Functional investigation of a schizophrenia GWAS signal at the CDC42 gene
TL;DR: Evidence is found thatrs2473307, in strong LD with the schizophrenia associated SNP rs2473277, is a functional variant at CDC42 that may increase risk for schizophrenia by reducing expression of CDC42.
Abstract: Objectives: SNP rs2473277 upstream of the cell division cycle 42 (CDC42) gene was associated with schizophrenia in a recent genome-wide association study (GWAS). Reduced expression of CDC42 in schizophrenia has previously been reported. Our objective was to test whether the associated SNP affected CDC42 expression.
Methods: Two available SNP × gene expression datasets were accessed to test the effect of rs2473277 on CDC42 expression: (i) the mRNA by SNP Browser, which presents results of a genome-wide linkage study of gene expression, and (ii) the Genevar HapMap expression dataset. rs2473277 is in strong linkage disequilibrium (LD) with the SNP rs2473307 (r(2) = 0.96), which is predicted to affect transcription factor binding. rs2473307 was directly tested for allelic effects on gene expression using a gene reporter assay in a human neuronal cell line.
Results: In both datasets, the schizophrenia risk allele at rs2473277 was associated with a reduction in CDC42 mRNA levels. In the reporter gene assay the risk allele at rs2473307 similarly reduced gene expression.
Conclusions: We found evidence that rs2473307, in strong LD with the schizophrenia associated SNP rs2473277, is a functional variant at CDC42 that may increase risk for schizophrenia by reducing expression of CDC42.
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TL;DR: Analysis of axonal projections of pyramidal neurons from both Zdhhc8-deficient and Df(16)A(+/-) mice, which model the 22q11.2 deletion, revealed deficits in axonal growth and terminal arborization, which can be prevented by reintroduction of active ZDHHC8 protein.
145 citations
Cites background from "Functional investigation of a schiz..."
...We focused on the reduction of palmitoylated Cdc42 in Zdhhc8-deficient neurons (Figure 1), given the well-established role of Cdc42 in axonal development and the fact that alterations in Cdc42 expression have been consistently reported in the brains of patients with psychiatric disorders, including schizophrenia (Gilks et al., 2012; Ide and Lewis, 2010)....
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...In that context, it is worth noting that an increasingly strong link between a dysregulation of Akt and Cdc42 signaling and schizophrenia is emerging in humans and an association between schizophrenia and common Akt1 and Cdc42 genetic variants has been reported in several patient cohorts (Arguello and Gogos, 2008; Gilks et al., 2012; Ide and Lewis, 2010)....
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...…link between a dysregulation of Akt and Cdc42 signaling and schizophrenia is emerging in humans and an association between schizophrenia and common Akt1 and Cdc42 genetic variants has been reported in several patient cohorts (Arguello and Gogos, 2008; Gilks et al., 2012; Ide and Lewis, 2010)....
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...…neurons (Figure 1), given the well-established role of Cdc42 in axonal development and the fact that alterations in Cdc42 expression have been consistently reported in the brains of patients with psychiatric disorders, including schizophrenia (Gilks et al., 2012; Ide and Lewis, 2010)....
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TL;DR: A method based on a latent Dirichlet allocation model for predicting functional effects of noncoding genetic variants in a cell-type- and/or tissue-specific way (FUN-LDA), which suggests that tissue- and cell- type-specific functional prediction methods tend to have substantially better prediction accuracy than organism-level prediction methods.
Abstract: We describe a method based on a latent Dirichlet allocation model for predicting functional effects of noncoding genetic variants in a cell-type- and/or tissue-specific way (FUN-LDA). Using this unsupervised approach, we predict tissue-specific functional effects for every position in the human genome in 127 different tissues and cell types. We demonstrate the usefulness of our predictions by using several validation experiments. Using eQTL data from several sources, including the GTEx project, Geuvadis project, and TwinsUK cohort, we show that eQTLs in specific tissues tend to be most enriched among the predicted functional variants in relevant tissues in Roadmap. We further show how these integrated functional scores can be used for (1) deriving the most likely cell or tissue type causally implicated for a complex trait by using summary statistics from genome-wide association studies and (2) estimating a tissue-based correlation matrix of various complex traits. We found large enrichment of heritability in functional components of relevant tissues for various complex traits, and FUN-LDA yielded higher enrichment estimates than existing methods. Finally, using experimentally validated functional variants from the literature and variants possibly implicated in disease by previous studies, we rigorously compare FUN-LDA with state-of-the-art functional annotation methods and show that FUN-LDA has better prediction accuracy and higher resolution than these methods. In particular, our results suggest that tissue- and cell-type-specific functional prediction methods tend to have substantially better prediction accuracy than organism-level prediction methods. Scores for each position in the human genome and for each ENCODE and Roadmap tissue are available online (see Web Resources).
77 citations
TL;DR: This paper will focus on how the schizophrenic brain processes language and, particularly, on its distinctive oscillatory profile during language processing and will show that candidate genes for schizophrenia are overrepresented among the set of genes that are believed to be important for the evolution of the human faculty of language.
