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The major histocompatibility complex (MHC) is one of the most intensively investigated, genetically diverse regions of the genome. In its extended form, it encodes more than 400 genes critical to immunity but is also involved in many other functions. In 2009, three simultaneously published genome-wide association studies (GWAS) reported the first compelling evidence for involvement of the MHC in schizophrenia susceptibility. In this review, we describe the structure and function of the MHC, discuss some of the challenges for genetic analysis of the region, and provide an update on findings from GWAS studies before describing potential approaches to interpreting the role of the locus in schizophrenia etiology. The GWAS literature supports involvement of the MHC locus in schizophrenia susceptibility. Current evidence suggests that the MHC plays a more significant role in schizophrenia susceptibility than in other psychiatric disorders. Because of the substantial diversity at the locus, there are differences in the implicated risk variants between ancestral groups, as there are for many other disorders. This is somewhat different than the pattern emerging at other loci. The association findings presently capture large genomic regions, with at least some evidence to suggest that multiple signals may be involved. Based on notable successes in other disorders, we suggest approaches to refining association signals at the locus. Finally, we discuss that these genetic data may be used to understand how the MHC contributes to the complex etiology of schizophrenia. [Copyright &y& Elsevier]

Abstract: Insulin-like growth factor-1 (IGF1) and its active peptide (1–3)IGF1 modulate brain growth and plasticity and are candidate molecules for treatment of brain disorders. IGF1 N-terminal portion is naturally cleaved to generate the tri-peptide (1–3)IGF1 (glycine–praline–glutamate). IGF1 and (1–3)IGF have been proposed as treatment for neuropathologies, yet their effect on nerve cells has not been directly compared. In this study we examine the effects of IGF1 and (1–3)IGF1 in primary cortical cultures and measure the expression levels of markers for intracellular pathways and synaptic function. We find that both treatments activate the IGF1 receptor and enhance the expression of synaptic markers, however, they activate different intracellular pathways. Furthermore, (1–3)IGF1 administration increases the expression of endogenous IGF1, suggesting a direct interaction between the two molecules. The results show that the two molecules increase the expression of synaptic proteins through activating different cellular mechanisms. [Copyright &y& Elsevier]

Copy-number variation (CNV) is the most prevalent type of structural variation in the human genome. There is emerging evidence that copy-number variants (CNVs) provide a new vista on understanding susceptibility to neuropsychiatric disorders. Some challenges in the interpretation of current CNV studies include the use of overlapping samples, differing phenotypic definitions, an absence of population norms for CNVs and a lack of consensus in methods for CNV detection and analysis. Here, we review current CNV association study methods and results in autism spectrum disorders (ASD) and schizophrenia, and provide suggestions for design approaches to future studies that might maximize the translation of this work to etiological understanding. [Copyright &y& Elsevier]

Abstract: Delineating relationships between susceptibility genes and clinical symptoms may be an important step in understanding the genetics of psychosis. Recent data suggests that the gene dysbindin (DTNBP1) may confer susceptibility across psychotic disorders and may particularly be associated with negative symptoms, i.e. affective flattening, alogia and avolition. We have previously published evidence of association with a dysbindin risk haplotype derived from alleles C-A-T at SNPs P1655 (rs2619539), P1635 (rs3213207) and SNP66961 (rs2619538) in two independent schizophrenia (SZ) case-control samples. The C-A-T haplotype impacts at the level of gene function and phenotype: the haplotype indexes lower cortical expression of the dysbindin gene in post-mortem SZ brain samples and haplotype carriers show greater deficits in spatial working memory and early visual processing than non-carrier SZ patients. The aim of this study was to establish if the C-A-T dysbindin risk haplotype is associated with a specific clinical symptom profile. We investigated the relationship between the haplotype and PANSS-derived symptom factors in 262 individuals with schizophrenia/schizoaffective disorder using principal components analysis (PCA) and analysis of variance (ANOVA). Dysbindin risk carriers scored significantly less than non-carriers on the ‘hostility/excitability’ factor (F 1,196 =8.468; p =.004), with a trend for higher negative symptom scores. This suggests that risk variation at the dysbindin gene may contribute to a more prototypical SZ presentation with less severe excitement/manic symptoms and more negative symptoms. [Copyright &y& Elsevier]

Abstract: A series of genetic studies have identified the d-amino acid oxidase (DAO) gene as potentially contributing to schizophrenia susceptibility. An interacting gene, d-amino acid oxidase activator (DAOA) has also been implicated and it has been suggested that variation at these genes may influence the efficiency of glutamate gating at N-methyl-d-aspartate-type (NMDA) receptors. However, recent data suggests that DAOA may influence susceptibility to mood episodes across the spectrum of psychotic disorders rather than contributing to a specific psychosis phenotype. The aim of this study was to determine whether risk variation at DAO is similarly associated with affective or other clinical symptoms in psychosis. We have previously reported association between risk variation at DAO and schizophrenia in an Irish case–control sample. In this study we investigated the relationship between a defined genetic risk variant at DAO and PANSS-derived clinical symptom factors in a sample of 249 patients using principal component and Kruskal–Wallis analyses. Carriers of the DAO risk variant scored significantly higher on the ‘depression/anxiety’ factor than non-carriers (H =9.02, d.f.=2, p =0.01). These data suggest a potential role for DAO in susceptibility to depressive symptoms in schizophrenia, but a more general role for DAO in affective disorders cannot be excluded. [Copyright &y& Elsevier]

Introduction . Although deficits in executive functioning in schizophrenia have been consistently reported, their precise relationship to symptomatology remains unclear. Recent approaches to executive functioning in nonschizophrenia studies have aimed to “fractionate” the individual cognitive processes involved. In this study, we hypothesised that if these processes are fractionable, then particular symptom syndromes may be selectively related to executive deficits. In particular, it was hoped that this approach could clarify whether negative and positive symptoms of schizophrenia are differentially related to particular aspects of executive/attentional functions. Methods . A total of 32 patients with schizophrenia and 16 matched controls were assessed on a series of tasks designed to tap the theoretically derived executive functions of Inhibition, Shifting set, Working memory, and Sustained attention. Results . Negative symptoms were significantly predicted by performance on an “Inhibition” task (Stroop), and not by performance on any other task. Furthermore, for a subgroup of patients with predominantly negative symptoms variance in positive symptoms was only significantly predicted by performance on a set-shifting task (Visual Elevator), and not by performance on other tasks, including inhibition. Conclusions . Our results support the contention that negative symptoms can, at least partly, be conceived of as cognitive behaviours expressing specific executive deficits. Specifically, we discuss the possibility that negative symptoms may, in part, express a failure in response monitoring. We further suggest that the disordered metacognition resulting in positive symptoms may be mediated by cognitive flexibility in patients with a predominantly negative symptom profile. [ABSTRACT FROM AUTHOR]

