Genetic association and identification of a functional SNP at GSK3β for schizophrenia susceptibility.
TL;DR: The findings suggest that GSK3β is likely a risk gene for schizophrenia, and its expression alteration caused by the risk SNP in the promoter region may contribute to the etiology of schizophrenia.
About: This article is published in Schizophrenia Research.The article was published on 2011-12-01. It has received 41 citations till now. The article focuses on the topics: Genetic model & Genetic association.
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TL;DR: An overview of how GSK-3β is regulated in physiological synaptic plasticity and how aberrant G SK-3 β activity contributes to the development of dysfunctional synaptic Plasticity in neuropsychiatric and neurodegenerative disorders is provided.
Abstract: In neurons, Glycogen Synthase Kinase-3β (GSK-3β) has been shown to regulate various critical processes underlying structural and functional synaptic plasticity. Mouse models with neuron-selective expression or deletion of GSK-3β present behavioral and cognitive abnormalities, positioning this protein kinase as a key signaling molecule in normal brain functioning. Furthermore, mouse models with defective GSK-3β activity display distinct structural and behavioral abnormalities, which model some aspects of different neurological and neuropsychiatric disorders. Equalizing GSK-3β activity in these mouse models by genetic or pharmacological interventions is able to rescue some of these abnormalities. Thus, GSK-3β is a relevant therapeutic target for the treatment of many brain disorders. Here, we provide an overview of how GSK-3β is regulated in physiological synaptic plasticity and how aberrant GSK-3β activity contributes to the development of dysfunctional synaptic plasticity in neuropsychiatric and neurodegenerative disorders.
74 citations
TL;DR: This review for the first time systematically presents the evidence for ZNF804A, describing its discovery and likely roles in brain development and schizophrenia pathogenesis, and summarizes this information with a systemic and broad assessment of recent findings.
Abstract: ZNF804A (zinc-finger protein 804A) has been recognized as a schizophrenia risk gene across multiple world populations. Its intronic single-nucleotide polymorphism (SNP) rs1344706 is among one of the strongest susceptibility variants that have achieved genome-wide significance in genome-wide association studies (GWAS) for schizophrenia and has been widely and intensively studied. To elucidate the biological mechanisms underlying the genetic risk conferred by rs1344706, we retrospectively analyzed the progresses in brain gene expression quantitative trait loci (eQTL) analyses, ZNF804A-induced pathway alterations in neural cells and changes in synaptic phenotypes associated with ZNF804A expression. Based on these data, we hypothesize a potential biological mechanism for a genetic risk allele of ZNF804A in schizophrenia pathogenesis. We also review the efforts being made to characterize the affected intermediate phenotypes using neuroimaging and neuropsychological approaches. We then discuss additional common and rare ZNF804A variants in schizophrenia susceptibility and the potential genetic heterogeneity of these genomic loci between Europeans and Asians. This review for we believe the first time systematically presents the evidence for ZNF804A, describing its discovery and likely roles in brain development and schizophrenia pathogenesis. We believe that this work has summarized this information with a systemic and broad assessment of recent findings.
56 citations
TL;DR: Data strongly suggest that the continuous blockade of DRD2 by antipsychotic(s) could eventually fail to control the psychosis in some point during long-term treatment, even if such treatment has successfully provided symptomatic improvement for the first-episode psychosis, or stability for the subsequent chronic stage.
Abstract: Although the dopamine D2 receptor (DRD2) has been a main target of antipsychotic pharmacotherapy for the treatment of schizophrenia, the standard treatment does not offer sufficient relief of symptoms to 20%–30% of patients suffering from this disorder. Moreover, over 80% of patients experience relapsed psychotic episodes within five years following treatment initiation. These data strongly suggest that the continuous blockade of DRD2 by antipsychotic(s) could eventually fail to control the psychosis in some point during long-term treatment, even if such treatment has successfully provided symptomatic improvement for the first-episode psychosis, or stability for the subsequent chronic stage. Dopamine supersensitivity psychosis (DSP) is historically known as a by-product of antipsychotic treatment in the manner of tardive dyskinesia or transient rebound psychosis. Numerous data in psychopharmacological studies suggest that the up-regulation of DRD2, caused by antipsychotic(s), is likely the mechanism underlying the development of the dopamine supersensitivity state. However, regardless of evolving notions of dopamine signaling, particularly dopamine release, signal transduction, and receptor recycling, most of this research has been conducted and discussed from the standpoint of disease etiology or action mechanism of the antipsychotic, not of DSP. Hence, the mechanism of the DRD2 up-regulation or mechanism evoking clinical DSP, both of which are caused by pharmacotherapy, remains unknown. Once patients experience a DSP episode, they become increasingly difficult to treat. Light was recently shed on a new aspect of DSP as a treatment-resistant factor. Clarification of the detailed mechanism of DSP is therefore crucial, and a preventive treatment strategy for DSP or treatment-resistant schizophrenia is urgently needed.
