The genetic architecture of schizophrenia, bipolar disorder, obsessive-compulsive disorder and autism spectrum disorder.
TL;DR: Regulation of the hippo signaling pathway was commonly associated with ASD, SCZ, BD and OCD, implicating neural development and neuronal maintenance as key in neuropsychiatric disorders.
About: This article is published in Molecular and Cellular Neuroscience.The article was published on 2018-04-01. It has received 59 citations till now. The article focuses on the topics: Schizophrenia & Autism spectrum disorder.
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TL;DR: This work demonstrates how sensitive the geographic patterns of current PSs are for small biases even within relatively homogeneous populations and provides simple tools to identify such biases.
Abstract: Polygenic scores (PSs) are becoming a useful tool to identify individuals with high genetic risk for complex diseases, and several projects are currently testing their utility for translational applications. It is also tempting to use PSs to assess whether genetic variation can explain a part of the geographic distribution of a phenotype. However, it is not well known how the population genetic properties of the training and target samples affect the geographic distribution of PSs. Here, we evaluate geographic differences, and related biases, of PSs in Finland in a geographically well-defined sample of 2,376 individuals from the National FINRISK study. First, we detect geographic differences in PSs for coronary artery disease (CAD), rheumatoid arthritis, schizophrenia, waist-hip ratio (WHR), body-mass index (BMI), and height, but not for Crohn disease or ulcerative colitis. Second, we use height as a model trait to thoroughly assess the possible population genetic biases in PSs and apply similar approaches to the other phenotypes. Most importantly, we detect suspiciously large accumulations of geographic differences for CAD, WHR, BMI, and height, suggesting bias arising from the population's genetic structure rather than from a direct genotype-phenotype association. This work demonstrates how sensitive the geographic patterns of current PSs are for small biases even within relatively homogeneous populations and provides simple tools to identify such biases. A thorough understanding of the effects of population genetic structure on PSs is essential for translational applications of PSs.
81 citations
TL;DR: Thirty hub genes with a high degree of connectivity in the PPI network are significantly enriched in positive regulation of transcription and might have important clinical implications for BD treatment and diagnosis.
Abstract: Bipolar disorder (BD) is a complex mental disorder with high mortality and disability rates worldwide; however, research on its pathogenesis and diagnostic methods remains limited. This study aimed to elucidate potential candidate hub genes and key pathways related to BD in a pre-frontal cortex sample. Raw gene expression profile files of GSE53987, including 36 samples, were obtained from the gene expression omnibus (GEO) database. After data pre-processing, 10,094 genes were selected for weighted gene co-expression network analysis (WGCNA). After dividing highly related genes into 19 modules, we found that the pink, midnight blue, and brown modules were highly correlated with BD. Functional annotation and pathway enrichment analysis for modules, which indicated some key pathways, were conducted based on the Enrichr database. One of the most remarkable significant pathways is the Hippo signaling pathway and its positive transcriptional regulation. Finally, 30 hub genes were identified in three modules. Hub genes with a high degree of connectivity in the PPI network are significantly enriched in positive regulation of transcription. In addition, the hub genes were validated based on another dataset (GSE12649). Taken together, the identification of these 30 hub genes and enrichment pathways might have important clinical implications for BD treatment and diagnosis.
62 citations
TL;DR: Findings largely suggest comparable levels of social cognitive impairment in ASD and SCZ, which may support the use of existing social cognitive interventions across disorders, but future work is needed to determine whether the mechanisms underlying these shared impairments are also similar or if these common behavioral profiles may emerge via different pathways.
Abstract: Background Autism spectrum disorder (ASD) and schizophrenia (SCZ) are separate neurodevelopmental disorders that are both characterized by difficulties in social cognition and social functioning. Due to methodological confounds, the degree of similarity in social cognitive impairments across these two disorders is currently unknown. This study therefore conducted a comprehensive comparison of social cognitive ability in ASD and SCZ to aid efforts to develop optimized treatment programs. Methods
In total, 101 individuals with ASD, 92 individuals with SCZ or schizoaffective disorder, and 101 typically developing (TD) controls, all with measured intelligence in the normal range and a mean age of 25.47 years, completed a large battery of psychometrically validated social cognitive assessments spanning the domains of emotion recognition, social perception, mental state attribution, and attributional style. Results
Both ASD and SCZ performed worse than TD controls, and very few differences were evident between the two clinical groups, with effect sizes (Cohen's d) ranging from 0.01 to 0.34. For those effects that did reach statistical significance, such as greater hostility in the SCZ group, controlling for symptom severity rendered them non-significant, suggesting that clinical distinctions may underlie these social cognitive differences. Additionally, the strength of the relationship between neurocognitive and social cognitive performance was of similar, moderate size for ASD and SCZ. Conclusions
Findings largely suggest comparable levels of social cognitive impairment in ASD and SCZ, which may support the use of existing social cognitive interventions across disorders. However, future work is needed to determine whether the mechanisms underlying these shared impairments are also similar or if these common behavioral profiles may emerge via different pathways.