Myocyte Enhancer Factor 2C (MEF2C) is a transcription factor that plays a crucial role in neurogenesis and synapse development. Genetic studies have identified MEF2C as a gene that influences cognition and risk for neuropsychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia (SCZ). Here, we investigated the involvement of MEF2C in these phenotypes using human-derived neural stem cells (NSCs) and glutamatergic induced neurons (iNs), which represented early and late neurodevelopmental stages. For these cellular models, MEF2C function had previously been disrupted, either by direct or indirect mutation, and gene expression assayed using RNA-seq. We integrated these RNA-seq data with MEF2C ChIP-seq data to identify dysregulated direct target genes of MEF2C in the NSCs and iNs models. Several MEF2C direct target gene-sets were enriched for SNP-based heritability for intelligence, educational attainment and SCZ, as well as being enriched for genes containing rare de novo mutations reported in ASD and/or developmental disorders. These gene-sets are enriched in both excitatory and inhibitory neurons in the prenatal and adult brain and are involved in a wide range of biological processes including neuron generation, differentiation and development, as well as mitochondrial function and energy production. We observed a trans expression quantitative trait locus (eQTL) effect of a single SNP at MEF2C (rs6893807, which is associated with IQ) on the expression of a target gene, BNIP3L. BNIP3L is a prioritized risk gene from the largest genome-wide association study of SCZ and has a function in mitophagy in mitochondria. Overall, our analysis reveals that either direct or indirect disruption of MEF2C dysregulates sets of genes that contain multiple alleles associated with SCZ risk and cognitive function and implicates neuron development and mitochondrial function in the etiology of these phenotypes. Author summary: Schizophrenia is a complex disorder caused by many genes. Current drugs for schizophrenia are only partially effective and do not treat cognitive deficits, which are key factors for explaining disability, leading to unemployment, homelessness and social isolation. Large-scale genetic studies of schizophrenia and cognitive function have been effective at identifying individual SNPs and genes that contribute to these phenotypes but have struggled to immediately uncover the bigger picture of the underlying biology of the disorder. Here we take an individual gene associated with schizophrenia and cognitive function called MEF2C, which on its own is a very important regulator of brain development. We use functional genomics data from studies where MEF2C has been mutated to identify sets of other genes that are influenced by MEF2C in developing and mature neurons. We show that several of these gene-sets are enriched for common variants associated with schizophrenia and cognitive function, and for rare variants that increase risk of various neurodevelopmental disorders. These gene-sets are involved in neuron development and mitochondrial function, providing evidence that these biological processes may be important in the context of the molecular mechanisms that underpin schizophrenia and cognitive function. [ABSTRACT FROM AUTHOR]

Next-generation sequencing studies are dependent on a high-quality reference genome for single nucleotide variant (SNV) calling. Although the two most recent builds of the human genome are widely used, position information is typically not directly comparable between them. Re-alignment gives the most accurate position information, but this procedure is often computationally expensive, and therefore, tools such as liftOver and CrossMap are used to convert data from one build to another. However, the positions of converted SNVs do not always match SNVs derived from aligned data, and in some instances, SNVs are known to change chromosome when converted. This is a significant problem when compiling sequencing resources or comparing results across studies. Here, we describe a novel algorithm to identify positions that are unstable when converting between human genome reference builds. These positions are detected independent of the conversion tools and are determined by the chain files, which provide a mapping of contiguous positions from one build to another. We also provide the list of unstable positions for converting between the two most commonly used builds GRCh37 and GRCh38. Pre-excluding SNVs at these positions, prior to conversion, results in SNVs that are stable to conversion. This simple procedure gives the same final list of stable SNVs as applying the algorithm and subsequently removing variants at unstable positions. This work highlights the care that must be taken when converting SNVs between genome builds and provides a simple method for ensuring higher confidence converted data. Unstable positions and algorithm code, available at https://github.com/cathaloruaidh/genomeBuildConversion [ABSTRACT FROM AUTHOR]

Highlights from the article: Multiplex schizophrenia pedigrees, often with multiple affected members in the same generation, thus represent the extreme of recurrence risk for schizophrenia. B Methods: b The whole genomes of 1367 members of 270 multiplex pedigrees, 2400 singleton cases and 2000 controls from Ireland are being sequenced to 30X average depth using Illumina X10 technology. This project will produce the largest whole genome sequence dataset for schizophrenia currently available.

• Increased inflammatory response is associated with childhood trauma and cognitive impairments. • Latent variable of inflammation mediates the association between physical neglect, inflammatory response and cognition. • Genetic risk for schizophrenia moderates the direct pathway between physical neglect and cognition. Recent studies have reported a negative association between exposure to childhood trauma, including physical neglect, and cognitive functioning in patients with schizophrenia. Childhood trauma has been found to influence immune functioning, which may contribute to the risk of schizophrenia and cognitive symptoms of the disorder. In this study, we aimed to test the hypothesis that physical neglect is associated with cognitive ability, and that this association is mediated by a combined latent measure of inflammatory response, and moderated by higher genetic risk for schizophrenia. The study included 279 Irish participants, comprising 102 patients and 177 healthy participants. Structural equation modelling was used to perform mediation and moderation analyses. Inflammatory response was measured via basal plasma levels of IL-6, TNF-α, and CRP, and cognitive performance was assessed across three domains: full-scale IQ, logical memory, and the emotion recognition task. Genetic variation for schizophrenia was estimated using a genome-wide polygenic score based on genome-wide association study summary statistics. The results showed that inflammatory response mediated the association between physical neglect and all measures of cognitive functioning, and explained considerably more variance than any of the inflammatory markers alone. Furthermore, genetic risk for schizophrenia was observed to moderate the direct pathway between physical neglect and measures of non-social cognitive functioning in both patient and healthy participants. However, genetic risk did not moderate the mediated pathway associated with inflammatory response. Therefore, we conclude that the mediating role of inflammatory response and the moderating role of higher genetic risk may independently influence the association between adverse early life experiences and cognitive function in patients and healthy participants. [ABSTRACT FROM AUTHOR]