52 citations
TL;DR: It is suggested that the potential role of Wnt/β-catenin signaling might lead to new therapeutic strategies for neurological diseases, including, but not limited to, spinal cord injury, Alzheimer’s disease, Parkinson's disease, and depression.
Abstract: Neural stem/progenitor cells (NSCs) maintain the ability of self-renewal and differentiation and compose the complex nervous system. Wnt signaling is thought to control the balance of NSC proliferation and differentiation via the transcriptional coactivator β-catenin during brain development and adult tissue homeostasis. Disruption of Wnt signaling may result in developmental defects and neurological diseases. Here, we summarize recent findings of the roles of Wnt/β-catenin signaling components in NSC homeostasis for the regulation of functional brain circuits. We also suggest that the potential role of Wnt/β-catenin signaling might lead to new therapeutic strategies for neurological diseases, including, but not limited to, spinal cord injury, Alzheimer's disease, Parkinson's disease, and depression.
43 citations
TL;DR: The present study provides a necessary framework to understand the role of LEF1/TCF factors in thalamic and midbrain development until adulthood and predicts that the regulatory role of these proteins in the adult brain is significantly different from their role in the embryonic brain or other non-neural tissues.
Abstract: β-Catenin signaling, leading to the activation of lymphoid enhancer-binding factor 1/T cell factor (LEF1/TCF) transcription factors, plays a well-established role in transcription regulation during development and tissue homeostasis. In the adult organism, the activity of this pathway has been found in stem cell niches and postmitotic thalamic neurons. Recently, studies show that mutations in components of β-catenin signaling networks have been associated with several psychiatric disorders, indicating the involvement of β-catenin and LEF1/TCF proteins in the proper functioning of the brain. Here, we report a comprehensive analysis of LEF1/TCF protein localization and the expression profile of their isoforms in cortical, thalamic, and midbrain regions in mice. We detected LEF1 and TCF7L2 proteins in neurons of the thalamus and dorsal midbrain, i.e., subcortical regions specialized in the integration of diverse sources of sensory information. These neurons also exhibited nuclear localization of β-catenin, suggesting the involvement of β-catenin/LEF1/TCF7L2 in the regulation of gene expression in these regions. Analysis of alternative splicing and promoter usage identified brain-specific TCF7L2 isoforms and revealed a developmentally coordinated transition in the composition of LEF1 and TCF7L2 isoforms. In the case of TCF7L2, the typical brain isoforms lack the so-called C clamp; in addition, the dominant-negative isoforms are predominant in the embryonic thalamus but disappear postnatally. The present study provides a necessary framework to understand the role of LEF1/TCF factors in thalamic and midbrain development until adulthood and predicts that the regulatory role of these proteins in the adult brain is significantly different from their role in the embryonic brain or other non-neural tissues.
37 citations
Cites background from "Genetic association and identificat..."
...In addition, several other Wnt pathway components, such as FZD3, GSK-3b, DKK4, and APC, have been shown to be associated with susceptibility to schizophrenia (Cui et al. 2005; Kishimoto et al. 2008; Proitsi et al. 2008; Li et al. 2011), and many proteins mutated in sporadic autism are part of the b-catenin signaling network (O’Roak et al....
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...…such as FZD3, GSK-3b, DKK4, and APC, have been shown to be associated with susceptibility to schizophrenia (Cui et al. 2005; Kishimoto et al. 2008; Proitsi et al. 2008; Li et al. 2011), and many proteins mutated in sporadic autism are part of the b-catenin signaling network (O’Roak et al. 2012)....
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References
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Book•
01 Dec 1969TL;DR: The concepts of power analysis are discussed in this paper, where Chi-square Tests for Goodness of Fit and Contingency Tables, t-Test for Means, and Sign Test are used.
Abstract: Contents: Prefaces. The Concepts of Power Analysis. The t-Test for Means. The Significance of a Product Moment rs (subscript s). Differences Between Correlation Coefficients. The Test That a Proportion is .50 and the Sign Test. Differences Between Proportions. Chi-Square Tests for Goodness of Fit and Contingency Tables. The Analysis of Variance and Covariance. Multiple Regression and Correlation Analysis. Set Correlation and Multivariate Methods. Some Issues in Power Analysis. Computational Procedures.
115,069 citations
49,129 citations
"Genetic association and identificat..." refers methods in this paper
...We performed a power calculation using the G* power program based on Cohen's method (Cohen, 1988)....
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TL;DR: G*Power 3 provides improved effect size calculators and graphic options, supports both distribution-based and design-based input modes, and offers all types of power analyses in which users might be interested.
