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      DNA methylation changes in the postmortem dorsolateral prefrontal cortex of patients with schizophrenia

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          Abstract

          Background: Schizophrenia is a complex psychiatric disorder with a lifetime morbidity rate of 0.5–1.0%. The pathophysiology of schizophrenia still remains obscure. Accumulating evidence indicates that DNA methylation, which is the addition of a methyl group to the cytosine in a CpG dinucleotide, might play an important role in the pathogenesis of schizophrenia.

          Methods: To gain further insight into the molecular mechanisms underlying schizophrenia, a genome-wide DNA methylation profiling (27,578 CpG dinucleotides spanning 14,495 genes) of the human dorsolateral prefrontal cortex (DLPFC) was conducted in a large cohort ( n = 216) of well characterized specimens from individuals with schizophrenia and non-psychiatric controls, combined with an analysis of genetic variance at ~880,000 SNPs.

          Results: Aberrant DNA methylation in schizophrenia was identified at 107 CpG sites at 5% Bonferroni correction ( p < 1.99 × 10 −6). Of these significantly altered sites, hyper-DNA methylation was observed at 79 sites (73.8%), mostly in the CpG islands (CGIs) and in the regions flanking CGIs (CGI: 31 sites; CGI shore: 35 sites; CGI shelf: 3 sites). Furthermore, a large number of cis-methylation quantitative trait loci (mQTL) were identified, including associations with risk SNPs implicated in schizophrenia.

          Conclusions: These results suggest that altered DNA methylation might be involved in the pathophysiology and/or treatment of schizophrenia, and that a combination of epigenetic and genetic approaches will be useful to understanding the molecular mechanism of this complex disorder.

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          Most cited references 39

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          Functional annotation of the human brain methylome identifies tissue-specific epigenetic variation across brain and blood

          Background Dynamic changes to the epigenome play a critical role in establishing and maintaining cellular phenotype during differentiation, but little is known about the normal methylomic differences that occur between functionally distinct areas of the brain. We characterized intra- and inter-individual methylomic variation across whole blood and multiple regions of the brain from multiple donors. Results Distinct tissue-specific patterns of DNA methylation were identified, with a highly significant over-representation of tissue-specific differentially methylated regions (TS-DMRs) observed at intragenic CpG islands and low CG density promoters. A large proportion of TS-DMRs were located near genes that are differentially expressed across brain regions. TS-DMRs were significantly enriched near genes involved in functional pathways related to neurodevelopment and neuronal differentiation, including BDNF, BMP4, CACNA1A, CACA1AF, EOMES, NGFR, NUMBL, PCDH9, SLIT1, SLITRK1 and SHANK3. Although between-tissue variation in DNA methylation was found to greatly exceed between-individual differences within any one tissue, we found that some inter-individual variation was reflected across brain and blood, indicating that peripheral tissues may have some utility in epidemiological studies of complex neurobiological phenotypes. Conclusions This study reinforces the importance of DNA methylation in regulating cellular phenotype across tissues, and highlights genomic patterns of epigenetic variation across functionally distinct regions of the brain, providing a resource for the epigenetics and neuroscience research communities.
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            Tobacco-smoking-related differential DNA methylation: 27K discovery and replication.

            Tobacco smoking is responsible for substantial morbidity and mortality worldwide, in particular through cardiovascular, pulmonary, and malignant pathology. CpG methylation might plausibly play a role in a variety of smoking-related phenomena, as suggested by candidate gene promoter or global methylation studies. Arrays allowing hypothesis-free searches on a scale resembling genome-wide studies of SNPs have become available only very recently. Methylation extents in peripheral-blood DNA were assessed at 27,578 sites in more than 14,000 gene promoter regions in 177 current smokers, former smokers, and those who had never smoked, with the use of the Illumina HumanMethylation 27K BeadChip. This revealed a single locus, cg03636183, located in F2RL3, with genome-wide significance for lower methylation in smokers (p = 2.68 × 10(-31)). This was similarly significant in 316 independent replication samples analyzed by mass spectrometry and Sequenom EpiTyper (p = 6.33 × 10(-34)). Our results, which were based on a rigorous replication approach, show that the gene coding for a potential drug target of cardiovascular importance features altered methylation patterns in smokers. To date, this gene had not attracted attention in the literature on smoking. Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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              Genome-wide DNA methylation profiling using Infinium® assay.

              Bisulfite sequence analysis of individual CpG sites within genomic DNA is a powerful approach for methylation analysis in the genome. The major limitation of bisulfite-based methods is parallelization. Both array and next-generation sequencing technology are capable of addressing this bottleneck. In this report, we describe the application of Infinium® genotyping technology to analyze bisulfite-converted DNA to simultaneously query the methylation state of over 27,000 CpG sites from promoters of consensus coding sequences (CCDS) genes. We adapted the Infinium genotyping assay to readout an array of over 27,000 pairs of CpG methylation-specific query probes complementary to bisulfite-converted DNA. Two probes were designed to each CpG site: a 'methylated' and an 'unmethylated' query probe. The probe design assumed that all underlying CpG sites were 'in phase' with the queried CpG site due to their close proximity. Bisulfite conversion was performed with a modified version of the Zymo EZ DNA Methylation™ kit. We applied this technology to measuring methylation levels across a panel of 14 different human tissues, four Coriell cell lines and six cancer cell lines. We observed that CpG sites within CpG islands (CGIs) were largely unmethylated across all tissues (~80% sites unmethylated, β < 0.2), whereas CpG sites in non-CGIs were moderately to highly methylated (only ~12% sites unmethylated, β < 0.2). Within CGIs, only approximately 3-6% of the loci were highly methylated; in contrast, outside of CGIs approximately 25-40% of loci were highly methylated. Moreover, tissue-specific methylation (variation in methylation across tissues) was much more prevalent in non-CGIs than within CGIs. Our results demonstrate a genome-wide scalable array-based methylation readout platform that is both highly reproducible and quantitative. In the near future, this platform should enable the analysis of hundreds of thousands to millions of CpG sites per sample.
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                Author and article information

                Contributors
                Journal
                Front Genet
                Front Genet
                Front. Genet.
                Frontiers in Genetics
                Frontiers Media S.A.
                1664-8021
                26 August 2014
                2014
                : 5
                Affiliations
                1Human Brain Collection Core, National Institute of Mental Health, National Institutes of Health Bethesda, MD, USA
                2Department of Psychiatry, Course of Integrated Brain Sciences, Medical Informatics, Institute of Health Biosciences, The University of Tokushima Tokushima, Japan
                3The Lieber Institute for Brain Development, Johns Hopkins University Medical Center Baltimore, MD, USA
                Author notes

                Edited by: Marta Barrachina, Bellvitge Biomedical Research Institute, Spain

                Reviewed by: Alexandra M. Lopes, University of Porto, Portugal; Ilan A. Kerman, University of Alabama at Birmingham, USA

                *Correspondence: Barbara K. Lipska, Human Brain Collection Core, National Institute of Mental Health, 10 Center Drive, R. 4N306, Bethesda, MD 20892-1385, USA e-mail: lipskab@ 123456mail.nih.gov

                This article was submitted to Neurogenomics, a section of the journal Frontiers in Genetics.

                Article
                10.3389/fgene.2014.00280
                4144343
                Copyright © 2014 Numata, Ye, Herman and Lipska.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 3, Tables: 0, Equations: 0, References: 64, Pages: 7, Words: 6169
                Categories
                Genetics
                Original Research Article

                Genetics

                expression, dna methylation, snp, postmortem, array, schizophrenia

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