We describe a large scale effort to systematically and comprehensively evaluated a large collection of densely affected pedigrees using WGS and rigorous statistical frameworks. Direct selection influences the genetic architectures so that common variants have very small effects (GRR<1.2). Rare mutations are a sizable reservoir of actionable genetic variation that could be missed by SNP arrays. De novo mutations can have large effects on ASD and SCZ (GRR 5-20). Although it is impossible for such alleles to become common, they can segregate for a few generations leading to densely affected pedigrees. Many such variants are pleiotropic and may be missed in pedigree studies of traditional “narrow” phenotype definitions. We have identified multiple large, unusually dense pedigrees with existing phenotypes and DNA from PGC and external groups including genetic isolates, and ID and epilepsy pedigrees with extensive psychiatric comorbidity. Karyotyping will be done on 2 affecteds to identify structural variants and all affecteds will have an Illumina SNP array to identify segregating known or novel CNVs. We will select the most densely/multiply affected pedigrees (normal karyotype, no segregating CNVs) with an apparently Mendelian pattern of inheritance (≥5 affecteds). We will derive GRS using the SNP array. From GRS, we will estimate the probability that the observed pattern of inheritance results from a polygenic model. We will prioritize pedigrees for WGS based on how unlikely the pedigree density is, given the GRS. For eg. if a pedigree mean GRS is at the population mean (lifetime risk ~1%), observing 5 of 10 affected is notable (P=2x10-8). Variants will be prioritized and incorporate frequency data from ExAC, and co-segregation with phenotype. Deleterious variation will be annotated. Any putative causal mutation requires: (a) statistically compelling co-segregation in the pedigree, (b) genetic replication in external studies (independent pedigrees, see below, or in case-control samples), and (c) supported by functional evidence. We will rank regions with LOD >1 and identify rare variants shared by cases within these regions. These will be cross-referenced with all sequenced pedigrees, exome variation databases, sequencing consortia, and with brain gene expression data. Even if high penetrance alleles exist, too few families would be linked to a locus to generate a clear signal across all pedigrees. We propose two approaches to this challenge. First, we will combine families with positive LOD scores in a region and then determine if the LOD score for each is attributable to rare variants in the same gene. If LOD scores reflect chance, they will not be underpinned by rare variants in same gene in different pedigrees. Second, WGS allows a genotype-first approach to linkage across families. For each gene, we consider only families where one affected carries a rare “prioritized” variant, eliminating all pedigrees without such a variant in any member from the composite linkage score of that gene. No single design will identify complete architecture for all disorders. If we show that the most densely affected pedigrees do not have rare variants of strong effect but rather result from some combination of GRS, environment, and/or chance, this would be a profoundly important finding for psychiatry and clinical genetics. [ABSTRACT FROM AUTHOR]

It is not only unclear why hallucinations in schizophrenia occur with different prevalence by modality, but also to what extent they do. Reliable prevalence estimates of hallucinations by modality in schizophrenia are currently lacking, particularly for non-auditory hallucinations. Studies have also tended to report lifetime, not point prevalence by modality. This study assessed the prevalence and co-occurrence of hallucinations, for both lifetime and point prevalence, across the auditory, visual, olfactory, and tactile modalities, in people diagnosed with chronic schizophrenia-spectrum disorders in Ireland (N=693) and Australia (N=218). Lifetime prevalence was 64–80% auditory, 23–31% visual, 9–19% tactile, and 6–10% olfactory. Past month prevalence was 23–27% auditory, 5–8% visual, 4–7% tactile, and 2% olfactory. The majority of participants had only hallucinated in one modality, with this nearly always being the auditory. Approximately one-third had hallucinated in two modalities, most commonly the auditory and visual. Most currently hallucinating patients also hallucinated in a single modality, again, nearly always the auditory. Whereas 30–37% of patients with lifetime auditory hallucinations had experienced visual hallucinations, 83–97% of patients with experience of visual hallucinations had experienced auditory hallucinations. These findings help delineate the modality distribution of hallucinations in schizophrenia, and provide an explanatory target for theoretical models. [ABSTRACT FROM AUTHOR]

Objective: Schizophrenia is a complex functionally debilitating neurodevelopmental disorder, with associated social cognitive impairment. Corpus Callosum (CC) white matter tracts deficits are reported for people with schizophrenia; however, few studies focus on interhemispheric processing relative to social cognition tasks. This study aimed to determine if a relationship between the CC and social cognition exists. Method: In this cross-section study, a sample of n = 178 typical controls and n = 58 people with schizophrenia completed measures of mentalising (Reading the Mind in the Eyes), emotion recognition outcome and reaction time (Emotion Recognition Test), and clinical symptoms (Positive and Negative Symptom Scale), alongside diffusion-based tract imaging. The CC and its subregions, i.e., the genu, body, and splenium were the regions of interest (ROI). Results: Reduced white matter tract integrity was observed in the CC for patients when compared to controls. Patients performed slower, and less accurately on emotion recognition tasks, which significantly and negatively correlated to the structural integrity of the CC genu. Tract integrity further significantly and negatively related to clinical symptomatology. Conclusions: People with schizophrenia have altered white matter integrity in the genu of the CC, compared to controls, which relates to cognitive deficits associated with recognising emotional stimuli accurately and quickly, and severity of clinical symptoms. [ABSTRACT FROM AUTHOR]

Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. Across disorders, genome-wide significant single nucleotide polymorphism–by-sex interaction was detected for a locus encompassing NKAIN 2 (rs117780815, p = 3.2 × 10−8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10−6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10−7; rs73033497, p = 8.8 × 10−7; rs7914279, p = 6.4 × 10−7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10−7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10−7) in a locus containing IDO2 , a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p <.05). In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels. [ABSTRACT FROM AUTHOR]