Abstract: G*Power (Erdfelder, Faul, & Buchner, 1996) was designed as a general stand-alone power analysis program for statistical tests commonly used in social and behavioral research. G*Power 3 is a major extension of, and improvement over, the previous versions. It runs on widely used computer platforms (i.e., Windows XP, Windows Vista, and Mac OS X 10.4) and covers many different statistical tests of thet, F, and χ2 test families. In addition, it includes power analyses forz tests and some exact tests. G*Power 3 provides improved effect size calculators and graphic options, supports both distribution-based and design-based input modes, and offers all types of power analyses in which users might be interested. Like its predecessors, G*Power 3 is free.
40,195 citations
"Genetic association and identificat..." refers methods in this paper
...The commonly used effect size of 0.1 and 0.2 were used in the power analysis, which are correspondentwith a “weak” gene effect, and a “weak to moderate” gene effect, respectively (Faul et al., 2007)....
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...2 were used in the power analysis, which are correspondentwith a “weak” gene effect, and a “weak to moderate” gene effect, respectively (Faul et al., 2007)....
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...Power analysis was performed using the software G*power (Faul et al., 2007)....
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TL;DR: This work introduces PLINK, an open-source C/C++ WGAS tool set, and describes the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation, which focuses on the estimation and use of identity- by-state and identity/descent information in the context of population-based whole-genome studies.
Abstract: Whole-genome association studies (WGAS) bring new computational, as well as analytic, challenges to researchers. Many existing genetic-analysis tools are not designed to handle such large data sets in a convenient manner and do not necessarily exploit the new opportunities that whole-genome data bring. To address these issues, we developed PLINK, an open-source C/C++ WGAS tool set. With PLINK, large data sets comprising hundreds of thousands of markers genotyped for thousands of individuals can be rapidly manipulated and analyzed in their entirety. As well as providing tools to make the basic analytic steps computationally efficient, PLINK also supports some novel approaches to whole-genome data that take advantage of whole-genome coverage. We introduce PLINK and describe the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation. In particular, we focus on the estimation and use of identity-by-state and identity-by-descent information in the context of population-based whole-genome studies. This information can be used to detect and correct for population stratification and to identify extended chromosomal segments that are shared identical by descent between very distantly related individuals. Analysis of the patterns of segmental sharing has the potential to map disease loci that contain multiple rare variants in a population-based linkage analysis.
26,280 citations
"Genetic association and identificat..." refers methods in this paper
...Allelic and genotypic associationswere accessedwith PLINK, and the results were corrected by Bonferroni method based on the total number of tests conducted (36 tests in total considering the 9 SNPs and four types of genetic models for allelic, additive, dominant and recessive tests ) (Purcell et al., 2007)....
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...…genotypic associationswere accessedwith PLINK, and the results were corrected by Bonferroni method based on the total number of tests conducted (36 tests in total considering the 9 SNPs and four types of genetic models for allelic, additive, dominant and recessive tests ) (Purcell et al., 2007)....
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TL;DR: Haploview is a software package that provides computation of linkage disequilibrium statistics and population haplotype patterns from primary genotype data in a visually appealing and interactive interface.
Abstract: Summary: Research over the last few years has revealed significant haplotype structure in the human genome. The characterization of these patterns, particularly in the context of medical genetic association studies, is becoming a routine research activity. Haploview is a software package that provides computation of linkage disequilibrium statistics and population haplotype patterns from primary genotype data in a visually appealing and interactive interface.
Availability: http://www.broad.mit.edu/mpg/haploview/
Contact: jcbarret@broad.mit.edu
13,862 citations
"Genetic association and identificat..." refers methods in this paper
...Similar results were obtained for rs13320980 librium (LD) of the tested SNPs was calculated using the r2 algorithm in the Haploview Table 1 Allele frequency and single SNP association (p value) of the 3 SNPs in our samples....
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...We first examined the LD pattern of GSK3β gene in the CHB population (Han Chinese from Beijing) using data from HapMap, and selected 8 tagging SNPs (rs3755557, rs334558, rs6774210, rs7431209, rs6782799, rs13320980, rs16830594 and rs4688043) with the use of the tagger procedure implemented in Haploview (Barrett et al., 2005)....
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...The Haploview program (version 4.1) was applied to test the genotypic distributions of SNPs for Hardy–Weinberg equilibrium (HWE), to estimate linkage disequilibrium (LD) between paired SNPs using the r2 algorithm, and to determine the haplotype blocks (Barrett et al., 2005)....
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...…of GSK3β gene in the CHB population (Han Chinese from Beijing) using data from HapMap, and selected 8 tagging SNPs (rs3755557, rs334558, rs6774210, rs7431209, rs6782799, rs13320980, rs16830594 and rs4688043) with the use of the tagger procedure implemented in Haploview (Barrett et al., 2005)....
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