Schizophrenia polygenic risk is plausibly manifested by complex transcriptional dysregulation in the brain, involving networks of co-expressed and functionally related genes. The main purpose of this ...study was to identify and prioritize co-expressed gene sets in a hierarchical manner, based on the strength of the relationships with clinical diagnosis and with polygenic risk for schizophrenia. Weighted Gene Co-expression Network Analysis (WGCNA) was applied to RNA-quality-adjusted DLPFC RNA-Seq data from the LIBD Postmortem Human Brain Repository (90 controls, 74 schizophrenia cases; all Caucasians) to construct co-expression networks and detect "modules" of co-expressed genes. After multiple internal and external validation procedures, modules of selected interest were tested for enrichment in biological ontologies, for association with schizophrenia polygenic risk scores (PRSs) and with diagnosis, and also for enrichment in genes within the significant GWAS loci reported by the Psychiatric Genomic Consortium (PGC2). The association between schizophrenia genetic signals and modules of co-expression converged on one module showing not only a significant association with both diagnosis and PRS but also significant overlap with 36 PGC2 loci genes, deemed the strongest candidates for drug targets. This module contained many genes involved in synaptic signaling and neuroplasticity. Fifty-three PGC2 genes were in modules associated only with diagnosis and 59 in modules unrelated to diagnosis or PRS. Our study highlights complex relationships between gene co-expression networks in the brain and clinical state and polygenic risk for SCZ and provides a strategy for using this information in selecting and prioritizing potentially targetable gene sets for therapeutic drug development.
The effect of schizophrenia (SCZ) genetic risk on gene expression in brain remains elusive. A popular approach to this problem has been the application of gene co-expression network algorithms (e.g., ...WGCNA). To improve reliability with this method it is critical to remove unwanted sources of variance while also preserving biological signals of interest. In this WCGNA study of RNA-Seq data from postmortem prefrontal cortex (78 neurotypical donors, EUR ancestry), we tested the effects of SCZ genetic risk on co-expression networks. Specifically, we implemented a novel design in which gene expression was adjusted by linear regression models to preserve or remove variance explained by biological signal of interest (GWAS genomic scores for SCZ risk-(GS-SCZ), and genomic scores- GS of height (GS-Ht) as a negative control), while removing variance explained by covariates of non-interest. We calculated co-expression networks from adjusted expression (GS-SCZ and GS-Ht preserved or removed), and consensus between them (representative of a "background" network free of genomic scores effects). We then tested the overlap between GS-SCZ preserved modules and background networks reasoning that modules with reduced overlap would be most affected by GS-SCZ biology. Additionally, we tested these modules for convergence of SCZ risk (i.e., enrichment in PGC3 SCZ GWAS priority genes, enrichment in SCZ risk heritability and relevant biological ontologies. Our results highlight key aspects of GS-SCZ effects on brain co-expression networks, specifically: 1) preserving/removing SCZ genetic risk alters the co-expression modules; 2) biological pathways enriched in modules affected by GS-SCZ implicate processes of transcription, translation and metabolism that converge to influence synaptic transmission; 3) priority PGC3 SCZ GWAS genes and SCZ risk heritability are enriched in modules associated with GS-SCZ effects. Overall, our results indicate that gene co-expression networks that selectively integrate information about genetic risk can reveal novel combinations of biological pathways involved in schizophrenia.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Autism spectrum conditions (ASC) affect more males than females. This suggests that the neurobiology of autism: 1) may overlap with mechanisms underlying typical sex-differentiation or 2) alternately ...reflect sex-specificity in how autism is expressed in males and females. Here we used functional magnetic resonance imaging (fMRI) to test these alternate hypotheses. Fifteen men and fourteen women with Asperger syndrome (AS), and sixteen typically developing men and sixteen typically developing women underwent fMRI during performance of mental rotation and verbal fluency tasks. All groups performed the tasks equally well. On the verbal fluency task, despite equivalent task-performance, both males and females with AS showed enhanced activation of left occipitoparietal and inferior prefrontal activity compared to controls. During mental rotation, there was a significant diagnosis-by-sex interaction across occipital, temporal, parietal, middle frontal regions, with greater activation in AS males and typical females compared to AS females and typical males. These findings suggest a complex relationship between autism and sex that is differentially expressed in verbal and visuospatial domains.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Gamma-aminobutyric acid (GABA)-ergic transmission is critical for normal cortical function and is likely abnormal in a variety of neuropsychiatric disorders. We tested the in vivo effects of ...variations in two genes implicated in GABA function on GABA concentrations in prefrontal cortex of living subjects: glutamic acid decarboxylase 1 (GAD1), which encodes GAD67, and catechol-o-methyltransferase (COMT), which regulates synaptic dopamine in the cortex. We studied six single nucleotide polymorphisms (SNPs) in GAD1 previously associated with risk for schizophrenia or cognitive dysfunction and the val158met polymorphism in COMT in 116 healthy volunteers using proton magnetic resonance spectroscopy. Two of the GAD1 SNPs (rs1978340 (p=0.005) and rs769390 (p=0.004)) showed effects on GABA levels as did COMT val158met (p=0.04). We then tested three SNPs in GAD1 (rs1978340, rs11542313, and rs769390) for interaction with COMT val158met based on previous clinical results. In this model, rs11542313 and COMT val158met showed significant main effects (p=0.001 and 0.003, respectively) and a trend toward a significant interaction (p=0.05). Interestingly, GAD1 risk alleles for schizophrenia were associated with higher GABA/Cre, and Val-Val homozygotes had high GABA/Cre levels when on a GAD1 risk genotype background (N=6). These results support the importance of genetic variation in GAD1 and COMT in regulating prefrontal cortical GABA function. The directionality of the effects, however, is inconsistent with earlier evidence of decreased GABA activity in schizophrenia.