Exposure to childhood trauma (CT) is associated with cognitive impairment in schizophrenia, and deficits in social cognition in particular. Here, we sought to test whether IL-6 mediated the association between CT and social cognition both directly, and sequentially via altered default mode network (DMN) connectivity. Three-hundred-and-eleven participants (104 patients and 207 healthy participants) were included, with MRI data acquired in a subset of n = 147. CT was measured using the childhood trauma questionnaire (CTQ). IL-6 was measured in both plasma and in toll like receptor (TLR) stimulated whole blood. The CANTAB emotion recognition task (ERT) was administered to assess social cognition, and cortical connectivity was assessed based on resting DMN connectivity. Higher IL-6 levels, measured both in plasma and in toll-like receptor (TLR-2) stimulated blood, were significantly correlated with higher CTQ scores and lower cognitive and social cognitive function. Plasma IL-6 was further observed to partly mediate the association between higher CT scores and lower emotion recognition performance (CTQ total: β indirect −0.0234, 95% CI: −0.0573 to −0.0074; CTQ physical neglect: β indirect = −0.0316, 95% CI: −0.0741 to −0.0049). Finally, sequential mediation was observed between plasma IL-6 levels and DMN connectivity in mediating the effects of higher CTQ on lower social cognitive function (β indirect = −0.0618, 95% CI: −0.1523 to −0.285). This work suggests that previous associations between CT and social cognition may be partly mediated via an increased inflammatory response. IL-6′s association with changes in DMN activity further suggest at least one cortical network via which CT related effects on cognition may be transmitted. [ABSTRACT FROM AUTHOR]

Cognitive impairment in schizophrenia is a major contributor to poor outcomes, yet its causes are poorly understood. Some rare copy number variants (CNVs) are associated with schizophrenia risk and affect cognition in healthy populations, but their contribution to cognitive impairment in schizophrenia has not been investigated. We examined the effect of 12 schizophrenia CNVs on cognition in those with schizophrenia. General cognitive ability was measured using the Measurement and Treatment Research to Improve Cognition in Schizophrenia composite z score in 875 patients with schizophrenia and in a replication sample of 519 patients with schizophrenia using Wechsler Adult Intelligence Scale Full Scale IQ. Using linear regression, we tested for association between cognition and schizophrenia CNV status, covarying for age and sex. In addition, we tested whether CNVs hitting genes in schizophrenia-enriched gene sets (loss-of-function intolerant and synaptic gene sets) were associated with cognitive impairment. A total of 23 schizophrenia CNV carriers were identified. Schizophrenia CNV carriers had lower general cognitive ability than nonschizophrenia CNV carriers in discovery (β = −0.66, 95% confidence interval [CI] = −1.31 to −0.01) and replication samples (β = −0.91, 95% CI = −1.71 to −0.11) and after meta-analysis (β = −0.76, 95% CI = −1.26 to −0.25, p =.003). CNVs hitting loss-of-function intolerant genes were associated with lower cognition (β = −0.15, 95% CI = −0.29 to −0.001, p =.048). In those with schizophrenia, cognitive ability in schizophrenia CNV carriers is 0.5–1.0 standard deviations below non-CNV carriers, which may have implications for clinical assessment and management. We also demonstrate that rare CNVs hitting genes intolerant to loss-of-function variation lead to more severe cognitive impairment, above and beyond the effect of known schizophrenia CNVs. [ABSTRACT FROM AUTHOR]

Highlights from the article: F125a molecular analysis of sdccag8, a schizophrenia risk gene that is required for efficient primary ciliogenesis Using online databases of centrosome proteins and genome-wide association study (GWAS) data for schizophrenia, we identified six schizophrenia risk genes encode proteins with centrosomal functions. The set of baseline DEGs were enriched for genes associated with cognitive ability (p=0.03) and the set of serum starved DEGs were enriched for genes associated with schizophrenia (p=0.05).

Schizophrenia affects 1% of adults and is a major global health problem. Although aetiology is complex, genetics represents a vital tool for probing the neurobiology of the disorder in the absence of biomarkers. We undertook an interdisciplinary project investigating the role of centrosome genes in schizophrenia. The centrosome, an organelle within cells, plays a crucial role in brain development where it directs cell shape, polarity and motility. The centrosome also seeds the growth of antenna-like signalling structures called primary cilia. Rare mutations in centrosome genes cause disorders that present with severe cognitive deficits and variable neuropsychiatric phenotypes. We mined online databases to generate a list of genes encoding proteins with centrosome function. These were cross-referenced with schizophrenia risk genes identified in the 2014 PGC GWAS. Neurocognitive analysis: prioritised candidate genes were taken forward to analysis in a sample of Irish psychosis patients and controls (n=1,200). Participants were grouped by genotype at genome-wide significant SNPs and linear regression was used to test if genotype at schizophrenia risk SNPs was significantly associated with different domains of cognitive function. Molecular analysis: CRISPR-Cas9 genome editing technology was used to generate SDCCAG8 knockout cell lines in hTERT-RPE1 epithelial cells and in SH-SY5Y cells, a neuronal cell line. After serum starvation, cilia and centrosome markers were used to perform ciliation counts by immunofluorescence. Centrosome amplification was induced by exposing cells to 5 Gy ionising radiation and the number of centrosomes was counted after 72 hours by immunofluorescence. We identified 7 schizophrenia risk genes that have centrosomal functions: SDCCAG8, NEK4, MPHOSPH9, MAD1L1, PRKD1, MAPK3 and GIGYF2. Neurocognitive analysis of schizophrenia risk SNPs within these seven genes identified nominally significant associations with at least one domain of cognition for 5 of these 7 genes. Most of the significant associations were identified for social cognition, with the effect of SDCCAG8 on this domain being the most significant finding (p=0.001). SDCCAG8 is also associated with educational attainment and the genome-wide significant SNPs for the two phenotypes are in high linkage disequilibrium indicating a pleiotropic effect. We successfully generated SDCCAG8 knockout in RPE1 cells and in SH-SY5Y cells. Preliminary data shows that SDCCAG8 knockout clones, while viable in a p53 wildtype background, have slower proliferation rates. The capacity of the clones to ciliate is also reduced, by 50% in RPE1 clones and 75% in SH-SY5Y clones. In response to DNA damage there was an increase in centrosome amplification in RPE1 knockout clones when compared to wildtype cells. SDCCAG8 is a schizophrenia risk gene that we find is also associated with social cognition and educational attainment. Our data suggest that loss of SDCCAG8 impairs cells' ability to make primary cilia and that their capacity to repair genome damage may be reduced. Further work will address whether SDCCAG8 affects activities that may contribute to schizophrenia, including cell migration and cell signalling. This could identify molecular mechanisms by which SDCCAG8 mutations contribute to schizophrenia risk and cognition, and help uncover the biological processes that implicate centrosome genes in various neurodevelopmental phenotypes. [ABSTRACT FROM AUTHOR]