60 citations
Cites background from "The genetic architecture of schizop..."
...Indeed, a growing literature has identified genetic overlap between SCZ and ASD, particularly in relation to dopaminergic and serotonergic pathways (Khanzada et al., 2017; O’Connell et al., 2018), and imaging studies have also highlighted comparable reductions of neural activation in frontolimbic networks and superior temporal sulcus during tasks of social cognition in ASD and SCZ (Pinkham et al....
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...…has identified genetic overlap between SCZ and ASD, particularly in relation to dopaminergic and serotonergic pathways (Khanzada et al., 2017; O’Connell et al., 2018), and imaging studies have also highlighted comparable reductions of neural activation in frontolimbic networks and superior…...
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TL;DR: A narrative review of the literature available through April 2020 on imaging studies of adolescents with either ASD or early-onset psychosis to better understand the shared and unique neural mechanisms of social difficulties across diagnosis from a developmental framework focuses on functional connectivity studies of the default mode network (DMN), as the most extensively studied brain network relevant to social cognition across both groups.
Abstract: Recent studies have demonstrated substantial phenotypic overlap, notably social impairment, between autism spectrum disorder (ASD) and schizophrenia However, the neural mechanisms underlying the pathogenesis of social impairments across these distinct neuropsychiatric disorders has not yet been fully examined Most neuroimaging studies to date have focused on adults with these disorders, with little known about the neural underpinnings of social impairments in younger populations Here, we present a narrative review of the literature available through April 2020 on imaging studies of adolescents with either ASD or early-onset psychosis (EOP), to better understand the shared and unique neural mechanisms of social difficulties across diagnosis from a developmental framework We specifically focus on functional connectivity studies of the default mode network (DMN), as the most extensively studied brain network relevant to social cognition across both groups Our review included 29 studies of DMN connectivity in adolescents with ASD (Mean age range = 112-216 years), and 14 studies in adolescents with EOP (Mean age range = 142-243 years) Of these, 15 of 29 studies in ASD adolescents found predominant underconnectivity when examining DMN connectivity In contrast, findings were mixed in adolescents with EOP, with five of 14 studies reporting DMN underconnectivity, and an additional six of 14 studies reporting both under- and over-connectivity of the DMN Specifically, intra-DMN networks were more frequently underconnected in ASD, but overconnected in EOP On the other hand, inter-DMN connectivity patterns were mixed (both under- and over-connected) for each group, especially DMN connectivity with frontal, sensorimotor, and temporoparietal regions in ASD, and with frontal, temporal, subcortical, and cerebellar regions in EOP Finally, disrupted DMN connectivity appeared to be associated with social impairments in both groups, less so with other features distinct to each condition, such as repetitive behaviors/restricted interests in ASD and hallucinations/delusions in EOP Further studies on demographically well-matched groups of adolescents with each of these conditions are needed to systematically explore additional contributing factors in DMN connectivity patterns such as clinical heterogeneity, pubertal development, and medication effects that would better inform treatment targets and facilitate prediction of outcomes in the context of these developmental neuropsychiatric conditions
42 citations
TL;DR: A computational model of obsessive-compulsive disorder is developed on the basis of the well-developed framework of the Bayesian brain, where a difficulty in relying on past events to predict the consequences of patients' own actions and the unfolding of possible events is proposed.