Abstract: Schizophrenia is characterized by marked language deficits, but it is not clear how these deficits arise from the alteration of genes related to the disease. The goal of this paper is to aid the bridging of the gap between genes and schizophrenia and, ultimately, give support to the view that the abnormal presentation of language in this condition is heavily rooted in the evolutionary processes that brought about modern language. To that end we will focus on how the schizophrenic brain processes language and, particularly, on its distinctive oscillatory profile during language processing. Additionally, we will show that candidate genes for schizophrenia are overrepresented among the set of genes that are believed to be important for the evolution of the human faculty of language. These genes crucially include (and are related to) genes involved in brain rhythmicity. We will claim that this translational effort and the links we uncover may help develop an understanding of language evolution, along with the etiology of schizophrenia, its clinical/linguistic profile, and its high prevalence among modern populations.
66 citations
TL;DR: There are changes in the extent of S-palmitoylation of many proteins in the frontal cortex in schizophrenia, suggesting a potential mechanism reconciling previous observations of abnormal intracellular targeting and trafficking of neurotransmitter receptors in this illness.
37 citations
TL;DR: A new method based on a latent Dirichlet allocation model for predicting functional effects of noncoding genetic variants in a cell type and tissue specific way (FUN-LDA) by integrating diverse epigenetic annotations for specific cell types and tissues from large scale epige-nomics projects such as ENCODE and Roadmap Epigenomics is described.
Abstract: We describe here a new method based on a latent Dirichlet allocation model for predicting functional effects of noncoding genetic variants in a cell type and tissue specific way (FUN-LDA) by integrating diverse epigenetic annotations for specific cell types and tissues from large scale epigenomics projects such as ENCODE and Roadmap Epigenomics. Using this unsupervised approach we predict tissue-specific functional effects for every position in the human genome. We demonstrate the usefulness of our predictions using several validation experiments. Using eQTL data from several sources, including the Genotype-Tissue Expression project, the Geuvadis project and TwinsUK cohort, we show that eQTLs in specific tissues tend to be most enriched among the predicted functional variants in relevant tissues in Roadmap. We further show how these integrated functional scores can be used to derive the most likely cell/tissue type causally implicated for a complex trait using summary statistics from genome-wide association studies, and estimate a tissue-based correlation matrix of various complex traits. We find large enrichment of heritability in functional components of relevant tissues for various complex traits, with FUN-LDA yielding the highest enrichment estimates relative to existing methods. Finally, using experimentally validated functional variants from the literature and variants possibly implicated in disease by previous studies, we rigorously compare FUN-LDA to state-of-the-art functional annotation methods such as GenoSkyline, ChromHMM, Segway, and IDEAS, and show that FUN-LDA has better prediction accuracy and higher resolution compared to these methods. In summary, we describe a new approach and perform rigorous comparisons with the most commonly used functional annotation methods, providing a valuable resource for the community interested in the functional annotation of noncoding variants. Scores for each position in the human genome and for each ENCODE/Roadmap tissue are available from http://www.columbia.edu/~ii2135/funlda.html.
17 citations
References
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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
"Functional investigation of a schiz..." refers methods in this paper
...In addition rs2473277 was tested for association with CDC42 mRNA level using PLINK (Purcell et al 2007)....
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...PLINK: a tool set for whole-genome association and population-based linkage analyses....
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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
"Functional investigation of a schiz..." refers methods in this paper
...SNPs in strong linkage disequilibrium (LD) with rs2473277 were identifi ed in the HapMap CEU genotype data using Haploview 4.1 (Barrett et al. 2005)....
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Broad Institute1, Harvard University2, QIMR Berghofer Medical Research Institute3, Cardiff University4, North Carolina State University5, Trinity College, Dublin6, University of Edinburgh7, Karolinska Institutet8, Uppsala University9, University of Southern California10, University of North Carolina at Chapel Hill11, University College London12, National Health Service13, University of Oxford14, University of Aberdeen15, Strathclyde Institute of Pharmacy and Biomedical Sciences16, State University of New York Upstate Medical University17, University of Coimbra18
TL;DR: The extent to which common genetic variation underlies the risk of schizophrenia is shown, using two analytic approaches, and the major histocompatibility complex is implicate, which is shown to involve thousands of common alleles of very small effect.
Abstract: Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%(1,2). We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.
4,573 citations
TL;DR: The recent availability of knockout mice for several members of the Rho family reveals new information about their roles in signalling to the cytoskeleton and in development.
Abstract: Rho GTPases are key regulators of cytoskeletal dynamics and affect many cellular processes, including cell polarity, migration, vesicle trafficking and cytokinesis. These proteins are conserved from plants and yeast to mammals, and function by interacting with and stimulating various downstream targets, including actin nucleators, protein kinases and phospholipases. The roles of Rho GTPases have been extensively studied in different mammalian cell types using mainly dominant negative and constitutively active mutants. The recent availability of knockout mice for several members of the Rho family reveals new information about their roles in signalling to the cytoskeleton and in development.
1,752 citations
"Functional investigation of a schiz..." refers background in this paper
...The GTPase gene family hydrolyse GTP, a major source of energy for a range of cellular functions, and behave as a molecular switch for particular pathways such as DNA replication, protein synthesis, vesicle traffi cking and signal transduction (Heasman and Ridley 2008)....
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Stephan Ripke1, Alan R. Sanders2, Kenneth S. Kendler3, Douglas F. Levinson4 +207 more•Institutions (71)
TL;DR: The authors examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects.
Abstract: We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 x 10(-11)) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 x 10(-9)), ANK3 (rs10994359, P = 2.5 x 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 x 10(-9)).
1,671 citations