Genes encoding glycosyltransferases can be under relatively high selection pressure, likely due to the involvement of the glycans synthesized in host-microbe interactions. Here, we used mice as an experimental model system to investigate whether loss of α−1,3-galactosyltransferase gene (GGTA1) function and Galα1-3Galβ1-4GlcNAcβ1-R (αGal) glycan expression affects host-microbiota interactions, as might have occurred during primate evolution. We found that Ggta1 deletion shaped the composition of the gut microbiota. This occurred via an immunoglobulin (Ig)-dependent mechanism, associated with targeting of αGal-expressing bacteria by IgA. Systemic infection with an Ig-shaped microbiota inoculum elicited a less severe form of sepsis compared to infection with non-Ig-shaped microbiota. This suggests that in the absence of host αGal, antibodies can shape the microbiota towards lower pathogenicity. Given the fitness cost imposed by bacterial sepsis, we infer that the observed reduction in microbiota pathogenicity upon Ggta1 deletion in mice may have contributed to increase the frequency of GGTA1 loss-of-function mutations in ancestral primates that gave rise to humans. [ABSTRACT FROM AUTHOR]

Objective: This study investigated associations between childhood trauma, parental bonding, and social cognition (i.e., Theory of Mind and emotion recognition) in patients with schizophrenia and healthy adults. Methods: Using cross‐sectional data, we examined the recollections of childhood trauma experiences and social cognitive abilities in 74 patients with schizophrenia and 116 healthy adults. Results: Patients had significantly higher scores compared with healthy participants on childhood trauma, and lower scores on parental bonding and social cognitive measures. Physical neglect was found to be the strongest predictor of emotion recognition impairments in both groups. Optimal parental bonding attenuated the impact of childhood trauma on emotion recognition. Conclusion: The present study provides evidence of an association between physical neglect and emotion recognition in patients with schizophrenia and healthy individuals and shows that both childhood trauma and parental bonding may influence social cognitive development. Psychosocial interventions should be developed to prevent and mitigate the long‐term effects of childhood adversities. [ABSTRACT FROM AUTHOR]

MECP2 and its product, Methyl-CpG binding protein 2 (MeCP2), are mostly known for their association to Rett Syndrome (RTT), a rare neurodevelopmental disorder. Additional evidence suggests that MECP2 may underlie other neuropsychiatric and neurological conditions, and perhaps modulate common presentations and pathophysiology across disorders. To clarify the mechanisms of these interactions, we develop a method that uses the binding properties of MeCP2 to identify its targets, and in particular, the genes recognized by MeCP2 and associated to several neurological and neuropsychiatric disorders. Analysing mechanisms and pathways modulated by these genes, we find that they are involved in three main processes: neuronal transmission, immuno-reactivity, and development. Also, while the nervous system is the most relevant in the pathophysiology of the disorders, additional systems may contribute to MeCP2 action through its target genes. We tested our results with transcriptome analysis on Mecp2-null models and cells derived from a patient with RTT, confirming that the genes identified by our procedure are directly modulated by MeCP2. Thus, MeCP2 may modulate similar mechanisms in different pathologies, suggesting that treatments for one condition may be effective for related disorders. [ABSTRACT FROM AUTHOR]

Childhood trauma, and in particular physical neglect, has been repeatedly associated with lower performance on measures of social cognition (e.g. emotion recognition tasks) in both psychiatric and non-clinical populations. The neural mechanisms underpinning this association have remained unclear. Here, we investigated whether volumetric changes in three stress-sensitive regions—the amygdala, hippocampus and anterior cingulate cortex (ACC)—mediate the association between childhood trauma and emotion recognition in a healthy participant sample (N  = 112) and a clinical sample of patients with schizophrenia (N  = 46). Direct effects of childhood trauma, specifically physical neglect, on Emotion Recognition Task were observed in the whole sample. In healthy participants, reduced total and left ACC volumes were observed to fully mediate the association between both physical neglect and total childhood trauma score, and emotion recognition. No mediating effects of the hippocampus and amygdala volumes were observed for either group. These results suggest that reduced ACC volume may represent part of the mechanism by which early life adversity results in poorer social cognitive function. Confirmation of the causal basis of this association would highlight the importance of resilience-building interventions to mitigate the detrimental effects of childhood trauma on brain structure and function. [ABSTRACT FROM AUTHOR]

Background: Previous studies using resting-state functional neuroimaging have revealed alterations in whole-brain images, connectome-wide functional connectivity and graph-based metrics in groups of patients with schizophrenia relative to groups of healthy controls. However, it is unclear which of these measures best captures the neural correlates of this disorder at the level of the individual patient. Methods: Here we investigated the relative diagnostic value of these measures. A total of 295 patients with schizophrenia and 452 healthy controls were investigated using resting-state functional Magnetic Resonance Imaging at five research centres. Connectome-wide functional networks were constructed by thresholding correlation matrices of 90 brain regions, and their topological properties were analyzed using graph theory-based methods. Single-subject classification was performed using three machine learning (ML) approaches associated with varying degrees of complexity and abstraction, namely logistic regression, support vector machine and deep learning technology. Results: Connectome-wide functional connectivity allowed single-subject classification of patients and controls with higher accuracy (average: 81%) than both whole-brain images (average: 53%) and graph-based metrics (average: 69%). Classification based on connectome-wide functional connectivity was driven by a distributed bilateral network including the thalamus and temporal regions. Conclusion: These results were replicated across the three employed ML approaches. Connectome-wide functional connectivity permits differentiation of patients with schizophrenia from healthy controls at single-subject level with greater accuracy; this pattern of results is consistent with the 'dysconnectivity hypothesis' of schizophrenia, which states that the neural basis of the disorder is best understood in terms of system-level functional connectivity alterations. [ABSTRACT FROM AUTHOR]

