Crucial timing in schizophrenia: role of DNA methylation in early neurodevelopment

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Abstract

An exciting recent study examining the methylation profile of human brain tissue implicates early-life epigenetic disruption in the neurodevelopmental origin of schizophrenia.

See related research, http://genomebiology.com/2014/15/10/483

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Methylome-wide association study of schizophrenia: identifying blood biomarker signatures of environmental insults.

Karolina Aberg, Joseph McClay, Srilaxmi Nerella … (2014)

Epigenetic studies present unique opportunities to advance schizophrenia research because they can potentially account for many of its clinical features and suggest novel strategies to improve disease management. To identify schizophrenia DNA methylation biomarkers in blood. The sample consisted of 759 schizophrenia cases and 738 controls (N = 1497) collected in Sweden. We used methyl-CpG-binding domain protein-enriched genome sequencing of the methylated genomic fraction, followed by next-generation DNA sequencing. We obtained a mean (SD) number of 68 (26.8) million reads per sample. This massive data set was processed using a specifically designed data analysis pipeline. Critical top findings from our methylome-wide association study (MWAS) were replicated in independent case-control participants using targeted pyrosequencing of bisulfite-converted DNA. Status of schizophrenia cases and controls. Our MWAS suggested a considerable number of effects, with 25 sites passing the highly conservative Bonferroni correction and 139 sites significant at a false discovery rate of 0.01. Our top MWAS finding, which was located in FAM63B, replicated with P = 2.3 × 10-10. It was part of the networks regulated by microRNA that can be linked to neuronal differentiation and dopaminergic gene expression. Many other top MWAS results could be linked to hypoxia and, to a lesser extent, infection, suggesting that a record of pathogenic events may be preserved in the methylome. Our findings also implicated a site in RELN, one of the most frequently studied candidates in methylation studies of schizophrenia. To our knowledge, the present study is one of the first MWASs of disease with a large sample size using a technology that provides good coverage of methylation sites across the genome. Our results demonstrated one of the unique features of methylation studies that can capture signatures of environmental insults in peripheral tissues. Our MWAS suggested testable hypotheses about disease mechanisms and yielded biomarkers that can potentially be used to improve disease management.

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Comprehensive DNA methylation analysis of peripheral blood cells derived from patients with first-episode schizophrenia.

C Kakiuchi, Shinsuke Koike, Tsuyoshi Araki … (2013)

Epidemiological studies have revealed that schizophrenia is highly heritable. However, genetic studies have not fully elucidated its etiology. Accumulating evidence suggests that epigenetic alterations may provide an additional explanation of its pathophysiology. We investigated the methylation profiles of DNA in peripheral blood cells from 18 patients with first-episode schizophrenia (FESZ) and from 15 normal controls. Schizophrenia patients were confined to those at the stage of first-episode psychosis. We analyzed the DNA methylation status of 27,578 CpG sites by means of the Illumina Infinium HumanMethylation27 BeadChip array. Differentially methylated CpG sites, which were particularly abundant within CpG islands, were enriched in genes related to the nuclear lumen, to transcription factor binding, and to nucleotide binding. We also observed differential methylation of the promoters of HTR1E and COMTD1, which are functionally related to genes found to be differentially methylated in schizophrenia patients in previous studies. Our results indicate the site-specific epigenetic alterations in patients with FESZ.

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

Shusuke Numata, Tianzhang Ye, Mary Herman … (2014)

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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Contributors

Joanne Ryan: joanne.ryan@mcri.edu.au

Richard Saffery: richard.saffery@mcri.edu.au

Journal

Journal ID (nlm-ta): Genome Biol

Title: Genome Biology

Publisher: BioMed Central (London )

ISSN (Print): 1465-6906

ISSN (Electronic): 1465-6914

Publication date (Electronic): 29 October 2014

Publication date (Print): 2014

Volume: 15

Issue: 10

Electronic Location Identifier: 495

Affiliations

[ ]Cancer and Disease Epigenetics, Murdoch Children’s Research Institute, Royal Children’s Hospital, University of Melbourne, Parkville, VIC 3052 Australia

[ ]Department of Paediatrics, University of Melbourne, Parkville, VIC 3052 Australia

[ ]Inserm U1061, Hopital La Colombiere and Universite Montpellier 1, Montpellier F-34093, France

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Publisher ID: 495

DOI: 10.1186/s13059-014-0495-y

PMC ID: 4281947

PubMed ID: 25418840

SO-VID: 3c1116db-c2cd-4b5a-9564-dde2de821580

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The licensee has exclusive rights to distribute this article, in any medium, for 12 months following its publication. After this time, the article is available under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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Crucial timing in schizophrenia: role of DNA methylation in early neurodevelopment

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Most cited references 6

Methylome-wide association study of schizophrenia: identifying blood biomarker signatures of environmental insults.

Comprehensive DNA methylation analysis of peripheral blood cells derived from patients with first-episode schizophrenia.

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

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