Abstract: In this article, we develop a computational model of obsessive-compulsive disorder (OCD). We propose that OCD is characterized by a difficulty in relying on past events to predict the consequences of patients' own actions and the unfolding of possible events. Clinically, this corresponds both to patients' difficulty in trusting their own actions (and therefore repeating them), and to their common preoccupation with unlikely chains of events. Critically, we develop this idea on the basis of the well-developed framework of the Bayesian brain, where this impairment is formalized as excessive uncertainty regarding state transitions. We illustrate the validity of this idea using quantitative simulations and use these to form specific empirical predictions. These predictions are evaluated in relation to existing evidence, and are used to delineate directions for future research. We show how seemingly unrelated findings and phenomena in OCD can be explained by the model, including a persistent experience that actions were not adequately performed and a tendency to repeat actions; excessive information gathering (i.e., checking); indecisiveness and pathological doubt; overreliance on habits at the expense of goal-directed behavior; and overresponsiveness to sensory stimuli, thoughts, and feedback. We discuss the relationship and interaction between our model and other prominent models of OCD, including models focusing on harm-avoidance, not-just-right experiences, or impairments in goal-directed behavior. Finally, we outline potential clinical implications and suggest lines for future research. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
38 citations
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Journal Article•
TL;DR: Diagnostic and statistical manual of mental disorders (DSM-5) was translated by psychiatrists and psychologists, mainly from the University psychiatric hospital Vrapce and published by the Naklada Slap publisher.
Abstract: Title: Diagnostic and statistical manual of mental disorders (DSM-5) Author: American Psychiatric Association Editors of Croatian Edition: Vlado Jukic, Goran Arbanas ISBN: 978-953-191-787-2 Publisher: Naklada Slap, Jastrebarsko, Croatia Number of pages: 936Diagnostic and statistical manual of mental disorders is a national classification, but since its third edition it became a worldwide used manual. [1] It has been published by the American Psychiatric Association and two years ago the fifth edition was released. [2] Croatian was among the first languages this book was translated to. [3] DSM-5 was translated by psychiatrists and psychologists, mainly from the University psychiatric hospital Vrapce and published by the Naklada Slap publisher.DSM has always been more publicly debated than the other main classification - the International Classification of Diseases (ICD). [4] The same happened with this fifth edition. Even before it was released, numerous individuals, organizations, groups and associations were publicly speaking about the classification, new diagnostic entities and changing criteria. [5]Although there is a tendency of authors of both DSM and ICD to synchronize these two classifications and to make them more harmonized with each new edition, there are several differences among them. While ICD covers all the diseases, disorders and reasons for making a contact with the health system, DSM covers "only" mental disorders. Other disorders (medical conditions, as they are named in DSM-5) are not included, except in situations when they lead to a development of a mental disorder. The other main difference is that DSM is more operational zed, and gives criteria for each of the disorders, listing how many criteria have to be met to make a diagnosis of a particular disorder, and what excluding criteria are.Due to the fact that it is used all around the globe and since it has become the most used psychiatric manual, it is sometimes said that DSM is a "psychiatric Bible". [6]Some critics of DSM say that it stigmatizes people and that in each edition it includes more diagnostic entities. It is true that in each edition of DSM there are more disorders listed, but this is due to the fact that medicine is a developing area and new insights are made every year, so some disorders are separated into different subtypes or subgroups and different new diagnoses, giving the impression more behaviour are being pathologized. The intention of the authors was to make more homogenous groups. But, the truth is that, compared with ICD, it is more difficult to get a diagnosis in DSM, than in ICD, with the same clinical presentation. [7] DSM requires functional impairment or distress to pathologize behaviour, while in ICD this criterion is not present in every case.During the process of developing DSM-5 there was an open public discussion. [2] For over a year any person was able to participate in the discussion about future criteria, inclusion or exclusion of diagnostic entities from DSM. More than 21000 letters was sent to the authors. This was the unprecedented way of developing a classification that ICD now tries to follow in preparation of its 11th edition.As a direct consequence of such an open and wide discussion, some new disorders were included (e.g. hoarding disorder), some were excluded even though they were included during the proposal period (e.g. hypersexual disorders), some were heavily debated (e.g. narcissistic personality disorder). [8-10]As previously mentioned, DSM and ICD systems try to harmonize more. There were more non-American authors included in DSM-5 than ever before and some of the experts in the field were in the task force of DSM-5 and ICD-11. [2, 11]What is new in DSM-5, compared to DSM-IV. The organization of the chapters has been changed, so now the flow of the disorders follow life cycle. The book starts with neurodevelopmental disorders, followed by schizophrenia, bipolar and depressive disorders, and closing with neurocognitive disorders. …
15,478 citations
TL;DR: H hierarchical and self-consistent orthology annotations are introduced for all interacting proteins, grouping the proteins into families at various levels of phylogenetic resolution in the STRING database.