Introduction: N-methyl-d-aspartate receptor antibody (NMDAR-Ab) encephalitis consensus criteria has recently been defined. We aimed to examine the prevalence of NMDAR-Ab encephalitis in patients with first episode psychosis (FEP) and treatment resistant schizophrenia (TRS) on clozapine, using clinical investigations, antibody testing and to retrospectively apply diagnostic consensus criteria.Methods: Adult (18-65 years old) cases of FEP meeting inclusion criteria were recruited over three years and assessed using the Structured Clinical Interview for DSM-IV disorders (SCID). NMDAR-Ab was identified using a live cell-based assay (L-CBA). Seropositive cases were clinically investigated for features of encephalitis including neuro-imaging, EEG and CSF where possible. Serum was retested using immunohistochemistry (IHC) as part of diagnostic criteria guidelines. A cohort of patients with TRS was also recruited.Results: 112 FEP patients were recruited over 3 years. NMDAR-Ab seroprevalence was 4/112 (3.5%) cases. One case (<1%) was diagnosed with definite NMDAR-Ab encephalitis and treated with immunotherapy. One of the three other seropositive cases met criteria for probable encephalitis. However all three were ultimately diagnosed with mood disorders with psychotic features. None have developed neurological features at three year follow up. 1/100 (1%) of patients with TRS was 100 patients with TRS were recruited. One case (1%) seropositive for NMDAR-Ab but did not meet criteria for encephalitis.Conclusions: NMDAR-Ab encephalitis as defined by consensus guidelines occured rarely in psychiatric services in this study. Further studies are needed to establish pathogenicity of serum NMDAR-Ab antibodies. Psychiatric services should be aware of the clinical features of encephalitis. [ABSTRACT FROM AUTHOR]

Objective: Schizophrenia has recently been associated with widespread white matter microstructural abnormalities, but the functional effects of these abnormalities remain unclear. Widespread heterogeneity of results from studies published to date preclude any definitive characterization of the relationship between white matter and cognitive performance in schizophrenia. Given the relevance of deficits in cognitive function to predicting social and functional outcomes in schizophrenia, the authors carried out a meta-analysis of available data through the ENIGMA Consortium, using a common analysis pipeline, to elucidate the relationship between white matter microstructure and a measure of general cognitive performance, IQ, in patients with schizophrenia and healthy participants.Methods: The meta-analysis included 760 patients with schizophrenia and 957 healthy participants from 11 participating ENIGMA Consortium sites. For each site, principal component analysis was used to calculate both a global fractional anisotropy component (gFA) and a fractional anisotropy component for six long association tracts (LA-gFA) previously associated with cognition.Results: Meta-analyses of regression results indicated that gFA accounted for a significant amount of variation in cognition in the full sample (effect size [Hedges' g]=0.27, CI=0.17-0.36), with similar effects sizes observed for both the patient (effect size=0.20, CI=0.05-0.35) and healthy participant groups (effect size=0.32, CI=0.18-0.45). Comparable patterns of association were also observed between LA-gFA and cognition for the full sample (effect size=0.28, CI=0.18-0.37), the patient group (effect size=0.23, CI=0.09-0.38), and the healthy participant group (effect size=0.31, CI=0.18-0.44).Conclusions: This study provides robust evidence that cognitive ability is associated with global structural connectivity, with higher fractional anisotropy associated with higher IQ. This association was independent of diagnosis; while schizophrenia patients tended to have lower fractional anisotropy and lower IQ than healthy participants, the comparable size of effect in each group suggested a more general, rather than disease-specific, pattern of association. [ABSTRACT FROM AUTHOR]

Schizophrenia is a severe psychiatric disorder associated with both structural and functional brain abnormalities. In the past few years, there has been growing interest in the application of machine learning techniques to neuroimaging data for the diagnostic and prognostic assessment of this disorder. However, the vast majority of studies published so far have used either structural or functional neuroimaging data, without accounting for the multimodal nature of the disorder. Structural MRI and resting‐state functional MRI data were acquired from a total of 295 patients with schizophrenia and 452 healthy controls at five research centers. We extracted features from the data including gray matter volume, white matter volume, amplitude of low‐frequency fluctuation, regional homogeneity and two connectome‐wide based metrics: structural covariance matrices and functional connectivity matrices. A support vector machine classifier was trained on each dataset separately to distinguish the subjects at individual level using each of the single feature as well as their combination, and 10‐fold cross‐validation was used to assess the performance of the model. Functional data allow higher accuracy of classification than structural data (mean 82.75% vs. 75.84%). Within each modality, the combination of images and matrices improves performance, resulting in mean accuracies of 81.63% for structural data and 87.59% for functional data. The use of all combined structural and functional measures allows the highest accuracy of classification (90.83%). We conclude that combining multimodal measures within a single model is a promising direction for developing biologically informed diagnostic tools in schizophrenia. [ABSTRACT FROM AUTHOR]

