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Background: 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., Methods: 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., Results: 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)., Conclusions: 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., (Copyright © 2021. Published by Elsevier Inc.)

Background: Copy number variants (CNVs) play a significant role in disease pathogenesis in a small subset of individuals with schizophrenia (~2.5%). Chromosomal microarray testing is a first-tier genetic test for many neurodevelopmental disorders. Similar testing could be useful in schizophrenia., Aims: To determine whether clinically identifiable phenotypic features could be used to successfully model schizophrenia-associated (SCZ-associated) CNV carrier status in a large schizophrenia cohort., Method: Logistic regression and receiver operating characteristic (ROC) curves tested the accuracy of readily identifiable phenotypic features in modelling SCZ-associated CNV status in a discovery data-set of 1215 individuals with psychosis. A replication analysis was undertaken in a second psychosis data-set (n = 479)., Results: In the discovery cohort, specific learning disorder (OR = 8.12; 95% CI 1.16-34.88, P = 0.012), developmental delay (OR = 5.19; 95% CI 1.58-14.76, P = 0.003) and comorbid neurodevelopmental disorder (OR = 5.87; 95% CI 1.28-19.69, P = 0.009) were significant independent variables in modelling positive carrier status for a SCZ-associated CNV, with an area under the ROC (AUROC) of 74.2% (95% CI 61.9-86.4%). A model constructed from the discovery cohort including developmental delay and comorbid neurodevelopmental disorder variables resulted in an AUROC of 83% (95% CI 52.0-100.0%) for the replication cohort., Conclusions: These findings suggest that careful clinical history taking to document specific neurodevelopmental features may be informative in screening for individuals with schizophrenia who are at higher risk of carrying known SCZ-associated CNVs. Identification of genomic disorders in these individuals is likely to have clinical benefits similar to those demonstrated for other neurodevelopmental disorders.

Genome-wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophrenia etiology but, with the exception of large copy number variants, are difficult to detect with GWAS. Exome and genome sequencing, which have accelerated the study of rare variants, are expensive so alternative methods are needed to aid detection of rare variants. Here we re-analyze an Irish schizophrenia GWAS dataset (n = 3,473) by performing identity-by-descent (IBD) mapping followed by exome sequencing of individuals identified as sharing risk haplotypes to search for rare risk variants in coding regions. We identified 45 rare haplotypes (>1 cM) that were significantly more common in cases than controls. By exome sequencing 105 haplotype carriers, we investigated these haplotypes for functional coding variants that could be tested for association in independent GWAS samples. We identified one rare missense variant in PCNT but did not find statistical support for an association with schizophrenia in a replication analysis. However, IBD mapping can prioritize both individual samples and genomic regions for follow-up analysis but genome rather than exome sequencing may be more effective at detecting risk variants on rare haplotypes., (© 2019 Wiley Periodicals, Inc.)

Multiple genome-wide association studies of schizophrenia have implicated genetic variants within the gene encoding microRNA-137. As risk variants within or regulated by MIR137 have been implicated in memory performance, we investigated the additive effects of schizophrenia-associated risk variants in genes empirically regulated by MIR137 on brain regions associated with memory function. A polygenic risk score (PRS) was calculated (at a p = 0.05 threshold), using this empirically regulated MIR137 gene set, to investigate associations between this PRS and structural brain measures. These measures included total brain volume, cortical thickness, cortical surface area, and hippocampal volume, in a sample of 216 individuals consisting of healthy participants (n = 171) and patients with psychosis (n = 45). We did not observe a significant association between MIR137 PRS and these cortical thickness, surface area or hippocampal volume measures linked to memory function; a significant association between increasing PRS and decreasing total brain volume, independent of diagnosis status (R 2  = 0.008, Beta = -0.09, p = 0.029), was observed. This did not survive correction for multiple testing. In conclusion, our study yielded only suggestive evidence that risk variants interacting with MIR137 impacts on cortical structure., (© 2018 Wiley Periodicals, Inc.)

With >100 common variants associated with schizophrenia risk, establishing their biological significance is a priority. We sought to establish cognitive effects of risk variants at loci implicated in synaptic transmission by (1) identifying GWAS schizophrenia variants whose associated gene function is related to synaptic transmission, and (2) testing for association between these and measures of neurocognitive function. We selected variants, reported in the largest GWAS to date, associated with genes involved in synaptic transmission. Associations between genotype and cognitive test score were analyzed in a discovery sample (988 Irish participants, including 798 with psychosis), and replication samples (528 UK patients with schizophrenia/schizoaffective disorder; 921 German participants including 362 patients with schizophrenia). Three loci showed significant associations with neuropsychological performance in the discovery samples. This included an association between the rs2007044 (risk allele G) within CACNA1C and poorer working memory performance (increased errors B (95% CI)=0.635-4.535, p=0.012), an effect driven mainly by the psychosis groups. In an fMRI analysis of working memory performance (n=84 healthy participants, a subset of the discovery sample), we further found evidence that the same CACNA1C allele was associated with decreased functional connectivity between the right dorsolateral prefrontal cortex and right superior occipital gyrus/cuneus and anterior cingulate cortex. In conclusion, these data provide evidence to suggest that the CACNA1C risk variant rs2007044 is associated with poorer memory function that may result from risk carriers' difficulty with top-down initiated responses caused by dysconnectivity between the right DLPFC and several cortical regions.