The widespread use of MRI has led to a wealth of structural and functional anatomical findings in patients with diverse psychiatric disorders that may represent insights into pathobiology. However, ...recent technical reports indicate that data from popular MRI research—particularly structural MRI, resting-state functional MRI, and diffusion tensor imaging—are highly sensitive to common artifacts (e.g., head motion and breathing effects) that may dominate the results. Because these and other important confounders of MRI data (e.g., smoking, body weight, metabolic variations, medical comorbidities, psychoactive drugs, alcohol use, mental state) tend to vary systematically between patient and control groups, the evidence that findings are neurobiologically meaningful is inconclusive and may represent artifacts or epiphenomena of uncertain value. The authors caution that uncritically accepting from study to study findings that may represent fallacies of all sorts carries the risk of misinforming practitioners and patients about biological abnormalities underlying psychiatric illness.
Dental bleaching is a common procedure, requested and accepted by patients with aesthetic requirements. The SEM images were taken at different degrees of magnification, always looking for cracks, ...porosities, or other changes at this level, which could be related to the sensitivity that appeared after such a procedure. The standard bleaching procedure was applied to the labial surface of the tooth. Biolase Laser white 20 bleaching putty was used, which contains 45% hydrogen peroxide and then activated with 940 nm laser light. The microscopic SEM images of the labial faces on which the 45% concentration hydrogen peroxide type bleaching gel was applied showed that they do not present any structural damage to the enamel.
We review studies that have used diffusion imaging (DI) and magnetic resonance spectroscopy (MRS) to investigate genetic associations. A brief description of the measures obtainable with these ...methods and of some methodological and interpretability limitations is given. The usefulness of DI and MRS in defining intermediate phenotypes and in demonstrating the effects of common genetic variants known to increase risk for psychiatric manifestations on anatomical and metabolic phenotypes is reviewed. The main focus is on schizophrenia where the greatest amount of data has been collected. Moreover, we present an example coming from a different approach, where the genetic alteration is known (the deletion that causes Williams syndrome) and the DI phenotype can shed new light on the function of genes affected by the mutation. We conclude that, although these are still early days of this type of research and many findings remain controversial, both techniques can significantly contribute to the understanding of genetic effects in the brain and the pathophysiology of psychiatric disorders.
The authors sought to study the transcriptomic and genomic features of completed suicide by parsing the method chosen, to capture molecular correlates of the distinctive frame of mind of individuals ...who die by suicide, while reducing heterogeneity.
The authors analyzed gene expression (RNA sequencing) from postmortem dorsolateral prefrontal cortex of patients who died by suicide with violent compared with nonviolent means, nonsuicide patients with the same psychiatric disorders, and a neurotypical group (total N=329). They then examined genomic risk scores (GRSs) for each psychiatric disorder included, and GRSs for cognition (IQ) and for suicide attempt, testing how they predict diagnosis or traits (total N=888).
Patients who died by suicide by violent means showed a transcriptomic pattern remarkably divergent from each of the other patient groups but less from the neurotypical group; consistently, their genomic profile of risk was relatively low for their diagnosed illness as well as for suicide attempt, and relatively high for IQ: they were more similar to the neurotypical group than to other patients. Differentially expressed genes (DEGs) associated with patients who died by suicide by violent means pointed to purinergic signaling in microglia, showing similarities to a genome-wide association study of
aggression. Weighted gene coexpression network analysis revealed that these DEGs were coexpressed in a context of mitochondrial metabolic activation unique to suicide by violent means.
These findings suggest that patients who die by suicide by violent means are in part biologically separable from other patients with the same diagnoses, and their behavioral outcome may be less dependent on genetic risk for conventional psychiatric disorders and be associated with an alteration of purinergic signaling and mitochondrial metabolism.
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