Background: People with schizophrenia are ten times more likely to commit homicide than a member of the general population. The relationship between symptoms of schizophrenia and acts of violence is unclear. There has also been limited research on what determines the seriousness and form of violence, such as reactive or instrumental violence. Moral cognition may play a paradoxical role in acts of violence for people with schizophrenia. Thoughts which have moral content arising from psychotic symptoms may be a cause of serious violence. Method: We investigated if psychotic symptoms and moral cognitions at the time of a violent act were associated with acts of violence using a cross-sectional national forensic cohort (n = 55). We examined whether moral cognitions were associated with violence when controlling for neurocognition and violence proneness. We explored the association between all psychotic symptoms present at the time of the violent act, psychotic symptoms judged relevant to the violent act and moral cognitions present at that time. Using mediation analysis, we examined whether moral cognitions were the missing link between symptoms and the relevance of symptoms for violence. We also investigated if specific moral cognitions mediated the relationship between specific psychotic symptoms, the seriousness of violence (including homicide), and the form of violence. Results: Psychotic symptoms generally were not associated with the seriousness or form of violence. However, specific moral cognitions were associated with the seriousness and form of violence even when controlling for neurocognition and violence proneness. Specific moral cognitions were associated with specific psychotic symptoms present and relevant to violence. Moral cognitions mediated the relationship between the presence of specific psychotic symptoms and their relevance for violence, homicide, seriousness of violence, and the form of violence. Conclusions: Moral cognitions including the need to reduce suffering, responding to an act of injustice or betrayal, the desire to comply with authority, or the wish to punish impure or disgusting behaviour, may be a key mediator explaining the relationship between psychotic symptoms and acts of violence. Our findings may have important implications for risk assessment, treatment and violence prevention. [ABSTRACT FROM AUTHOR]

Forensic patients with schizophrenia who had carried out a homicide scored higher on a measure of moral cognition (MFQ-30) than other violent patients. Neurocognitive impairment was associated with homicide by mediation via higher scores for in-group loyalty. [ABSTRACT FROM AUTHOR]

Objective: More than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium.Methods: The samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders.Results: Three genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%).Conclusions: This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt. [ABSTRACT FROM AUTHOR]

Schizophrenia has been conceived as a disorder of brain connectivity, but it is unclear how this network phenotype is related to the underlying genetics. We used morphometric similarity analysis of MRI data as a marker of interareal cortical connectivity in three prior case-control studies of psychosis: in total, n = 185 cases and n = 227 controls. Psychosis was associated with globally reduced morphometric similarity in all three studies. There was also a replicable pattern of case-control differences in regional morphometric similarity, which was significantly reduced in patients in frontal and temporal cortical areas but increased in parietal cortex. Using prior brain-wide gene expression data, we found that the cortical map of case-control differences in morphometric similarity was spatially correlated with cortical expression of a weighted combination of genes enriched for neurobiologically relevant ontology terms and pathways. In addition, genes that were normally overexpressed in cortical areas with reduced morphometric similarity were significantly up-regulated in three prior post mortem studies of schizophrenia. We propose that this combined analysis of neuroimaging and transcriptional data provides insight into how previously implicated genes and proteins as well as a number of unreported genes in their topological vicinity on the protein interaction network may drive structural brain network changes mediating the genetic risk of schizophrenia. [ABSTRACT FROM AUTHOR]

Abstract Background Sequencing studies have pointed to the involvement in schizophrenia of rare coding variants in neuronally expressed genes, including activity-regulated cytoskeleton-associated protein (ARC) and N -methyl-D-aspartate receptor (NMDAR) complexes; however, larger samples are required to reveal novel genes and specific biological mechanisms. Methods We sequenced 187 genes, selected for prior evidence of association with schizophrenia, in a new dataset of 5207 cases and 4991 controls. Included among these genes were members of ARC and NMDAR postsynaptic protein complexes, as well as voltage-gated sodium and calcium channels. We performed a rare variant meta-analysis with published sequencing data for a total of 11,319 cases, 15,854 controls, and 1136 trios. Results While no individual gene was significantly associated with schizophrenia after genome-wide correction for multiple testing, we strengthen the evidence that rare exonic variants in the ARC (p = 4.0 × 10–4) and NMDAR (p = 1.7 × 10–5) synaptic complexes are risk factors for schizophrenia. In addition, we found that loss-of-function variants and missense variants at paralog-conserved sites were enriched in voltage-gated sodium channels, particularly the alpha subunits (p = 8.6 × 10–4). Conclusions In one of the largest sequencing studies of schizophrenia to date, we provide novel evidence that multiple voltage-gated sodium channels are involved in schizophrenia pathogenesis and confirm the involvement of ARC and NMDAR postsynaptic complexes. [ABSTRACT FROM AUTHOR]

• We examined whether delusions are maintained by ongoing anomalous perceptions or neuropsychological impairment or both. • We compared ability to ask 'good questions', and to 'update beliefs' in schizophrenia (n = 40, 19 deluded v 21 remitted). • Cardiff Anomalous Perception Scale (CAPS), Twenty Questions Test (TQT) and Word Context Test (WCT) were all significant. • All three variables combined accounted for 57% variance of treatment resistant delusions, 85% classification accuracy. • A measure of general cognitive impairment (MATRICS Consensus Cognitive Battery MCCB) did not contribute to the model. [ABSTRACT FROM AUTHOR]

Abstract: Working memory‐based cognitive remediation therapy (CT) for psychosis has recently been associated with broad improvements in performance on untrained tasks measuring working memory, episodic memory and IQ, and changes in associated brain regions. However, it is unclear whether these improvements transfer to the domain of social cognition and neural activity related to performance on social cognitive tasks. We examined performance on the Reading the Mind in the Eyes test (Eyes test) in a large sample of participants with psychosis who underwent working memory‐based CT (N = 43) compared to a control group of participants with psychosis (N = 35). In a subset of this sample, we used functional magnetic resonance imaging (fMRI) to examine changes in neural activity during a facial emotion recognition task in participants who underwent CT (N = 15) compared to a control group (N = 15). No significant effects of CT were observed on Eyes test performance or on neural activity during facial emotion recognition, either at p < 0.05 family‐wise error or at a p < 0.001 uncorrected threshold, within a priori social cognitive regions of interest. This study suggests that working memory‐based CT does not significantly impact an aspect of social cognition which was measured behaviourally and neurally. It provides further evidence that deficits in the ability to decode mental state from facial expressions are dissociable from working memory deficits, and suggests that future CT programmes should target social cognition in addition to working memory for the purposes of further enhancing social function. [ABSTRACT FROM AUTHOR]