Epigenetic mechanisms are an important heritable and dynamic means of regulating various genomic functions, including gene expression, to orchestrate brain development, adult neurogenesis, and synaptic plasticity. These processes when perturbed are thought to contribute to schizophrenia pathophysiology. A core feature of schizophrenia is cognitive dysfunction. For genetic disorders where cognitive impairment is more severe such as intellectual disability, there are a disproportionally high number of genes involved in the epigenetic regulation of gene transcription. Evidence now supports some shared genetic aetiology between schizophrenia and intellectual disability. GWAS have identified 108 chromosomal regions associated with schizophrenia risk that span 350 genes. This study identified genes mapping to those loci that have epigenetic functions, and tested the risk alleles defining those loci for association with cognitive deficits. We developed a list of 350 genes with epigenetic functions and cross-referenced this with the GWAS loci. This identified eight candidate genes: BCL11B, CHD7, EP300, EPC2, GATAD2A, KDM3B, RERE, SATB2. Using a dataset of Irish psychosis cases and controls (n = 1235), the schizophrenia risk SNPs at these loci were tested for effects on IQ, working memory, episodic memory, and attention. Strongest associations were for rs6984242 with both measures of IQ (P = 0.001) and episodic memory (P = 0.007). We link rs6984242 to CHD7 via a long range eQTL. These associations were not replicated in independent samples. Our study highlights that a number of genes mapping to risk loci for schizophrenia may function as epigenetic regulators of gene expression but further studies are required to establish a role for these genes in cognition. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Variation in cognitive performance, which strongly predicts functional outcome in schizophrenia (SZ), has been associated with multiple immune‐relevant genetic loci. These loci include complement component 4 (C4A), structural variation at which was recently associated with SZ risk and synaptic pruning during neurodevelopment and cognitive function. Here, we test whether this genetic association with cognition and SZ risk is specific to C4A, or extends more broadly to genes related to the complement system. Using a gene‐set with an identified role in "complement" function (excluding C4A), we used MAGMA to test if this gene‐set was enriched for genes associated with human intelligence and SZ risk, using genome‐wide association summary statistics (IQ; N = 269 867, SZ; N = 105 318). We followed up this gene‐set analysis with a complement gene‐set polygenic score (PGS) regression analysis in an independent data set of patients with psychotic disorders and healthy participants with cognitive and genomic data (N = 1000). Enrichment analysis suggested that genes within the complement pathway were significantly enriched for genes associated with IQ, but not SZ. In a gene‐based analysis of 90 genes, SERPING1 was the most enriched gene for the phenotype of IQ. In a PGS regression analysis, we found that a complement pathway PGS associated with IQ genome‐wide association studies statistics also predicted variation in IQ in our independent sample. This association (observed across both patients and controls) remained significant after controlling for the relationship between C4A and cognition. These results suggest a robust association between the complement system and cognitive function, extending beyond structural variation at C4A. [ABSTRACT FROM AUTHOR]

Highlights from the article: B Background: b Rare copy number variations (CNVs) are associated with increased risk of neuropsychiatric disorders and lower cognitive ability in healthy individuals. B Results: b In CardiffCOGS, individuals with a schizophrenia CNV (N=8) performed over one standard deviation below cases without a schizophrenia CNV (N=471) on the MATRICS composite z-score ( =-1.16., 95%CI = -2.06 to -0.25, p=0.011). B Discussion: b In the largest combined schizophrenia sample to date with cognition data, we have demonstrated that individuals with the disorder who are carriers of schizophrenia CNVs display clinically important levels of cognitive impairment.

The aim of this study is to characterise the effects of 8 already identified genetic risk variants on social cognitive deficits in schizophrenia. Although the aetiology of schizophrenia is largely unknown, it is increasingly clear that genetic and environmental interactions contribute to cognitive deficits associated with this disorder. The 'Immune Hypothesis' suggests that schizophrenia is often predicted by early environmentally-driven immune challenges, and genetically driven sub-optimal immune responsiveness. In the largest genetic study of schizophrenia to date, recent Genome-Wide Association Studies (GWAS) have established the strongest association with schizophrenia was found at a region of the genome that is synonymous with immune function- the major histocompatibility complex, or MHC. Social cognitive deficits are core features of Schizophrenia, which relate to genetic risk. The current study analyses the effects of immune challenge (genetic and environmental) on social cognition, examining a set of genes related to immune function and schizophrenia risk, as well as environmental factors that may contribute to cognitive deficit. To test if genetic variants related to immune function impair cognition, 8 genes were selected by cross referencing "Immunology" Gene Ontology lists with the most recent list of genes implicated in GWAS for schizophrenia. 1013 participants were genotyped and cognitively assessed in an Irish population of schizophrenia sufferers and healthy controls, and this cohort was used for primary analysis of a gene-cognition relationship. A separate cohort of already collected data was also examined from the Avon Longitudinal Study of Parents and Children (ALSPAC) for replication of results and mediation analysis, consisting of ~5000 participants. Block regression analysis using SPSS statistical software was performed, testing a relationship between genetic risk levels and cognitive deficits. In a second element to the study, environmental factors were examined as possible mediators of the relationship between genetic risk variants and cognitive impairment (PROCESS mediation, SPSS) in the ALSPAC sample. Regression analysis suggests that 7 of 8 genetic variants selected contribute to impairments in cognition across an Irish sample, and these findings were replicated in the ALSPAC sample. Cognitive deficits overlapped for the majority of genes examined, across domains of social cognition, IQ and episodic memory. In examining ALSPAC as a replication sample, many of the same genetic variants also showed negative effects on social cognition, as well as more generalized effects of these genes on various cognitive domains. In mediation analysis, environmental factors such as childhood abuse were also found to impact on this gene-cognition relationship. The "Immune 8" may serve as significant risk markers for schizophrenia, and further elucidate aetiology of this disorder. Future studies on neurobiology of social cognition, and greater knowledge of genetic risk may establish targets for interventions. Childhood abuse was also found to be significantly related to cognitive deficit. The role of environmental stressors contributing to genetic risk and immune function is an interesting avenue for future research in schizophrenia. [ABSTRACT FROM AUTHOR]

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]