Unknown,Transcriptomics,Genomics,Proteomics

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Global DNA methylation comparison of olfactory neurosphere-derived cells, fibroblasts and induced pluripotent stem cells derived from the same schizophrenic donors

ABSTRACT: Epigenetics describes mechanisms via which the environment can act on the genome, including DNA methylation of promoter regions of genes. This could be a way that environmental risk factors could affect neurodevelopment in individuals at risk for schizophrenia. Patient-derived cells provide a means whereby epigenetics and gene-environment interactions might be investigated. Induced pluripotent stem cells (iPS cells) present an attractive patient-derived cellular model because they can be differentiated into cell types of interest in schizophrenia. In this study the influence of the reprogramming process on schizophrenia-associated DNA methylation was investigated through genome-wide DNA methylation profiling and gene expression of patient-derived iPS cells and the fibroblasts from which they were derived. Olfactory neurosphere-derived cells (ONS cells) from the same patients were also profiled to provide a window on epigenetic regulation in three distinct cell types. Patient-derived cell were compared to cells derived from healthy controls to identify differences in DNA methylation and gene expression associated with schizophrenia in three cell types. The main finding is that iPS cells, prior to neuronal differentiation, demonstrated significant schizophrenia-associated differences in DNA methylation. This is in contrast to the fibroblasts from which they were derived, which show lesser schizophrenia-associated differences in DNA methylation. Like iPS cells, ONS cells showed robust significant schizophrenia-associated differences in DNA methylation. Notably, the schizophrenia-associated differences in DNA methylation were unique for each cell type, with little overlap between them, and only 5 genes commonly methylated in all cell types. Gene expression differences among the cell types mirrored the DNA methylation differences in magnitude, again with little overlap in specific genes affected. Gene Ontology analysis of the affected genes identified common cellular process affected in all three cell types without the same genes contributing. These data suggest that most DNA methylation differences are driven by the demands imposed by each cell type with schizophrenia-associated differences also being cell-type specific. Thus DNA methylation may not be a cause of schizophrenia-associated differences in cell functions in these cells but rather a downstream consequence of some unidentified causative mechanisms. This dataset represents the DNA methylation part of the study. The gene expression data is deposited under accession E-MTAB-5016.

ORGANISM(S): Homo sapiens

SUBMITTER: Nicholas Matigian

PROVIDER: E-MTAB-2154 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Background: Schizophrenia is a severe, highly heritable, neuropsychiatric disorder characterized by episodic psychosis and altered cognitive function. Despite success in identifying genetic variants associated with schizophrenia, there remains uncertainty about the causal genes involved in disease pathogenesis and how their function is regulated. Insights into the functional complexity of the genome have focussed attention on the role of non-sequence-based genomic variation in health and disease. Although a better understanding of the molecular mechanisms underlying disease phenotypes is best achieved using an integrated functional genomics strategy, few studies have attempted to systematically integrate genetic and epigenetic epidemiological approaches. Results: We performed a multi-stage epigenome-wide association study (EWAS), quantifying genome-wide patterns of DNA methylation in a total of 1,801 individuals from three independent sample cohorts. We identified multiple differentially methylated positions (DMPs) and region (DMRs) associated with schizophrenia, independently of important confounders such as smoking, with consistent effects across the three independent cohorts. We also show that polygenic burden for schizophrenia is associated with epigenetic variation at multiple loci across the genome, independently of loci implicated in the analysis of diagnosed schizophrenia. Finally, we show how DNA methylation quantitative trait loci (mQTL) analyses can be used to annotate the extended genomic regions nominated by genetic studies of schizophrenia, with Bayesian co-localization analyses highlighting potential regulatory variation causally involved in disease. Conclusion: This study represents the first systematic integrated analysis of genetic and epigenetic variation in schizophrenia, introducing a methodological pipeline that can be used to inform EWAS analyses of other complex traits and diseases. We demonstrate the utility of using polygenic risk score (PRS) for identifying molecular variation associated with etiological variation, and mQTLs for refining the functional/regulatory variation associated with schizophrenia risk variants. Finally, we present strong evidence for the co-localization of genetic associations for schizophrenia and differential DNA methylation. 675 whole blood derived DNA samples (353 schizophrenia cases and 322 controls) representing phase 1 of our meta-analysis. Bisulfite converted DNA from these samples were hybridized to the Illumina Infinium 450k Human Methylation Beadchip v1.0.

Project description:Abstract Background: Schizophrenia is a severe, highly heritable, neuropsychiatric disorder characterized by episodic psychosis and altered cognitive function. Despite success in identifying genetic variants associated with schizophrenia, there remains uncertainty about the causal genes involved in disease pathogenesis and how their function is regulated. Insights into the functional complexity of the genome have focussed attention on the role of non-sequence-based genomic variation in health and disease. Although a better understanding of the molecular mechanisms underlying disease phenotypes is best achieved using an integrated functional genomics strategy, few studies have attempted to systematically integrate genetic and epigenetic epidemiological approaches. Results: We performed a multi-stage epigenome-wide association study (EWAS), quantifying genome-wide patterns of DNA methylation in a total of 1,801 individuals from three independent sample cohorts. We identified multiple differentially methylated positions (DMPs) and region (DMRs) associated with schizophrenia, independently of important confounders such as smoking, with consistent effects across the three independent cohorts. We also show that polygenic burden for schizophrenia is associated with epigenetic variation at multiple loci across the genome, independently of loci implicated in the analysis of diagnosed schizophrenia. Finally, we show how DNA methylation quantitative trait loci (mQTL) analyses can be used to annotate the extended genomic regions nominated by genetic studies of schizophrenia, with Bayesian co-localization analyses highlighting potential regulatory variation causally involved in disease. Conclusion: This study represents the first systematic integrated analysis of genetic and epigenetic variation in schizophrenia, introducing a methodological pipeline that can be used to inform EWAS analyses of other complex traits and diseases. We demonstrate the utility of using polygenic risk score (PRS) for identifying molecular variation associated with etiological variation, and mQTLs for refining the functional/regulatory variation associated with schizophrenia risk variants. Finally, we present strong evidence for the co-localization of genetic associations for schizophrenia and differential DNA methylation. 847 whole blood derived DNA samples (414 schizophrenia cases and 433 controls) representing phase 2 of our meta-analysis. Bisulfite converted DNA from these samples were hybridised to the Illumina Infinium 450k Human Methylation Beadchip v1.0.

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Global DNA methylation comparison of olfactory neurosphere-derived cells, fibroblasts and induced pluripotent stem cells derived from the same schizophrenic donors

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