Background: Resting-state functional magnetic resonance imaging (rs-fMRI) has repeatedly shown evidence of altered functional connectivity of large-scale networks in schizophrenia. The relationship between these connectivity changes and behaviour (e.g. symptoms, neuropsychological performance) remains unclear.Methods: Functional connectivity in 27 patients with schizophrenia or schizoaffective disorder, and 25 age and gender matched healthy controls was examined using rs-fMRI. Based on seed regions from previous studies, we examined functional connectivity of the default, cognitive control, affective and attention networks. Effects of symptom severity and theory of mind performance on functional connectivity were also examined.Results: Patients showed increased connectivity between key nodes of the default network including the precuneus and medial prefrontal cortex compared to controls (p<0.01, FWE-corrected). Increasing positive symptoms and increasing theory of mind performance were both associated with altered connectivity of default regions within the patient group (p<0.01, FWE-corrected).Discussion: This study confirms previous findings of default hyper-connectivity in schizophrenia spectrum patients and reveals an association between altered default connectivity and positive symptom severity. As a novel find, this study also shows that default connectivity is correlated to and predictive of theory of mind performance. Extending these findings by examining the effects of emerging social cognition treatments on both default connectivity and theory of mind performance is now an important goal for research. [ABSTRACT FROM AUTHOR]

• Individuals with schizophrenia showed fractional anisotropy (FA) reductions compared to controls. • High trauma levels were related to FA reductions compared to those with none/low levels. • No interaction between diagnosis and high levels of childhood trauma was found. • The effects of trauma severity on white matter organization may be independent of schizophrenia. It has been reported that childhood trauma (CT) is associated with reductions in fractional anisotropy (FA) in individuals with schizophrenia (SZ). Here, we hypothesized that SZ with high levels of CT will show the greatest reductions in FA in frontolimbic and frontoparietal regions compared to healthy controls (HC) with high trauma levels and participants with no/low levels of CT. Thirty-seven SZ and 129 HC with CT experience were dichotomized into groups of 'none/low' or 'high' levels. Participants underwent diffusion-weighted MRI, and Tract-based spatial statistics were employed to assess the main effect of diagnosis, main effect of CT severity irrespective of diagnosis, and interaction between diagnosis and CT severity. SZ showed FA reductions in the corpus callosum and corona radiata compared to HC. Irrespective of a diagnosis, high CT levels (n = 48) were related to FA reductions in frontolimbic and frontoparietal regions compared to those with none/low levels of CT (n = 118). However, no significant interaction between diagnosis and high levels of CT was found (n = 13). Across all participants, we observed effects of CT on late developing frontolimbic and frontoparietal regions, suggesting that the effects of CT severity on white matter organization may be independent of schizophrenia. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "What Have the Genomics Ever Done for PSychoses?," by M. Gill, G. Donohoe and A. Corvin in the 2010 issue of Psychological Medicine."

Cognitive remediation (CR) has emerged as the treatment of choice for impaired cognition in psychosis. However, little is known about adherence rates and factors predicting adherence to CR, particularly in clinical settings where high-level therapist support is unavailable. This study aimed to establish adherence rates and examine variables predicting adherence to a computerized CR program for psychosis (with minimal support). Patients with psychosis (n = 61) participated in an 8-week CR program. Results showed 46% completed a meaningful amount of CR training. The fully adherent (>80% of the prescribed amount) and nonadherent groups differed where adherent participants had poorer working-memory and higher negative symptom scores. These findings suggest that approximately half of the sample were adherent to treatment despite minimal therapist support. Furthermore, higher cognitive deficits and negative symptoms did not impede adherence, and may have contributed to patients' motivation to complete the program. [ABSTRACT FROM AUTHOR]

Methyl-CpG binding protein 2 (MECP2) is a chromosome-binding protein that regulates the development and maintenance of brain circuits. Altered function of the protein product of MECP2 plays an important role in the etiology of many neurodevelopmental disorders. Mutations involving a loss of function are implicated in the etiology of Rett syndrome, intellectual disability, psychosis and severe encephalopathy. Conversely, MECP2 duplications have been identified in autism and intellectual disability. MECP2 action is dependent on neuronal function, as the DNA binding is modulated by activity, and it is phosphorylated in response to stimulation. Although MECP2 is considered a major risk factor for neurodevelopmental disorders, and it is a mediator of activity-dependent mechanisms, the expression levels in response to neuronal activity have never been measured. We studied the expression of Mecp2 protein and RNA in mice neuronal cultures in response to different stimulation conditions and in the presence of insulin-like growth factor1 (IGF1): a growth factor involved in brain development and plasticity. The stimulation protocols were selected according to their ability to induce different forms of synaptic plasticity: rapid depolarization, feed-forward plasticity (LTP, LTD) and feedback forms of plasticity (TTX, KCl). We find a significant reduction of Mecp2 protein nuclear expression in neurons in response to stimuli that induce a potentiation of neuronal response, suggesting that Mecp2 protein expression is modulated by neuronal activation. Application of IGF1 to the cultures induces an increase in the expression of Mecp2 transcript and nuclear Mecp2 protein in neurons. These results show that Mecp2 is responsive to neuronal stimulation and IGF1, and different stimuli have different effects on Mecp2 expression; this differential response may have downstream effects on functional mechanisms regulating brain development and plasticity. [ABSTRACT FROM AUTHOR]

Genome-wide association studies implicate the MIR137HG risk variant rs1625579 (MIR137HGrv) within the host gene for microRNA-137 as a potential regulator of schizophrenia susceptibility. We examined the influence of MIR137HGrv genotype on 17 subcortical and callosal volumes in a large sample of individuals with schizophrenia and healthy controls ( n = 841). Although the volumes were overall reduced relative to healthy controls, for individuals with schizophrenia the homozygous MIR137HGrv risk genotype was associated with attenuated reduction of mid-posterior corpus callosum volume ( p = 0.001), along with trend-level effects in the adjacent central and posterior corpus callosum. These findings are unique in the literature and remain robust after analysis in ethnically homogenous and single-scanner subsets of the larger sample. Thus, our study suggests that the mechanisms whereby MIR137HGrv works to increase schizophrenia risk are not those that generate the corpus callosum volume reductions commonly found in the disorder. [ABSTRACT FROM AUTHOR]