Abstract: The many functional partnerships and interactions that occur between proteins are at the core of cellular processing and their systematic characterization helps to provide context in molecular systems biology. However, known and predicted interactions are scattered over multiple resources, and the available data exhibit notable differences in terms of quality and completeness. The STRING database (http://string-db.org) aims to provide a critical assessment and integration of protein-protein interactions, including direct (physical) as well as indirect (functional) associations. The new version 10.0 of STRING covers more than 2000 organisms, which has necessitated novel, scalable algorithms for transferring interaction information between organisms. For this purpose, we have introduced hierarchical and self-consistent orthology annotations for all interacting proteins, grouping the proteins into families at various levels of phylogenetic resolution. Further improvements in version 10.0 include a completely redesigned prediction pipeline for inferring protein-protein associations from co-expression data, an API interface for the R computing environment and improved statistical analysis for enrichment tests in user-provided networks.
8,224 citations
"The genetic architecture of schizop..." refers methods in this paper
...org) was used to produce a network diagram of the genes common to ASD, BD, SCZ and OCD (Szklarczyk et al., 2015)....
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...STRING v10 (http://version10.string-db.org) was used to produce a network diagram of the genes common to ASD, BD, SCZ and OCD (Szklarczyk et al., 2015)....
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TL;DR: A significant update to one of the tools in this domain called Enrichr, a comprehensive resource for curated gene sets and a search engine that accumulates biological knowledge for further biological discoveries is presented.
Abstract: Enrichment analysis is a popular method for analyzing gene sets generated by genome-wide experiments. Here we present a significant update to one of the tools in this domain called Enrichr. Enrichr currently contains a large collection of diverse gene set libraries available for analysis and download. In total, Enrichr currently contains 180 184 annotated gene sets from 102 gene set libraries. New features have been added to Enrichr including the ability to submit fuzzy sets, upload BED files, improved application programming interface and visualization of the results as clustergrams. Overall, Enrichr is a comprehensive resource for curated gene sets and a search engine that accumulates biological knowledge for further biological discoveries. Enrichr is freely available at: http://amp.pharm.mssm.edu/Enrichr.
6,201 citations
"The genetic architecture of schizop..." refers methods in this paper
...Finally, the combined score is a combination of the p-value and z-score calculated by multiplying the two scores (combined score= log(p-value ∗ Z-score)) (Kuleshov et al., 2016)....
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...Genes identified to be common to all disorders, or unique to one specific disorder, were included for enrichment analyses using Enrichr (http://amp.pharm.mssm.edu/Enrichr) (Kuleshov et al., 2016)....
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...The Z-score is computed for deviation from an expected rank using a modification to Fisher's exact test....
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...Enrichr computes enrichment by assessing 35 gene-set libraries (including KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways and GO (gene ontology) biological processes) and calculates p-values, adjusted p-values, Z-scores and combined scores representative of Fisher exact and Z-score statistics....
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TL;DR: The first genome-wide, single-base-resolution maps of methylated cytosines in a mammalian genome, from both human embryonic stem cells and fetal fibroblasts, along with comparative analysis of messenger RNA and small RNA components of the transcriptome, several histone modifications, and sites of DNA-protein interaction for several key regulatory factors were presented in this article.
Abstract: DNA cytosine methylation is a central epigenetic modification that has essential roles in cellular processes including genome regulation, development and disease. Here we present the first genome-wide, single-base-resolution maps of methylated cytosines in a mammalian genome, from both human embryonic stem cells and fetal fibroblasts, along with comparative analysis of messenger RNA and small RNA components of the transcriptome, several histone modifications, and sites of DNA-protein interaction for several key regulatory factors. Widespread differences were identified in the composition and patterning of cytosine methylation between the two genomes. Nearly one-quarter of all methylation identified in embryonic stem cells was in a non-CG context, suggesting that embryonic stem cells may use different methylation mechanisms to affect gene regulation. Methylation in non-CG contexts showed enrichment in gene bodies and depletion in protein binding sites and enhancers. Non-CG methylation disappeared upon induced differentiation of the embryonic stem cells, and was restored in induced pluripotent stem cells. We identified hundreds of differentially methylated regions proximal to genes involved in pluripotency and differentiation, and widespread reduced methylation levels in fibroblasts associated with lower transcriptional activity. These reference epigenomes provide a foundation for future studies exploring this key epigenetic modification in human disease and development.
4,266 citations