction as reported findings on schizophrenia and it adds to the list of evidence that COMT or a nearby gene in linkage disequilibrium is involved in the pathogenesis of the disease.

Evidence that three dimensions of psychosis have a distribution in the general population.

BACKGROUND: The aims of the study were: first to examine, using clinical symptoms of patients as a template, whether the correlated but independent dimensions of positive, negative and depressive symptoms that have been identified in clinical psychosis, also have a distribution as non-clinical experiences in the general population; and second, to establish to what degree population variation in experience of positive and negative features of psychosis is actually independent of experience of depression. METHOD: In a representative population sample of 932 young men, we measured experiences of positive, negative and depressive features of psychosis, using a 40-item self-report instrument. Confirmatory factor analysis was used to compare the fit of hypothesized one-, two- and three-factor solutions. RESULTS: A three-factor model of separate depressive, positive and negative dimensions provided a better fit to the data than either a two-factor or unidimensional model. All three dimensions were correlated with each other, but also showed good discriminant validity in relation to established scales, confirming their relative independence. CONCLUSION: The data suggest that the correlated dimensions of clinical psychosis also have a distribution in the general population, and that depressive symptoms may form an integral part of psychosis-like experiences in the general population.